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Showing 1 - 200 of 3089 Journals sorted alphabetically
A Practical Logic of Cognitive Systems     Full-text available via subscription   (Followers: 7)
AASRI Procedia     Open Access   (Followers: 15)
Academic Pediatrics     Hybrid Journal   (Followers: 25, SJR: 1.402, h-index: 51)
Academic Radiology     Hybrid Journal   (Followers: 22, SJR: 1.008, h-index: 75)
Accident Analysis & Prevention     Partially Free   (Followers: 86, SJR: 1.109, h-index: 94)
Accounting Forum     Hybrid Journal   (Followers: 25, SJR: 0.612, h-index: 27)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 30, SJR: 2.515, h-index: 90)
Achievements in the Life Sciences     Open Access   (Followers: 4)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 5, SJR: 0.338, h-index: 19)
Acta Astronautica     Hybrid Journal   (Followers: 363, SJR: 0.726, h-index: 43)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 3)
Acta Biomaterialia     Hybrid Journal   (Followers: 25, SJR: 2.02, h-index: 104)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription   (Followers: 1)
Acta de Investigación Psicológica     Open Access   (Followers: 2)
Acta Ecologica Sinica     Open Access   (Followers: 8, SJR: 0.172, h-index: 29)
Acta Haematologica Polonica     Free   (SJR: 0.123, h-index: 8)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.604, h-index: 38)
Acta Materialia     Hybrid Journal   (Followers: 229, SJR: 3.683, h-index: 202)
Acta Mathematica Scientia     Full-text available via subscription   (Followers: 5, SJR: 0.615, h-index: 21)
Acta Mechanica Solida Sinica     Full-text available via subscription   (Followers: 9, SJR: 0.442, h-index: 21)
Acta Oecologica     Hybrid Journal   (Followers: 10, SJR: 0.915, h-index: 53)
Acta Otorrinolaringologica (English Edition)     Full-text available via subscription   (Followers: 1)
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 3, SJR: 0.311, h-index: 16)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 1)
Acta Poética     Open Access   (Followers: 4)
Acta Psychologica     Hybrid Journal   (Followers: 24, SJR: 1.365, h-index: 73)
Acta Sociológica     Open Access  
Acta Tropica     Hybrid Journal   (Followers: 6, SJR: 1.059, h-index: 77)
Acta Urológica Portuguesa     Open Access  
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 4)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 3)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 4, SJR: 0.383, h-index: 19)
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Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 5, SJR: 0.141, h-index: 3)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 4, SJR: 0.112, h-index: 2)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 4)
Acute Pain     Full-text available via subscription   (Followers: 13)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.967, h-index: 57)
Addictive Behaviors     Hybrid Journal   (Followers: 15, SJR: 1.514, h-index: 92)
Addictive Behaviors Reports     Open Access   (Followers: 6)
Additive Manufacturing     Hybrid Journal   (Followers: 7, SJR: 1.039, h-index: 5)
Additives for Polymers     Full-text available via subscription   (Followers: 21)
Advanced Cement Based Materials     Full-text available via subscription   (Followers: 3)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 132, SJR: 5.2, h-index: 222)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 11, SJR: 1.265, h-index: 53)
Advanced Powder Technology     Hybrid Journal   (Followers: 17, SJR: 0.739, h-index: 33)
Advances in Accounting     Hybrid Journal   (Followers: 9, SJR: 0.299, h-index: 15)
Advances in Agronomy     Full-text available via subscription   (Followers: 15, SJR: 2.071, h-index: 82)
Advances in Anesthesia     Full-text available via subscription   (Followers: 26, SJR: 0.169, h-index: 4)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 3)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 6, SJR: 1.054, h-index: 35)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 11, SJR: 0.801, h-index: 26)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 22, SJR: 1.286, h-index: 49)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 16, SJR: 3.31, h-index: 42)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.277, h-index: 43)
Advances in Botanical Research     Full-text available via subscription   (Followers: 3, SJR: 0.619, h-index: 48)
Advances in Cancer Research     Full-text available via subscription   (Followers: 25, SJR: 2.215, h-index: 78)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 9, SJR: 0.9, h-index: 30)
Advances in Catalysis     Full-text available via subscription   (Followers: 5, SJR: 2.139, h-index: 42)
Advances in Cell Aging and Gerontology     Full-text available via subscription   (Followers: 4)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 12)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 27, SJR: 0.183, h-index: 23)
Advances in Child Development and Behavior     Full-text available via subscription   (Followers: 10, SJR: 0.665, h-index: 29)
Advances in Chronic Kidney Disease     Full-text available via subscription   (Followers: 9, SJR: 1.268, h-index: 45)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 29, SJR: 0.938, h-index: 33)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 18, SJR: 2.314, h-index: 130)
Advances in Computers     Full-text available via subscription   (Followers: 16, SJR: 0.223, h-index: 22)
Advances in Dermatology     Full-text available via subscription   (Followers: 12)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 11)
Advances in Digestive Medicine     Open Access   (Followers: 7)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 5)
Advances in Drug Research     Full-text available via subscription   (Followers: 22)
Advances in Ecological Research     Full-text available via subscription   (Followers: 45, SJR: 3.25, h-index: 43)
Advances in Engineering Software     Hybrid Journal   (Followers: 26, SJR: 0.486, h-index: 10)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 7)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 43, SJR: 5.465, h-index: 64)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 3)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 8)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 51, SJR: 0.674, h-index: 38)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 16)
Advances in Genetics     Full-text available via subscription   (Followers: 15, SJR: 2.558, h-index: 54)
Advances in Genome Biology     Full-text available via subscription   (Followers: 11)
Advances in Geophysics     Full-text available via subscription   (Followers: 6, SJR: 2.325, h-index: 20)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 22, SJR: 0.906, h-index: 24)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 9, SJR: 0.497, h-index: 31)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 26)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 2, SJR: 0.396, h-index: 27)
Advances in Immunology     Full-text available via subscription   (Followers: 36, SJR: 4.152, h-index: 85)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 9, SJR: 1.132, h-index: 42)
Advances in Insect Physiology     Full-text available via subscription   (Followers: 3, SJR: 1.274, h-index: 27)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 6)
Advances in Intl. Accounting     Full-text available via subscription   (Followers: 4)
Advances in Life Course Research     Hybrid Journal   (Followers: 8, SJR: 0.764, h-index: 15)
Advances in Lipobiology     Full-text available via subscription   (Followers: 2)
Advances in Magnetic and Optical Resonance     Full-text available via subscription   (Followers: 9)
Advances in Marine Biology     Full-text available via subscription   (Followers: 16, SJR: 1.645, h-index: 45)
Advances in Mathematics     Full-text available via subscription   (Followers: 10, SJR: 3.261, h-index: 65)
Advances in Medical Sciences     Hybrid Journal   (Followers: 6, SJR: 0.489, h-index: 25)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 4, SJR: 1.44, h-index: 51)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 22)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 10)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 8, SJR: 0.324, h-index: 8)
Advances in Nanoporous Materials     Full-text available via subscription   (Followers: 4)
Advances in Oncobiology     Full-text available via subscription   (Followers: 3)
Advances in Organ Biology     Full-text available via subscription   (Followers: 2)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15, SJR: 2.885, h-index: 45)
Advances in Parallel Computing     Full-text available via subscription   (Followers: 7, SJR: 0.148, h-index: 11)
Advances in Parasitology     Full-text available via subscription   (Followers: 7, SJR: 2.37, h-index: 73)
Advances in Pediatrics     Full-text available via subscription   (Followers: 24, SJR: 0.4, h-index: 28)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 13)
Advances in Pharmacology     Full-text available via subscription   (Followers: 15, SJR: 1.718, h-index: 58)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 0.384, h-index: 26)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.248, h-index: 11)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 8)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 5)
Advances in Porous Media     Full-text available via subscription   (Followers: 4)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 17)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20, SJR: 1.5, h-index: 62)
Advances in Psychology     Full-text available via subscription   (Followers: 62)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5, SJR: 0.478, h-index: 32)
Advances in Radiation Oncology     Open Access  
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 2, SJR: 0.1, h-index: 2)
Advances in Space Biology and Medicine     Full-text available via subscription   (Followers: 5)
Advances in Space Research     Full-text available via subscription   (Followers: 360, SJR: 0.606, h-index: 65)
Advances in Structural Biology     Full-text available via subscription   (Followers: 8)
Advances in Surgery     Full-text available via subscription   (Followers: 7, SJR: 0.823, h-index: 27)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 30, SJR: 1.321, h-index: 56)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 16)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 13)
Advances in Virus Research     Full-text available via subscription   (Followers: 5, SJR: 1.878, h-index: 68)
Advances in Water Resources     Hybrid Journal   (Followers: 44, SJR: 2.408, h-index: 94)
Aeolian Research     Hybrid Journal   (Followers: 5, SJR: 0.973, h-index: 22)
Aerospace Science and Technology     Hybrid Journal   (Followers: 331, SJR: 0.816, h-index: 49)
AEU - Intl. J. of Electronics and Communications     Hybrid Journal   (Followers: 8, SJR: 0.318, h-index: 36)
African J. of Emergency Medicine     Open Access   (Followers: 5, SJR: 0.344, h-index: 6)
Ageing Research Reviews     Hybrid Journal   (Followers: 8, SJR: 3.289, h-index: 78)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 417, SJR: 1.385, h-index: 72)
Agri Gene     Hybrid Journal  
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 16, SJR: 2.18, h-index: 116)
Agricultural Systems     Hybrid Journal   (Followers: 30, SJR: 1.275, h-index: 74)
Agricultural Water Management     Hybrid Journal   (Followers: 40, SJR: 1.546, h-index: 79)
Agriculture and Agricultural Science Procedia     Open Access  
Agriculture and Natural Resources     Open Access   (Followers: 2)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 55, SJR: 1.879, h-index: 120)
Ain Shams Engineering J.     Open Access   (Followers: 5, SJR: 0.434, h-index: 14)
Air Medical J.     Hybrid Journal   (Followers: 5, SJR: 0.234, h-index: 18)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.285, h-index: 3)
Alcohol     Hybrid Journal   (Followers: 11, SJR: 0.922, h-index: 66)
Alcoholism and Drug Addiction     Open Access   (Followers: 8)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 1)
Alexandria Engineering J.     Open Access   (Followers: 1, SJR: 0.436, h-index: 12)
Alexandria J. of Medicine     Open Access   (Followers: 1)
Algal Research     Partially Free   (Followers: 8, SJR: 2.05, h-index: 20)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 3)
Allergologia et Immunopathologia     Full-text available via subscription   (Followers: 1, SJR: 0.46, h-index: 29)
Allergology Intl.     Open Access   (Followers: 4, SJR: 0.776, h-index: 35)
Alpha Omegan     Full-text available via subscription   (SJR: 0.121, h-index: 9)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 9, SJR: 0.158, h-index: 9)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 46, SJR: 4.289, h-index: 64)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 4)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 4)
Ambulatory Pediatrics     Hybrid Journal   (Followers: 5)
American Heart J.     Hybrid Journal   (Followers: 49, SJR: 3.157, h-index: 153)
American J. of Cardiology     Hybrid Journal   (Followers: 48, SJR: 2.063, h-index: 186)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 40, SJR: 0.574, h-index: 65)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 9, SJR: 1.091, h-index: 45)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 14, SJR: 1.653, h-index: 93)
American J. of Human Genetics     Hybrid Journal   (Followers: 32, SJR: 8.769, h-index: 256)
American J. of Infection Control     Hybrid Journal   (Followers: 26, SJR: 1.259, h-index: 81)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 32, SJR: 2.313, h-index: 172)
American J. of Medicine     Hybrid Journal   (Followers: 46, SJR: 2.023, h-index: 189)
American J. of Medicine Supplements     Full-text available via subscription   (Followers: 3)
American J. of Obstetrics and Gynecology     Hybrid Journal   (Followers: 199, SJR: 2.255, h-index: 171)
American J. of Ophthalmology     Hybrid Journal   (Followers: 59, SJR: 2.803, h-index: 148)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 6)
American J. of Orthodontics and Dentofacial Orthopedics     Full-text available via subscription   (Followers: 6, SJR: 1.249, h-index: 88)
American J. of Otolaryngology     Hybrid Journal   (Followers: 25, SJR: 0.59, h-index: 45)
American J. of Pathology     Hybrid Journal   (Followers: 27, SJR: 2.653, h-index: 228)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 25, SJR: 2.764, h-index: 154)
American J. of Surgery     Hybrid Journal   (Followers: 35, SJR: 1.286, h-index: 125)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 12, SJR: 0.653, h-index: 70)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 6)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.066, h-index: 51)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 58, SJR: 0.124, h-index: 9)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 12)
Anales de Cirugia Vascular     Full-text available via subscription  
Anales de Pediatría     Full-text available via subscription   (Followers: 2, SJR: 0.209, h-index: 27)
Anales de Pediatría (English Edition)     Full-text available via subscription  
Anales de Pediatría Continuada     Full-text available via subscription   (SJR: 0.104, h-index: 3)
Analytic Methods in Accident Research     Hybrid Journal   (Followers: 4, SJR: 2.577, h-index: 7)
Analytica Chimica Acta     Hybrid Journal   (Followers: 37, SJR: 1.548, h-index: 152)
Analytical Biochemistry     Hybrid Journal   (Followers: 167, SJR: 0.725, h-index: 154)
Analytical Chemistry Research     Open Access   (Followers: 8, SJR: 0.18, h-index: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 12)
Anesthésie & Réanimation     Full-text available via subscription   (Followers: 1)
Anesthesiology Clinics     Full-text available via subscription   (Followers: 22, SJR: 0.421, h-index: 40)
Angiología     Full-text available via subscription   (SJR: 0.124, h-index: 9)
Angiologia e Cirurgia Vascular     Open Access  

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Journal Cover American Journal of Human Genetics
  [SJR: 8.769]   [H-I: 256]   [32 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0002-9297 - ISSN (Online) 1537-6605
   Published by Elsevier Homepage  [3049 journals]
  • So Long, and Thanks for All the Genes!
    • Authors: David L. Nelson
      Pages: 871 - 873
      Abstract: Publication date: 7 December 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 6
      Author(s): David L. Nelson

      PubDate: 2017-12-12T05:02:50Z
      DOI: 10.1016/j.ajhg.2017.11.012
  • A Selection Operator for Summary Association Statistics Reveals Allelic
           Heterogeneity of Complex Traits
    • Authors: Zheng Ning; Youngjo Lee; Peter K. Joshi; James F. Wilson; Yudi Pawitan; Xia Shen
      Pages: 903 - 912
      Abstract: Publication date: 7 December 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 6
      Author(s): Zheng Ning, Youngjo Lee, Peter K. Joshi, James F. Wilson, Yudi Pawitan, Xia Shen
      In recent years, as a secondary analysis in genome-wide association studies (GWASs), conditional and joint multiple-SNP analysis (GCTA-COJO) has been successful in allowing the discovery of additional association signals within detected loci. This suggests that many loci mapped in GWASs harbor more than a single causal variant. In order to interpret the underlying mechanism regulating a complex trait of interest in each discovered locus, researchers must assess the magnitude of allelic heterogeneity within the locus. We developed a penalized selection operator for jointly analyzing multiple variants (SOJO) within each mapped locus on the basis of LASSO (least absolute shrinkage and selection operator) regression derived from summary association statistics. We found that, compared to stepwise conditional multiple-SNP analysis, SOJO provided better sensitivity and specificity in predicting the number of alleles associated with complex traits in each locus. SOJO suggested causal variants potentially missed by GCTA-COJO. Compared to using top variants from genome-wide significant loci in GWAS, using SOJO increased the proportion of variance prediction for height by 65% without additional discovery samples or additional loci in the genome. Our empirical results indicate that human height is not only a highly polygenic trait, but also has high allelic heterogeneity within its established hundreds of loci.

      PubDate: 2017-12-12T05:02:50Z
      DOI: 10.1016/j.ajhg.2017.09.027
  • Penetrance of Polygenic Obesity Susceptibility Loci across the Body Mass
           Index Distribution
    • Authors: Arkan Abadi; Akram Alyass; Sebastien Robiou du Pont; Ben Bolker; Pardeep Singh; Viswanathan Mohan; Rafael Diaz; James C. Engert; Salim Yusuf; Hertzel C. Gerstein; Sonia S. Anand; David Meyre
      Pages: 925 - 938
      Abstract: Publication date: 7 December 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 6
      Author(s): Arkan Abadi, Akram Alyass, Sebastien Robiou du Pont, Ben Bolker, Pardeep Singh, Viswanathan Mohan, Rafael Diaz, James C. Engert, Salim Yusuf, Hertzel C. Gerstein, Sonia S. Anand, David Meyre
      A growing number of single-nucleotide polymorphisms (SNPs) have been associated with body mass index (BMI) and obesity, but whether the effects of these obesity-susceptibility loci are uniform across the BMI distribution remains unclear. We studied the effects of 37 BMI-associated SNPs in 75,230 adults of European ancestry across BMI percentiles by using conditional quantile regression (CQR) and meta-regression (MR) models. The effects of nine SNPs (24%)—rs1421085 (FTO; p = 8.69 × 10−15), rs6235 (PCSK1; p = 7.11 × 10−6), rs7903146 (TCF7L2; p = 9.60 × 10−6), rs11873305 (MC4R; p = 5.08 × 10−5), rs12617233 (FANCL; p = 5.30 × 10−5), rs11672660 (GIPR; p = 1.64 × 10−4), rs997295 (MAP2K5; p = 3.25 × 10−4), rs6499653 (FTO; p = 6.23 × 10−4), and rs3824755 (NT5C2; p = 7.90 × 10−4)—increased significantly across the sample BMI distribution. We showed that such increases stemmed from unadjusted gene interactions that enhanced the effects of SNPs in persons with a high BMI. When 125 height-associated SNPs were analyzed for comparison, only one (<1%), rs6219 (IGF1, p = 1.80 × 10−4), showed effects that varied significantly across height percentiles. Cumulative gene scores of these SNPs (GS-BMI and GS-height) showed that only GS-BMI had effects that increased significantly across the sample distribution (BMI: p = 7.03 × 10−37; height: p = 0.499). Overall, these findings underscore the importance of gene-gene and gene-environment interactions in shaping the genetic architecture of BMI and advance a method for detecting such interactions by using only the sample outcome distribution.

      PubDate: 2017-12-12T05:02:50Z
      DOI: 10.1016/j.ajhg.2017.10.007
  • Allelic Expression Imbalance Promoting a Mutant PEX6 Allele Causes
           Zellweger Spectrum Disorder
    • Authors: Kim D. Falkenberg; Nancy E. Braverman; Ann B. Moser; Steven J. Steinberg; Femke C.C. Klouwer; Agatha Schlüter; Montserrat Ruiz; Aurora Pujol; Martin Engvall; Karin Naess; FrancJan van Spronsen; Irene Körver-Keularts; M. Estela Rubio-Gozalbo; Sacha Ferdinandusse; Ronald J.A. Wanders; Hans R. Waterham
      Pages: 965 - 976
      Abstract: Publication date: 7 December 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 6
      Author(s): Kim D. Falkenberg, Nancy E. Braverman, Ann B. Moser, Steven J. Steinberg, Femke C.C. Klouwer, Agatha Schlüter, Montserrat Ruiz, Aurora Pujol, Martin Engvall, Karin Naess, FrancJan van Spronsen, Irene Körver-Keularts, M. Estela Rubio-Gozalbo, Sacha Ferdinandusse, Ronald J.A. Wanders, Hans R. Waterham
      Zellweger spectrum disorders (ZSDs) are autosomal-recessive disorders that are caused by defects in peroxisome biogenesis due to bi-allelic mutations in any of 13 different PEX genes. Here, we identified seven unrelated individuals affected with an apparent dominant ZSD in whom a heterozygous mutant PEX6 allele (c.2578C>T [p.Arg860Trp]) was overrepresented due to allelic expression imbalance (AEI). We demonstrated that AEI of PEX6 is a common phenomenon and is correlated with heterozygosity for a frequent variant in the 3′ untranslated region (UTR) of the mutant allele, which disrupts the most distal of two polyadenylation sites. Asymptomatic parents, who were heterozygous for PEX c.2578C>T, did not show AEI and were homozygous for the 3′ UTR variant. Overexpression models confirmed that the overrepresentation of the pathogenic PEX6 c.2578T variant compared to wild-type PEX6 c.2578C results in a peroxisome biogenesis defect and thus constitutes the cause of disease in the affected individuals. AEI promoting the overrepresentation of a mutant allele might also play a role in other autosomal-recessive disorders, in which only one heterozygous pathogenic variant is identified.

      PubDate: 2017-12-12T05:02:50Z
      DOI: 10.1016/j.ajhg.2017.11.007
  • De Novo Variants in GRIA4 Lead to Intellectual Disability with or without
           Seizures and Gait Abnormalities
    • Authors: Sonja Martin; Adam Chamberlin; Deepali N. Shinde; Maja Hempel; Tim M. Strom; Allison Schreiber; Jessika Johannsen; Lilian Bomme Ousager; Martin J. Larsen; Lars Kjaersgaard Hansen; Ali Fatemi; Julie S. Cohen; Johannes Lemke; Kristina P. Sørensen; Katherine L. Helbig; Davor Lessel; Rami Abou Jamra
      Pages: 1013 - 1020
      Abstract: Publication date: 7 December 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 6
      Author(s): Sonja Martin, Adam Chamberlin, Deepali N. Shinde, Maja Hempel, Tim M. Strom, Allison Schreiber, Jessika Johannsen, Lilian Bomme Ousager, Martin J. Larsen, Lars Kjaersgaard Hansen, Ali Fatemi, Julie S. Cohen, Johannes Lemke, Kristina P. Sørensen, Katherine L. Helbig, Davor Lessel, Rami Abou Jamra
      Using trio whole-exome sequencing, we have identified de novo heterozygous pathogenic variants in GRIA4 in five unrelated individuals with intellectual disability and other symptoms. GRIA4 encodes an AMPA receptor subunit known as GluR4, which is found on excitatory glutamatergic synapses and is important for learning and memory. Four of the variants are located in the highly conserved SYTANLAAF motif in the transmembrane protein M3, and the fifth is in an extra-cellular domain. Molecular modeling of the altered protein showed that three of the variants in the SYTANLAAF motif orient toward the center of the pore region and most likely lead to disturbance of the gating mechanism. The fourth variant in the SYTANLAAF motif most likely results in reduced permeability. The variant in the extracellular domain potentially interferes with the binding between the monomers. On the basis of clinical information and genetic results, and the fact that other subunits of the AMPA receptor have already been associated with neurodevelopmental disorders, we suggest that pathogenic de novo variants in GRIA4 lead to intellectual disability with or without seizures, gait abnormalities, problems of social behavior, and other variable features.

      PubDate: 2017-12-12T05:02:50Z
      DOI: 10.1016/j.ajhg.2017.11.004
  • ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental
    • Authors: Sara Cuvertino; Helen M. Stuart; Kate E. Chandler; Neil A. Roberts; Ruth Armstrong; Laura Bernardini; Sanjeev Bhaskar; Bert Callewaert; Jill Clayton-Smith; Cristina Hernando Davalillo; Charu Deshpande; Koenraad Devriendt; Maria C. Digilio; Abhijit Dixit; Matthew Edwards; Jan M. Friedman; Antonio Gonzalez-Meneses; Shelagh Joss; Bronwyn Kerr; Anne Katrin Lampe; Sylvie Langlois; Rachel Lennon; Philippe Loget; David Y.T. Ma; Ruth McGowan; Maryse Des Medt; James O’Sullivan; Sylvie Odent; Michael J. Parker; Céline Pebrel-Richard; Florence Petit; Zornitza Stark; Sylvia Stockler-Ipsiroglu; Sigrid Tinschert; Pradeep Vasudevan; Olaya Villa; Susan M. White; Farah R. Zahir; Adrian S. Woolf; Siddharth Banka
      Pages: 1021 - 1033
      Abstract: Publication date: 7 December 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 6
      Author(s): Sara Cuvertino, Helen M. Stuart, Kate E. Chandler, Neil A. Roberts, Ruth Armstrong, Laura Bernardini, Sanjeev Bhaskar, Bert Callewaert, Jill Clayton-Smith, Cristina Hernando Davalillo, Charu Deshpande, Koenraad Devriendt, Maria C. Digilio, Abhijit Dixit, Matthew Edwards, Jan M. Friedman, Antonio Gonzalez-Meneses, Shelagh Joss, Bronwyn Kerr, Anne Katrin Lampe, Sylvie Langlois, Rachel Lennon, Philippe Loget, David Y.T. Ma, Ruth McGowan, Maryse Des Medt, James O’Sullivan, Sylvie Odent, Michael J. Parker, Céline Pebrel-Richard, Florence Petit, Zornitza Stark, Sylvia Stockler-Ipsiroglu, Sigrid Tinschert, Pradeep Vasudevan, Olaya Villa, Susan M. White, Farah R. Zahir, Adrian S. Woolf, Siddharth Banka
      ACTB encodes β-actin, an abundant cytoskeletal housekeeping protein. In humans, postulated gain-of-function missense mutations cause Baraitser-Winter syndrome (BRWS), characterized by intellectual disability, cortical malformations, coloboma, sensorineural deafness, and typical facial features. To date, the consequences of loss-of-function ACTB mutations have not been proven conclusively. We describe heterozygous ACTB deletions and nonsense and frameshift mutations in 33 individuals with developmental delay, apparent intellectual disability, increased frequency of internal organ malformations (including those of the heart and the renal tract), growth retardation, and a recognizable facial gestalt (interrupted wavy eyebrows, dense eyelashes, wide nose, wide mouth, and a prominent chin) that is distinct from characteristics of individuals with BRWS. Strikingly, this spectrum overlaps with that of several chromatin-remodeling developmental disorders. In wild-type mouse embryos, β-actin expression was prominent in the kidney, heart, and brain. ACTB mRNA expression levels in lymphoblastic lines and fibroblasts derived from affected individuals were decreased in comparison to those in control cells. Fibroblasts derived from an affected individual and ACTB siRNA knockdown in wild-type fibroblasts showed altered cell shape and migration, consistent with known roles of cytoplasmic β-actin. We also demonstrate that ACTB haploinsufficiency leads to reduced cell proliferation, altered expression of cell-cycle genes, and decreased amounts of nuclear, but not cytoplasmic, β-actin. In conclusion, we show that heterozygous loss-of-function ACTB mutations cause a distinct pleiotropic malformation syndrome with intellectual disability. Our biological studies suggest that a critically reduced amount of this protein alters cell shape, migration, proliferation, and gene expression to the detriment of brain, heart, and kidney development.

      PubDate: 2017-12-12T05:02:50Z
      DOI: 10.1016/j.ajhg.2017.11.006
  • Exome-wide Association Study Identifies GREB1L Mutations in Congenital
           Kidney Malformations
    • Authors: Simone Sanna-Cherchi; Kamal Khan; Rik Westland; Priya Krithivasan; Lorraine Fievet; Hila Milo Rasouly; Iuliana Ionita-Laza; Valentina P. Capone; David A. Fasel; Krzysztof Kiryluk; Sitharthan Kamalakaran; Monica Bodria; Edgar A. Otto; Matthew G. Sampson; Christopher E. Gillies; Virginia Vega-Warner; Katarina Vukojevic; Igor Pediaditakis; Gabriel S. Makar; Adele Mitrotti; Miguel Verbitsky; Jeremiah Martino; Qingxue Liu; Young-Ji Na; Vinicio Goj; Gianluigi Ardissino; Maddalena Gigante; Loreto Gesualdo; Magdalena Janezcko; Marcin Zaniew; Cathy Lee Mendelsohn; Shirlee Shril; Friedhelm Hildebrandt; Joanna A.E. van Wijk; Adela Arapovic; Marijan Saraga; Landino Allegri; Claudia Izzi; Francesco Scolari; Velibor Tasic; Gian Marco Ghiggeri; Anna Latos-Bielenska; Anna Materna-Kiryluk; Shrikant Mane; David B. Goldstein; Richard P. Lifton; Nicholas Katsanis; Erica E. Davis; Ali G. Gharavi
      First page: 1034
      Abstract: Publication date: 7 December 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 6
      Author(s): Simone Sanna-Cherchi, Kamal Khan, Rik Westland, Priya Krithivasan, Lorraine Fievet, Hila Milo Rasouly, Iuliana Ionita-Laza, Valentina P. Capone, David A. Fasel, Krzysztof Kiryluk, Sitharthan Kamalakaran, Monica Bodria, Edgar A. Otto, Matthew G. Sampson, Christopher E. Gillies, Virginia Vega-Warner, Katarina Vukojevic, Igor Pediaditakis, Gabriel S. Makar, Adele Mitrotti, Miguel Verbitsky, Jeremiah Martino, Qingxue Liu, Young-Ji Na, Vinicio Goj, Gianluigi Ardissino, Maddalena Gigante, Loreto Gesualdo, Magdalena Janezcko, Marcin Zaniew, Cathy Lee Mendelsohn, Shirlee Shril, Friedhelm Hildebrandt, Joanna A.E. van Wijk, Adela Arapovic, Marijan Saraga, Landino Allegri, Claudia Izzi, Francesco Scolari, Velibor Tasic, Gian Marco Ghiggeri, Anna Latos-Bielenska, Anna Materna-Kiryluk, Shrikant Mane, David B. Goldstein, Richard P. Lifton, Nicholas Katsanis, Erica E. Davis, Ali G. Gharavi

      PubDate: 2017-12-12T05:02:50Z
      DOI: 10.1016/j.ajhg.2017.11.003
  • Profiling of Short-Tandem-Repeat Disease Alleles in 12,632 Human Whole
    • Authors: Haibao Tang; Ewen F. Kirkness; Christoph Lippert; William H. Biggs; Martin Fabani; Ernesto Guzman; Smriti Ramakrishnan; Victor Lavrenko; Boyko Kakaradov; Claire Hou; Barry Hicks; David Heckerman; Franz J. Och; C. Thomas Caskey; J. Craig Venter; Amalio Telenti
      Pages: 700 - 715
      Abstract: Publication date: 2 November 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 5
      Author(s): Haibao Tang, Ewen F. Kirkness, Christoph Lippert, William H. Biggs, Martin Fabani, Ernesto Guzman, Smriti Ramakrishnan, Victor Lavrenko, Boyko Kakaradov, Claire Hou, Barry Hicks, David Heckerman, Franz J. Och, C. Thomas Caskey, J. Craig Venter, Amalio Telenti
      Short tandem repeats (STRs) are hyper-mutable sequences in the human genome. They are often used in forensics and population genetics and are also the underlying cause of many genetic diseases. There are challenges associated with accurately determining the length polymorphism of STR loci in the genome by next-generation sequencing (NGS). In particular, accurate detection of pathological STR expansion is limited by the sequence read length during whole-genome analysis. We developed TREDPARSE, a software package that incorporates various cues from read alignment and paired-end distance distribution, as well as a sequence stutter model, in a probabilistic framework to infer repeat sizes for genetic loci, and we used this software to infer repeat sizes for 30 known disease loci. Using simulated data, we show that TREDPARSE outperforms other available software. We sampled the full genome sequences of 12,632 individuals to an average read depth of approximately 30× to 40× with Illumina HiSeq X. We identified 138 individuals with risk alleles at 15 STR disease loci. We validated a representative subset of the samples (n = 19) by Sanger and by Oxford Nanopore sequencing. Additionally, we validated the STR calls against known allele sizes in a set of GeT-RM reference cell-line materials (n = 6). Several STR loci that are entirely guanine or cytosines (G or C) have insufficient read evidence for inference and therefore could not be assayed precisely by TREDPARSE. TREDPARSE extends the limit of STR size detection beyond the physical sequence read length. This extension is critical because many of the disease risk cutoffs are close to or beyond the short sequence read length of 100 to 150 bases.

      PubDate: 2017-11-05T10:27:28Z
      DOI: 10.1016/j.ajhg.2017.09.013
  • De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a
           Neurodevelopmental Disorder
    • Authors: Davor Lessel; Claudia Schob; Sébastien Küry; Margot R.F. Reinders; Tamar Harel; Mohammad K. Eldomery; Zeynep Coban-Akdemir; Jonas Denecke; Shimon Edvardson; Estelle Colin; Alexander P.A. Stegmann; Erica H. Gerkes; Marine Tessarech; Dominique Bonneau; Magalie Barth; Thomas Besnard; Benjamin Cogné; Anya Revah-Politi; Tim M. Strom; Jill A. Rosenfeld; Yaping Yang; Jennifer E. Posey; LaDonna Immken; Nelly Oundjian; Katherine L. Helbig; Naomi Meeks; Kelsey Zegar; Jenny Morton; Jolanda H. Schieving; Ana Claasen; Matthew Huentelman; Vinodh Narayanan; Keri Ramsey; Han G. Brunner; Orly Elpeleg; Sandra Mercier; Stéphane Bézieau; Christian Kubisch; Tjitske Kleefstra; Stefan Kindler; James R. Lupski; Hans-Jürgen Kreienkamp
      Pages: 716 - 724
      Abstract: Publication date: 2 November 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 5
      Author(s): Davor Lessel, Claudia Schob, Sébastien Küry, Margot R.F. Reinders, Tamar Harel, Mohammad K. Eldomery, Zeynep Coban-Akdemir, Jonas Denecke, Shimon Edvardson, Estelle Colin, Alexander P.A. Stegmann, Erica H. Gerkes, Marine Tessarech, Dominique Bonneau, Magalie Barth, Thomas Besnard, Benjamin Cogné, Anya Revah-Politi, Tim M. Strom, Jill A. Rosenfeld, Yaping Yang, Jennifer E. Posey, LaDonna Immken, Nelly Oundjian, Katherine L. Helbig, Naomi Meeks, Kelsey Zegar, Jenny Morton, Jolanda H. Schieving, Ana Claasen, Matthew Huentelman, Vinodh Narayanan, Keri Ramsey, Han G. Brunner, Orly Elpeleg, Sandra Mercier, Stéphane Bézieau, Christian Kubisch, Tjitske Kleefstra, Stefan Kindler, James R. Lupski, Hans-Jürgen Kreienkamp
      DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder.

      PubDate: 2017-11-05T10:27:28Z
      DOI: 10.1016/j.ajhg.2017.09.014
  • Genome-wide Ancestry and Demographic History of African-Descendant Maroon
           Communities from French Guiana and Suriname
    • Authors: Cesar Fortes-Lima; Antoine Gessain; Andres Ruiz-Linares; Maria-Cátira Bortolini; Florence Migot-Nabias; Gil Bellis; J. Víctor Moreno-Mayar; Berta Nelly Restrepo; Winston Rojas; Efren Avendaño-Tamayo; Gabriel Bedoya; Ludovic Orlando; Antonio Salas; Agnar Helgason; M. Thomas P. Gilbert; Martin Sikora; Hannes Schroeder; Jean-Michel Dugoujon
      Pages: 725 - 736
      Abstract: Publication date: 2 November 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 5
      Author(s): Cesar Fortes-Lima, Antoine Gessain, Andres Ruiz-Linares, Maria-Cátira Bortolini, Florence Migot-Nabias, Gil Bellis, J. Víctor Moreno-Mayar, Berta Nelly Restrepo, Winston Rojas, Efren Avendaño-Tamayo, Gabriel Bedoya, Ludovic Orlando, Antonio Salas, Agnar Helgason, M. Thomas P. Gilbert, Martin Sikora, Hannes Schroeder, Jean-Michel Dugoujon
      The transatlantic slave trade was the largest forced migration in world history. However, the origins of the enslaved Africans and their admixture dynamics remain unclear. To investigate the demographic history of African-descendant Marron populations, we generated genome-wide data (4.3 million markers) from 107 individuals from three African-descendant populations in South America, as well as 124 individuals from six west African populations. Throughout the Americas, thousands of enslaved Africans managed to escape captivity and establish lasting communities, such as the Noir Marron. We find that this population has the highest proportion of African ancestry (∼98%) of any African-descendant population analyzed to date, presumably because of centuries of genetic isolation. By contrast, African-descendant populations in Brazil and Colombia harbor substantially more European and Native American ancestry as a result of their complex admixture histories. Using ancestry tract-length analysis, we detect different dates for the European admixture events in the African-Colombian (1749 CE; confidence interval [CI]: 1737–1764) and African-Brazilian (1796 CE; CI: 1789–1804) populations in our dataset, consistent with the historically attested earlier influx of Africans into Colombia. Furthermore, we find evidence for sex-specific admixture patterns, resulting from predominantly European paternal gene flow. Finally, we detect strong genetic links between the African-descendant populations and specific source populations in Africa on the basis of haplotype sharing patterns. Although the Noir Marron and African-Colombians show stronger affinities with African populations from the Bight of Benin and the Gold Coast, the African-Brazilian population from Rio de Janeiro has greater genetic affinity with Bantu-speaking populations from the Bight of Biafra and west central Africa.

      PubDate: 2017-11-05T10:27:28Z
      DOI: 10.1016/j.ajhg.2017.09.021
  • Local Genetic Correlation Gives Insights into the Shared Genetic
           Architecture of Complex Traits
    • Authors: Huwenbo Shi; Nicholas Mancuso; Sarah Spendlove; Bogdan Pasaniuc
      Pages: 737 - 751
      Abstract: Publication date: 2 November 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 5
      Author(s): Huwenbo Shi, Nicholas Mancuso, Sarah Spendlove, Bogdan Pasaniuc
      Although genetic correlations between complex traits provide valuable insights into epidemiological and etiological studies, a precise quantification of which genomic regions disproportionately contribute to the genome-wide correlation is currently lacking. Here, we introduce ρ-HESS, a technique to quantify the correlation between pairs of traits due to genetic variation at a small region in the genome. Our approach requires GWAS summary data only and makes no distributional assumption on the causal variant effect sizes while accounting for linkage disequilibrium (LD) and overlapping GWAS samples. We analyzed large-scale GWAS summary data across 36 quantitative traits, and identified 25 genomic regions that contribute significantly to the genetic correlation among these traits. Notably, we find 6 genomic regions that contribute to the genetic correlation of 10 pairs of traits that show negligible genome-wide correlation, further showcasing the power of local genetic correlation analyses. Finally, we report the distribution of local genetic correlations across the genome for 55 pairs of traits that show putative causal relationships.

      PubDate: 2017-11-05T10:27:28Z
      DOI: 10.1016/j.ajhg.2017.09.022
  • Natural Selection on Genes Related to Cardiovascular Health in
           High-Altitude Adapted Andeans
    • Authors: Jacob E. Crawford; Ricardo Amaru; Jihyun Song; Colleen G. Julian; Fernando Racimo; Jade Yu Cheng; Xiuqing Guo; Jie Yao; Bharath Ambale-Venkatesh; João A. Lima; Jerome I. Rotter; Josef Stehlik; Lorna G. Moore; Josef T. Prchal; Rasmus Nielsen
      Pages: 752 - 767
      Abstract: Publication date: 2 November 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 5
      Author(s): Jacob E. Crawford, Ricardo Amaru, Jihyun Song, Colleen G. Julian, Fernando Racimo, Jade Yu Cheng, Xiuqing Guo, Jie Yao, Bharath Ambale-Venkatesh, João A. Lima, Jerome I. Rotter, Josef Stehlik, Lorna G. Moore, Josef T. Prchal, Rasmus Nielsen
      The increase in red blood cell mass (polycythemia) due to the reduced oxygen availability (hypoxia) of residence at high altitude or other conditions is generally thought to be beneficial in terms of increasing tissue oxygen supply. However, the extreme polycythemia and accompanying increased mortality due to heart failure in chronic mountain sickness most likely reduces fitness. Tibetan highlanders have adapted to high altitude, possibly in part via the selection of genetic variants associated with reduced polycythemic response to hypoxia. In contrast, high-altitude-adapted Quechua- and Aymara-speaking inhabitants of the Andean Altiplano are not protected from high-altitude polycythemia in the same way, yet they exhibit other adaptive features for which the genetic underpinnings remain obscure. Here, we used whole-genome sequencing to scan high-altitude Andeans for signals of selection. The genes showing the strongest evidence of selection—including BRINP3, NOS2, and TBX5—are associated with cardiovascular development and function but are not in the response-to-hypoxia pathway. Using association mapping, we demonstrated that the haplotypes under selection are associated with phenotypic variations related to cardiovascular health. We hypothesize that selection in response to hypoxia in Andeans could have vascular effects and could serve to mitigate the deleterious effects of polycythemia rather than reduce polycythemia itself.

      PubDate: 2017-11-05T10:27:28Z
      DOI: 10.1016/j.ajhg.2017.09.023
  • De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause
           Intellectual Disability
    • Authors: Sébastien Küry; Geeske M. van Woerden; Thomas Besnard; Martina Proietti Onori; Xénia Latypova; Meghan C. Towne; Megan T. Cho; Trine E. Prescott; Melissa A. Ploeg; Stephan Sanders; Holly A.F. Stessman; Aurora Pujol; Ben Distel; Laurie A. Robak; Jonathan A. Bernstein; Anne-Sophie Denommé-Pichon; Gaëtan Lesca; Elizabeth A. Sellars; Jonathan Berg; Wilfrid Carré; Øyvind Løvold Busk; Bregje W.M. van Bon; Jeff L. Waugh; Matthew Deardorff; George E. Hoganson; Katherine B. Bosanko; Diana S. Johnson; Tabib Dabir; Øystein Lunde Holla; Ajoy Sarkar; Kristian Tveten; Julitta de Bellescize; Geir J. Braathen; Paulien A. Terhal; Dorothy K. Grange; Arie van Haeringen; Christina Lam; Ghayda Mirzaa; Jennifer Burton; Elizabeth J. Bhoj; Jessica Douglas; Avni B. Santani; Addie I. Nesbitt; Katherine L. Helbig; Marisa V. Andrews; Amber Begtrup; Sha Tang; Koen L.I. van Gassen; Jane Juusola; Kimberly Foss; Gregory M. Enns; Ute Moog; Katrin Hinderhofer; Nagarajan Paramasivam; Sharyn Lincoln; Brandon H. Kusako; Pierre Lindenbaum; Eric Charpentier; Catherine B. Nowak; Elouan Cherot; Thomas Simonet; Claudia A.L. Ruivenkamp; Sihoun Hahn; Catherine A. Brownstein; Fan Xia; Sébastien Schmitt; Wallid Deb; Dominique Bonneau; Mathilde Nizon; Delphine Quinquis; Jamel Chelly; Gabrielle Rudolf; Damien Sanlaville; Philippe Parent; Brigitte Gilbert-Dussardier; Annick Toutain; Vernon R. Sutton; Jenny Thies; Lisenka E.L.M. Peart-Vissers; Pierre Boisseau; Marie Vincent; Andreas M. Grabrucker; Christèle Dubourg; Wen-Hann Tan; Nienke E. Verbeek; Martin Granzow; Gijs W.E. Santen; Jay Shendure; Bertrand Isidor; Laurent Pasquier; Richard Redon; Yaping Yang; Matthew W. State; Tjitske Kleefstra; Benjamin Cogné; Slavé Petrovski; Kyle Retterer; Evan E. Eichler; Jill A. Rosenfeld; Pankaj B. Agrawal; Stéphane Bézieau; Sylvie Odent; Ype Elgersma; Sandra Mercier
      Pages: 768 - 788
      Abstract: Publication date: 2 November 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 5
      Author(s): Sébastien Küry, Geeske M. van Woerden, Thomas Besnard, Martina Proietti Onori, Xénia Latypova, Meghan C. Towne, Megan T. Cho, Trine E. Prescott, Melissa A. Ploeg, Stephan Sanders, Holly A.F. Stessman, Aurora Pujol, Ben Distel, Laurie A. Robak, Jonathan A. Bernstein, Anne-Sophie Denommé-Pichon, Gaëtan Lesca, Elizabeth A. Sellars, Jonathan Berg, Wilfrid Carré, Øyvind Løvold Busk, Bregje W.M. van Bon, Jeff L. Waugh, Matthew Deardorff, George E. Hoganson, Katherine B. Bosanko, Diana S. Johnson, Tabib Dabir, Øystein Lunde Holla, Ajoy Sarkar, Kristian Tveten, Julitta de Bellescize, Geir J. Braathen, Paulien A. Terhal, Dorothy K. Grange, Arie van Haeringen, Christina Lam, Ghayda Mirzaa, Jennifer Burton, Elizabeth J. Bhoj, Jessica Douglas, Avni B. Santani, Addie I. Nesbitt, Katherine L. Helbig, Marisa V. Andrews, Amber Begtrup, Sha Tang, Koen L.I. van Gassen, Jane Juusola, Kimberly Foss, Gregory M. Enns, Ute Moog, Katrin Hinderhofer, Nagarajan Paramasivam, Sharyn Lincoln, Brandon H. Kusako, Pierre Lindenbaum, Eric Charpentier, Catherine B. Nowak, Elouan Cherot, Thomas Simonet, Claudia A.L. Ruivenkamp, Sihoun Hahn, Catherine A. Brownstein, Fan Xia, Sébastien Schmitt, Wallid Deb, Dominique Bonneau, Mathilde Nizon, Delphine Quinquis, Jamel Chelly, Gabrielle Rudolf, Damien Sanlaville, Philippe Parent, Brigitte Gilbert-Dussardier, Annick Toutain, Vernon R. Sutton, Jenny Thies, Lisenka E.L.M. Peart-Vissers, Pierre Boisseau, Marie Vincent, Andreas M. Grabrucker, Christèle Dubourg, Wen-Hann Tan, Nienke E. Verbeek, Martin Granzow, Gijs W.E. Santen, Jay Shendure, Bertrand Isidor, Laurent Pasquier, Richard Redon, Yaping Yang, Matthew W. State, Tjitske Kleefstra, Benjamin Cogné, Slavé Petrovski, Kyle Retterer, Evan E. Eichler, Jill A. Rosenfeld, Pankaj B. Agrawal, Stéphane Bézieau, Sylvie Odent, Ype Elgersma, Sandra Mercier
      Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.

      PubDate: 2017-11-05T10:27:28Z
      DOI: 10.1016/j.ajhg.2017.10.003
  • Exome-wide Association Study Identifies GREB1L Mutations in Congenital
           Kidney Malformations
    • Authors: Simone Sanna-Cherchi; Kamal Khan; Rik Westland; Priya Krithivasan; Lorraine Fievet; Hila Milo Rasouly; Iuliana Ionita-Laza; Valentina P. Capone; David A. Fasel; Krzysztof Kiryluk; Sitharthan Kamalakaran; Monica Bodria; Edgar A. Otto; Matthew G. Sampson; Christopher E. Gillies; Virginia Vega-Warner; Katarina Vukojevic; Igor Pediaditakis; Gabriel S. Makar; Adele Mitrotti; Miguel Verbitsky; Jeremiah Martino; Qingxue Liu; Young-Ji Na; Vinicio Goj; Gianluigi Ardissino; Maddalena Gigante; Loreto Gesualdo; Magdalena Janezcko; Marcin Zaniew; Cathy Lee Mendelsohn; Shirlee Shril; Friedhelm Hildebrandt; Joanna A.E. van Wijk; Adela Arapovic; Marijan Saraga; Landino Allegri; Claudia Izzi; Francesco Scolari; Velibor Tasic; Gian Marco Ghiggeri; Anna Latos-Bielenska; Anna-Materna Kiryluk; Shrikant Mane; David B. Goldstein; Richard P. Lifton; Nicholas Katsanis; Erica E. Davis; Ali G. Gharavi
      Pages: 789 - 802
      Abstract: Publication date: 2 November 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 5
      Author(s): Simone Sanna-Cherchi, Kamal Khan, Rik Westland, Priya Krithivasan, Lorraine Fievet, Hila Milo Rasouly, Iuliana Ionita-Laza, Valentina P. Capone, David A. Fasel, Krzysztof Kiryluk, Sitharthan Kamalakaran, Monica Bodria, Edgar A. Otto, Matthew G. Sampson, Christopher E. Gillies, Virginia Vega-Warner, Katarina Vukojevic, Igor Pediaditakis, Gabriel S. Makar, Adele Mitrotti, Miguel Verbitsky, Jeremiah Martino, Qingxue Liu, Young-Ji Na, Vinicio Goj, Gianluigi Ardissino, Maddalena Gigante, Loreto Gesualdo, Magdalena Janezcko, Marcin Zaniew, Cathy Lee Mendelsohn, Shirlee Shril, Friedhelm Hildebrandt, Joanna A.E. van Wijk, Adela Arapovic, Marijan Saraga, Landino Allegri, Claudia Izzi, Francesco Scolari, Velibor Tasic, Gian Marco Ghiggeri, Anna Latos-Bielenska, Anna-Materna Kiryluk, Shrikant Mane, David B. Goldstein, Richard P. Lifton, Nicholas Katsanis, Erica E. Davis, Ali G. Gharavi
      Renal agenesis and hypodysplasia (RHD) are major causes of pediatric chronic kidney disease and are highly genetically heterogeneous. We conducted whole-exome sequencing in 202 case subjects with RHD and identified diagnostic mutations in genes known to be associated with RHD in 7/202 case subjects. In an additional affected individual with RHD and a congenital heart defect, we found a homozygous loss-of-function (LOF) variant in SLIT3, recapitulating phenotypes reported with Slit3 inactivation in the mouse. To identify genes associated with RHD, we performed an exome-wide association study with 195 unresolved case subjects and 6,905 control subjects. The top signal resided in GREB1L, a gene implicated previously in Hoxb1 and Shha signaling in zebrafish. The significance of the association, which was p = 2.0 × 10−5 for novel LOF, increased to p = 4.1 × 10−6 for LOF and deleterious missense variants combined, and augmented further after accounting for segregation and de novo inheritance of rare variants (joint p = 2.3 × 10−7). Finally, CRISPR/Cas9 disruption or knockdown of greb1l in zebrafish caused specific pronephric defects, which were rescued by wild-type human GREB1L mRNA, but not mRNA containing alleles identified in case subjects. Together, our study provides insight into the genetic landscape of kidney malformations in humans, presents multiple candidates, and identifies SLIT3 and GREB1L as genes implicated in the pathogenesis of RHD.

      PubDate: 2017-11-05T10:27:28Z
      DOI: 10.1016/j.ajhg.2017.09.018
  • Mutations in GREB1L Cause Bilateral Kidney Agenesis in Humans and Mice
    • Authors: Lara De Tomasi; Pierre David; Camille Humbert; Flora Silbermann; Christelle Arrondel; Frédéric Tores; Stéphane Fouquet; Audrey Desgrange; Olivier Niel; Christine Bole-Feysot; Patrick Nitschké; Joëlle Roume; Marie-Pierre Cordier; Christine Pietrement; Bertrand Isidor; Philippe Khau Van Kien; Marie Gonzales; Marie-Hélène Saint-Frison; Jelena Martinovic; Robert Novo; Juliette Piard; Christelle Cabrol; Ishwar C. Verma; Ratna Puri; Hubert Journel; Jacqueline Aziza; Laurent Gavard; Marie-Hélène Said-Menthon; Laurence Heidet; Sophie Saunier; Cécile Jeanpierre
      Pages: 803 - 814
      Abstract: Publication date: 2 November 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 5
      Author(s): Lara De Tomasi, Pierre David, Camille Humbert, Flora Silbermann, Christelle Arrondel, Frédéric Tores, Stéphane Fouquet, Audrey Desgrange, Olivier Niel, Christine Bole-Feysot, Patrick Nitschké, Joëlle Roume, Marie-Pierre Cordier, Christine Pietrement, Bertrand Isidor, Philippe Khau Van Kien, Marie Gonzales, Marie-Hélène Saint-Frison, Jelena Martinovic, Robert Novo, Juliette Piard, Christelle Cabrol, Ishwar C. Verma, Ratna Puri, Hubert Journel, Jacqueline Aziza, Laurent Gavard, Marie-Hélène Said-Menthon, Laurence Heidet, Sophie Saunier, Cécile Jeanpierre
      Congenital anomalies of the kidney and urinary tract (CAKUT) constitute a major cause of chronic kidney disease in children and 20% of prenatally detected anomalies. CAKUT encompass a spectrum of developmental kidney defects, including renal agenesis, hypoplasia, and cystic and non-cystic dysplasia. More than 50 genes have been reported as mutated in CAKUT-affected case subjects. However, the pathophysiological mechanisms leading to bilateral kidney agenesis (BKA) remain largely elusive. Whole-exome or targeted exome sequencing of 183 unrelated familial and/or severe CAKUT-affected case subjects, including 54 fetuses with BKA, led to the identification of 16 heterozygous variants in GREB1L (growth regulation by estrogen in breast cancer 1-like), a gene reported as a target of retinoic acid signaling. Four loss-of-function and 12 damaging missense variants, 14 being absent from GnomAD, were identified. Twelve of them were present in familial or simplex BKA-affected case subjects. Female BKA-affected fetuses also displayed uterus agenesis. We demonstrated a significant association between GREB1L variants and BKA. By in situ hybridization, we showed expression of Greb1l in the nephrogenic zone in developing mouse kidney. We generated a Greb1l knock-out mouse model by CRISPR-Cas9. Analysis at E13.5 revealed lack of kidneys and genital tract anomalies in male and female Greb1l −/− embryos and a slight decrease in ureteric bud branching in Greb1l +/− embryos. We showed that Greb1l invalidation in mIMCD3 cells affected tubulomorphogenesis in 3D-collagen culture, a phenotype rescued by expression of the wild-type human protein. This demonstrates that GREB1L plays a major role in early metanephros and genital development in mice and humans.

      PubDate: 2017-11-05T10:27:28Z
      DOI: 10.1016/j.ajhg.2017.09.026
  • Mutations in Fibronectin Cause a Subtype of Spondylometaphyseal Dysplasia
           with “Corner Fractures”
    • Authors: Chae Syng Lee; He Fu; Nissan Baratang; Justine Rousseau; Heena Kumra; V. Reid Sutton; Marcello Niceta; Andrea Ciolfi; Guilherme Yamamoto; Débora Bertola; Carlo L. Marcelis; Dorien Lugtenberg; Andrea Bartuli; Choel Kim; Julie Hoover-Fong; Nara Sobreira; Richard Pauli; Carlos Bacino; Deborah Krakow; Jillian Parboosingh; Patrick Yap; Ariana Kariminejad; Marie T. McDonald; Mariana I. Aracena; Ekkehart Lausch; Sheila Unger; Andrea Superti-Furga; James T. Lu; Dan H. Cohn; Marco Tartaglia; Brendan H. Lee; Dieter P. Reinhardt; Philippe M. Campeau
      Pages: 815 - 823
      Abstract: Publication date: 2 November 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 5
      Author(s): Chae Syng Lee, He Fu, Nissan Baratang, Justine Rousseau, Heena Kumra, V. Reid Sutton, Marcello Niceta, Andrea Ciolfi, Guilherme Yamamoto, Débora Bertola, Carlo L. Marcelis, Dorien Lugtenberg, Andrea Bartuli, Choel Kim, Julie Hoover-Fong, Nara Sobreira, Richard Pauli, Carlos Bacino, Deborah Krakow, Jillian Parboosingh, Patrick Yap, Ariana Kariminejad, Marie T. McDonald, Mariana I. Aracena, Ekkehart Lausch, Sheila Unger, Andrea Superti-Furga, James T. Lu, Dan H. Cohn, Marco Tartaglia, Brendan H. Lee, Dieter P. Reinhardt, Philippe M. Campeau
      Fibronectin is a master organizer of extracellular matrices (ECMs) and promotes the assembly of collagens, fibrillin-1, and other proteins. It is also known to play roles in skeletal tissues through its secretion by osteoblasts, chondrocytes, and mesenchymal cells. Spondylometaphyseal dysplasias (SMDs) comprise a diverse group of skeletal dysplasias and often manifest as short stature, growth-plate irregularities, and vertebral anomalies, such as scoliosis. By comparing the exomes of individuals with SMD with the radiographic appearance of “corner fractures” at metaphyses, we identified three individuals with fibronectin (FN1) variants affecting highly conserved residues. Furthermore, using matching tools and the SkelDys emailing list, we identified other individuals with de novo FN1 variants and a similar phenotype. The severe scoliosis in most individuals and rare developmental coxa vara distinguish individuals with FN1 mutations from those with classical Sutcliffe-type SMD. To study functional consequences of these FN1 mutations on the protein level, we introduced three disease-associated missense variants (p.Cys87Phe [c.260G>T], p.Tyr240Asp [c.718T>G], and p.Cys260Gly [c.778T>G]) into a recombinant secreted N-terminal 70 kDa fragment (rF70K) and the full-length fibronectin (rFN). The wild-type rF70K and rFN were secreted into the culture medium, whereas all mutant proteins were either not secreted or secreted at significantly lower amounts. Immunofluorescence analysis demonstrated increased intracellular retention of the mutant proteins. In summary, FN1 mutations that cause defective fibronectin secretion are found in SMD, and we thus provide additional evidence for a critical function of fibronectin in cartilage and bone.

      PubDate: 2017-11-05T10:27:28Z
      DOI: 10.1016/j.ajhg.2017.09.019
  • De Novo Mutations in SLC25A24 Cause a Craniosynostosis Syndrome with
           Hypertrichosis, Progeroid Appearance, and Mitochondrial Dysfunction
    • Authors: Nadja Ehmke; Luitgard Graul-Neumann; Lukasz Smorag; Rainer Koenig; Lara Segebrecht; Pilar Magoulas; Fernando Scaglia; Esra Kilic; Anna F. Hennig; Nicolai Adolphs; Namrata Saha; Beatrix Fauler; Vera M. Kalscheuer; Friederike Hennig; Janine Altmüller; Christian Netzer; Holger Thiele; Peter Nürnberg; Gökhan Yigit; Marten Jäger; Jochen Hecht; Ulrike Krüger; Thorsten Mielke; Peter M. Krawitz; Denise Horn; Markus Schuelke; Stefan Mundlos; Carlos A. Bacino; Penelope E. Bonnen; Bernd Wollnik; Björn Fischer-Zirnsak; Uwe Kornak
      Pages: 833 - 843
      Abstract: Publication date: 2 November 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 5
      Author(s): Nadja Ehmke, Luitgard Graul-Neumann, Lukasz Smorag, Rainer Koenig, Lara Segebrecht, Pilar Magoulas, Fernando Scaglia, Esra Kilic, Anna F. Hennig, Nicolai Adolphs, Namrata Saha, Beatrix Fauler, Vera M. Kalscheuer, Friederike Hennig, Janine Altmüller, Christian Netzer, Holger Thiele, Peter Nürnberg, Gökhan Yigit, Marten Jäger, Jochen Hecht, Ulrike Krüger, Thorsten Mielke, Peter M. Krawitz, Denise Horn, Markus Schuelke, Stefan Mundlos, Carlos A. Bacino, Penelope E. Bonnen, Bernd Wollnik, Björn Fischer-Zirnsak, Uwe Kornak
      Gorlin-Chaudhry-Moss syndrome (GCMS) is a dysmorphic syndrome characterized by coronal craniosynostosis and severe midface hypoplasia, body and facial hypertrichosis, microphthalmia, short stature, and short distal phalanges. Variable lipoatrophy and cutis laxa are the basis for a progeroid appearance. Using exome and genome sequencing, we identified the recurrent de novo mutations c.650G>A (p.Arg217His) and c.649C>T (p.Arg217Cys) in SLC25A24 in five unrelated girls diagnosed with GCMS. Two of the girls had pronounced neonatal progeroid features and were initially diagnosed with Wiedemann-Rautenstrauch syndrome. SLC25A24 encodes a mitochondrial inner membrane ATP-Mg/Pi carrier. In fibroblasts from affected individuals, the mutated SLC25A24 showed normal stability. In contrast to control cells, the probands’ cells showed mitochondrial swelling, which was exacerbated upon treatment with hydrogen peroxide (H2O2). The same effect was observed after overexpression of the mutant cDNA. Under normal culture conditions, the mitochondrial membrane potential of the probands’ fibroblasts was intact, whereas ATP content in the mitochondrial matrix was lower than that in control cells. However, upon H2O2 exposure, the membrane potential was significantly elevated in cells harboring the mutated SLC25A24. No reduction of mitochondrial DNA copy number was observed. These findings demonstrate that mitochondrial dysfunction with increased sensitivity to oxidative stress is due to the SLC25A24 mutations. Our results suggest that the SLC25A24 mutations induce a gain of pathological function and link mitochondrial ATP-Mg/Pi transport to the development of skeletal and connective tissue.

      PubDate: 2017-11-05T10:27:28Z
      DOI: 10.1016/j.ajhg.2017.09.016
  • De Novo Mutations in SLC25A24 Cause a Disorder Characterized by Early
           Aging, Bone Dysplasia, Characteristic Face, and Early Demise
    • Authors: Karin Writzl; Ales Maver; Lidija Kovačič; Paula Martinez-Valero; Laura Contreras; Jorgina Satrustegui; Marco Castori; Laurence Faivre; Pablo Lapunzina; André B.P. van Kuilenburg; Slobodanka Radović; Christel Thauvin-Robinet; Borut Peterlin; Araceli del Arco; Raoul C. Hennekam
      Pages: 844 - 855
      Abstract: Publication date: 2 November 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 5
      Author(s): Karin Writzl, Ales Maver, Lidija Kovačič, Paula Martinez-Valero, Laura Contreras, Jorgina Satrustegui, Marco Castori, Laurence Faivre, Pablo Lapunzina, André B.P. van Kuilenburg, Slobodanka Radović, Christel Thauvin-Robinet, Borut Peterlin, Araceli del Arco, Raoul C. Hennekam
      A series of simplex cases have been reported under various diagnoses sharing early aging, especially evident in congenitally decreased subcutaneous fat tissue and sparse hair, bone dysplasia of the skull and fingers, a distinctive facial gestalt, and prenatal and postnatal growth retardation. For historical reasons, we suggest naming the entity Fontaine syndrome. Exome sequencing of four unrelated affected individuals showed that all carried the de novo missense variant c.649C>T (p.Arg217Cys) or c.650G>A (p.Arg217His) in SLC25A24, a solute carrier 25 family member coding for calcium-binding mitochondrial carrier protein (SCaMC-1, also known as SLC25A24). SLC25A24 allows an electro-neutral and reversible exchange of ATP-Mg and phosphate between the cytosol and mitochondria, which is required for maintaining optimal adenine nucleotide levels in the mitochondrial matrix. Molecular dynamic simulation studies predict that p.Arg217Cys and p.Arg217His narrow the substrate cavity of the protein and disrupt transporter dynamics. SLC25A24-mutant fibroblasts and cells expressing p.Arg217Cys or p.Arg217His variants showed altered mitochondrial morphology, a decreased proliferation rate, increased mitochondrial membrane potential, and decreased ATP-linked mitochondrial oxygen consumption. The results suggest that the SLC25A24 mutations lead to impaired mitochondrial ATP synthesis and cause hyperpolarization and increased proton leak in association with an impaired energy metabolism. Our findings identify SLC25A24 mutations affecting codon 217 as the underlying genetic cause of human progeroid Fontaine syndrome.

      PubDate: 2017-11-05T10:27:28Z
      DOI: 10.1016/j.ajhg.2017.09.017
  • Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause
           Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia
    • Authors: Thi Tuyet Mai Nguyen; Yoshiko Murakami; Eamonn Sheridan; Sophie Ehresmann; Justine Rousseau; Anik St-Denis; Guoliang Chai; Norbert F. Ajeawung; Laura Fairbrother; Tyler Reimschisel; Alexandra Bateman; Elizabeth Berry-Kravis; Fan Xia; Jessica Tardif; David A. Parry; Clare V. Logan; Christine Diggle; Christopher P. Bennett; Louise Hattingh; Jill A. Rosenfeld; Michael Scott Perry; Michael J. Parker; Françoise Le Deist; Maha S. Zaki; Erika Ignatius; Pirjo Isohanni; Tuula Lönnqvist; Christopher J. Carroll; Colin A. Johnson; Joseph G. Gleeson; Taroh Kinoshita; Philippe M. Campeau
      Pages: 856 - 865
      Abstract: Publication date: 2 November 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 5
      Author(s): Thi Tuyet Mai Nguyen, Yoshiko Murakami, Eamonn Sheridan, Sophie Ehresmann, Justine Rousseau, Anik St-Denis, Guoliang Chai, Norbert F. Ajeawung, Laura Fairbrother, Tyler Reimschisel, Alexandra Bateman, Elizabeth Berry-Kravis, Fan Xia, Jessica Tardif, David A. Parry, Clare V. Logan, Christine Diggle, Christopher P. Bennett, Louise Hattingh, Jill A. Rosenfeld, Michael Scott Perry, Michael J. Parker, Françoise Le Deist, Maha S. Zaki, Erika Ignatius, Pirjo Isohanni, Tuula Lönnqvist, Christopher J. Carroll, Colin A. Johnson, Joseph G. Gleeson, Taroh Kinoshita, Philippe M. Campeau
      Approximately one in every 200 mammalian proteins is anchored to the cell membrane through a glycosylphosphatidylinositol (GPI) anchor. These proteins play important roles notably in neurological development and function. To date, more than 20 genes have been implicated in the biogenesis of GPI-anchored proteins. GPAA1 (glycosylphosphatidylinositol anchor attachment 1) is an essential component of the transamidase complex along with PIGK, PIGS, PIGT, and PIGU (phosphatidylinositol-glycan biosynthesis classes K, S, T, and U, respectively). This complex orchestrates the attachment of the GPI anchor to the C terminus of precursor proteins in the endoplasmic reticulum. Here, we report bi-allelic mutations in GPAA1 in ten individuals from five families. Using whole-exome sequencing, we identified two frameshift mutations (c.981_993del [p.Gln327Hisfs∗102] and c.920delG [p.Gly307Alafs∗11]), one intronic splicing mutation (c.1164+5C>T), and six missense mutations (c.152C>T [p.Ser51Leu], c.160_161delinsAA [p.Ala54Asn], c.527G>C [p.Trp176Ser], c.869T>C [p.Leu290Pro], c.872T>C [p.Leu291Pro], and c.1165G>C [p.Ala389Pro]). Most individuals presented with global developmental delay, hypotonia, early-onset seizures, cerebellar atrophy, and osteopenia. The splicing mutation was found to decrease GPAA1 mRNA. Moreover, flow-cytometry analysis of five available individual samples showed that several GPI-anchored proteins had decreased cell-surface abundance in leukocytes (FLAER, CD16, and CD59) or fibroblasts (CD73 and CD109). Transduction of fibroblasts with a lentivirus encoding the wild-type protein partially rescued the deficiency of GPI-anchored proteins. These findings highlight the role of the transamidase complex in the development and function of the cerebellum and the skeletal system.

      PubDate: 2017-11-05T10:27:28Z
      DOI: 10.1016/j.ajhg.2017.09.020
  • Fine Mapping and Functional Analysis Reveal a Role of SLC22A1 in
           Acylcarnitine Transport
    • Authors: Hye In Kim; Johannes Raffler; Wenyun Lu; Jung-Jin Lee; Deepti Abbey; Danish Saleheen; Joshua D. Rabinowitz; Michael J. Bennett; Nicholas J. Hand; Christopher Brown; Daniel J. Rader
      Pages: 489 - 502
      Abstract: Publication date: 5 October 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 4
      Author(s): Hye In Kim, Johannes Raffler, Wenyun Lu, Jung-Jin Lee, Deepti Abbey, Danish Saleheen, Joshua D. Rabinowitz, Michael J. Bennett, Nicholas J. Hand, Christopher Brown, Daniel J. Rader
      Genome-wide association studies have identified a signal at the SLC22A1 locus for serum acylcarnitines, intermediate metabolites of mitochondrial oxidation whose plasma levels associate with metabolic diseases. Here, we refined the association signal, performed conditional analyses, and examined the linkage structure to find coding variants of SLC22A1 that mediate independent association signals at the locus. We also employed allele-specific expression analysis to find potential regulatory variants of SLC22A1 and demonstrated the effect of one variant on the splicing of SLC22A1. SLC22A1 encodes a hepatic plasma membrane transporter whose role in acylcarnitine physiology has not been described. By targeted metabolomics and isotope tracing experiments in loss- and gain-of-function cell and mouse models of Slc22a1, we uncovered a role of SLC22A1 in the efflux of acylcarnitines from the liver to the circulation. We further validated the impacts of human variants on SLC22A1-mediated acylcarnitine efflux in vitro, explaining their association with serum acylcarnitine levels. Our findings provide the detailed molecular mechanisms of the GWAS association for serum acylcarnitines at the SLC22A1 locus by functionally validating the impact of SLC22A1 and its variants on acylcarnitine transport.

      PubDate: 2017-10-29T09:27:30Z
      DOI: 10.1016/j.ajhg.2017.08.008
  • Haploinsufficiency of the Chromatin Remodeler BPTF Causes Syndromic
           Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic
    • Authors: Paweł Stankiewicz; Tahir N. Khan; Przemyslaw Szafranski; Leah Slattery; Haley Streff; Francesco Vetrini; Jonathan A. Bernstein; Chester W. Brown; Jill A. Rosenfeld; Surya Rednam; Sarah Scollon; Katie L. Bergstrom; Donald W. Parsons; Sharon E. Plon; Marta W. Vieira; Caio R.D.C. Quaio; Wagner A.R. Baratela; Johanna C. Acosta Guio; Ruth Armstrong; Sarju G. Mehta; Patrick Rump; Rolph Pfundt; Raymond Lewandowski; Erica M. Fernandes; Deepali N. Shinde; Sha Tang; Juliane Hoyer; Christiane Zweier; André Reis; Carlos A. Bacino; Rui Xiao; Amy M. Breman; Janice L. Smith; Nicholas Katsanis; Bret Bostwick; Bernt Popp; Erica E. Davis; Yaping Yang
      Pages: 503 - 515
      Abstract: Publication date: 5 October 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 4
      Author(s): Paweł Stankiewicz, Tahir N. Khan, Przemyslaw Szafranski, Leah Slattery, Haley Streff, Francesco Vetrini, Jonathan A. Bernstein, Chester W. Brown, Jill A. Rosenfeld, Surya Rednam, Sarah Scollon, Katie L. Bergstrom, Donald W. Parsons, Sharon E. Plon, Marta W. Vieira, Caio R.D.C. Quaio, Wagner A.R. Baratela, Johanna C. Acosta Guio, Ruth Armstrong, Sarju G. Mehta, Patrick Rump, Rolph Pfundt, Raymond Lewandowski, Erica M. Fernandes, Deepali N. Shinde, Sha Tang, Juliane Hoyer, Christiane Zweier, André Reis, Carlos A. Bacino, Rui Xiao, Amy M. Breman, Janice L. Smith, Nicholas Katsanis, Bret Bostwick, Bernt Popp, Erica E. Davis, Yaping Yang
      Bromodomain PHD finger transcription factor (BPTF) is the largest subunit of nucleosome remodeling factor (NURF), a member of the ISWI chromatin-remodeling complex. However, the clinical consequences of disruption of this complex remain largely uncharacterized. BPTF is required for anterior-posterior axis formation of the mouse embryo and was shown to promote posterior neuroectodermal fate by enhancing Smad2-activated wnt8 expression in zebrafish. Here, we report eight loss-of-function and two missense variants (eight de novo and two of unknown origin) in BPTF on 17q24.2. The BPTF variants were found in unrelated individuals aged between 2.1 and 13 years, who manifest variable degrees of developmental delay/intellectual disability (10/10), speech delay (10/10), postnatal microcephaly (7/9), and dysmorphic features (9/10). Using CRISPR-Cas9 genome editing of bptf in zebrafish to induce a loss of gene function, we observed a significant reduction in head size of F0 mutants compared to control larvae. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and phospho-histone H3 (PH3) staining to assess apoptosis and cell proliferation, respectively, showed a significant increase in cell death in F0 mutants compared to controls. Additionally, we observed a substantial increase of the ceratohyal angle of the craniofacial skeleton in bptf F0 mutants, indicating abnormal craniofacial patterning. Taken together, our data demonstrate the pathogenic role of BPTF haploinsufficiency in syndromic neurodevelopmental anomalies and extend the clinical spectrum of human disorders caused by ablation of chromatin remodeling complexes.

      PubDate: 2017-10-29T09:27:30Z
      DOI: 10.1016/j.ajhg.2017.08.014
  • De Novo Mutations in PPP3CA Cause Severe Neurodevelopmental Disease with
    • Authors: Candace T. Myers; Nicholas Stong; Emily I. Mountier; Katherine L. Helbig; Saskia Freytag; Joseph E. Sullivan; Bruria Ben Zeev; Andreea Nissenkorn; Michal Tzadok; Gali Heimer; Deepali N. Shinde; Arezoo Rezazadeh; Brigid M. Regan; Karen L. Oliver; Michelle E. Ernst; Natalie C. Lippa; Maureen S. Mulhern; Zhong Ren; Annapurna Poduri; Danielle M. Andrade; Lynne M. Bird; Melanie Bahlo; Samuel F. Berkovic; Daniel H. Lowenstein; Ingrid E. Scheffer; Lynette G. Sadleir; David B. Goldstein; Heather C. Mefford; Erin L. Heinzen
      Pages: 516 - 524
      Abstract: Publication date: 5 October 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 4
      Author(s): Candace T. Myers, Nicholas Stong, Emily I. Mountier, Katherine L. Helbig, Saskia Freytag, Joseph E. Sullivan, Bruria Ben Zeev, Andreea Nissenkorn, Michal Tzadok, Gali Heimer, Deepali N. Shinde, Arezoo Rezazadeh, Brigid M. Regan, Karen L. Oliver, Michelle E. Ernst, Natalie C. Lippa, Maureen S. Mulhern, Zhong Ren, Annapurna Poduri, Danielle M. Andrade, Lynne M. Bird, Melanie Bahlo, Samuel F. Berkovic, Daniel H. Lowenstein, Ingrid E. Scheffer, Lynette G. Sadleir, David B. Goldstein, Heather C. Mefford, Erin L. Heinzen
      Exome sequencing has readily enabled the discovery of the genetic mutations responsible for a wide range of diseases. This success has been particularly remarkable in the severe epilepsies and other neurodevelopmental diseases for which rare, often de novo, mutations play a significant role in disease risk. Despite significant progress, the high genetic heterogeneity of these disorders often requires large sample sizes to identify a critical mass of individuals with disease-causing mutations in a single gene. By pooling genetic findings across multiple studies, we have identified six individuals with severe developmental delay (6/6), refractory seizures (5/6), and similar dysmorphic features (3/6), each harboring a de novo mutation in PPP3CA. PPP3CA encodes the alpha isoform of a subunit of calcineurin. Calcineurin encodes a calcium- and calmodulin-dependent serine/threonine protein phosphatase that plays a role in a wide range of biological processes, including being a key regulator of synaptic vesicle recycling at nerve terminals. Five individuals with de novo PPP3CA mutations were identified among 4,760 trio probands with neurodevelopmental diseases; this is highly unlikely to occur by chance (p = 1.2 × 10−8) given the size and mutability of the gene. Additionally, a sixth individual with a de novo mutation in PPP3CA was connected to this study through GeneMatcher. Based on these findings, we securely implicate PPP3CA in early-onset refractory epilepsy and further support the emerging role for synaptic dysregulation in epilepsy.

      PubDate: 2017-10-29T09:27:30Z
      DOI: 10.1016/j.ajhg.2017.08.013
  • Biallelic C1QBP Mutations Cause Severe Neonatal-, Childhood-, or
           Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain
    • Authors: René G. Feichtinger; Monika Oláhová; Yoshihito Kishita; Caterina Garone; Laura S. Kremer; Mikako Yagi; Takeshi Uchiumi; Alexis A. Jourdain; Kyle Thompson; Aaron R. D’Souza; Robert Kopajtich; Charlotte L. Alston; Johannes Koch; Wolfgang Sperl; Elisa Mastantuono; Tim M. Strom; Saskia B. Wortmann; Thomas Meitinger; Germaine Pierre; Patrick F. Chinnery; Zofia M. Chrzanowska-Lightowlers; Robert N. Lightowlers; Salvatore DiMauro; Sarah E. Calvo; Vamsi K. Mootha; Maurizio Moggio; Monica Sciacco; Giacomo P. Comi; Dario Ronchi; Kei Murayama; Akira Ohtake; Pedro Rebelo-Guiomar; Masakazu Kohda; Dongchon Kang; Johannes A. Mayr; Robert W. Taylor; Yasushi Okazaki; Michal Minczuk; Holger Prokisch
      Pages: 525 - 538
      Abstract: Publication date: 5 October 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 4
      Author(s): René G. Feichtinger, Monika Oláhová, Yoshihito Kishita, Caterina Garone, Laura S. Kremer, Mikako Yagi, Takeshi Uchiumi, Alexis A. Jourdain, Kyle Thompson, Aaron R. D’Souza, Robert Kopajtich, Charlotte L. Alston, Johannes Koch, Wolfgang Sperl, Elisa Mastantuono, Tim M. Strom, Saskia B. Wortmann, Thomas Meitinger, Germaine Pierre, Patrick F. Chinnery, Zofia M. Chrzanowska-Lightowlers, Robert N. Lightowlers, Salvatore DiMauro, Sarah E. Calvo, Vamsi K. Mootha, Maurizio Moggio, Monica Sciacco, Giacomo P. Comi, Dario Ronchi, Kei Murayama, Akira Ohtake, Pedro Rebelo-Guiomar, Masakazu Kohda, Dongchon Kang, Johannes A. Mayr, Robert W. Taylor, Yasushi Okazaki, Michal Minczuk, Holger Prokisch
      Complement component 1 Q subcomponent-binding protein (C1QBP; also known as p32) is a multi-compartmental protein whose precise function remains unknown. It is an evolutionary conserved multifunctional protein localized primarily in the mitochondrial matrix and has roles in inflammation and infection processes, mitochondrial ribosome biogenesis, and regulation of apoptosis and nuclear transcription. It has an N-terminal mitochondrial targeting peptide that is proteolytically processed after import into the mitochondrial matrix, where it forms a homotrimeric complex organized in a doughnut-shaped structure. Although C1QBP has been reported to exert pleiotropic effects on many cellular processes, we report here four individuals from unrelated families where biallelic mutations in C1QBP cause a defect in mitochondrial energy metabolism. Infants presented with cardiomyopathy accompanied by multisystemic involvement (liver, kidney, and brain), and children and adults presented with myopathy and progressive external ophthalmoplegia. Multiple mitochondrial respiratory-chain defects, associated with the accumulation of multiple deletions of mitochondrial DNA in the later-onset myopathic cases, were identified in all affected individuals. Steady-state C1QBP levels were decreased in all individuals’ samples, leading to combined respiratory-chain enzyme deficiency of complexes I, III, and IV. C1qbp −/− mouse embryonic fibroblasts (MEFs) resembled the human disease phenotype by showing multiple defects in oxidative phosphorylation (OXPHOS). Complementation with wild-type, but not mutagenized, C1qbp restored OXPHOS protein levels and mitochondrial enzyme activities in C1qbp −/− MEFs. C1QBP deficiency represents an important mitochondrial disorder associated with a clinical spectrum ranging from infantile lactic acidosis to childhood (cardio)myopathy and late-onset progressive external ophthalmoplegia.

      PubDate: 2017-10-29T09:27:30Z
      DOI: 10.1016/j.ajhg.2017.08.015
  • Prospects of Fine-Mapping Trait-Associated Genomic Regions by Using
           Summary Statistics from Genome-wide Association Studies
    • Authors: Christian Benner; Aki S. Havulinna; Marjo-Riitta Järvelin; Veikko Salomaa; Samuli Ripatti; Matti Pirinen
      Pages: 539 - 551
      Abstract: Publication date: 5 October 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 4
      Author(s): Christian Benner, Aki S. Havulinna, Marjo-Riitta Järvelin, Veikko Salomaa, Samuli Ripatti, Matti Pirinen
      During the past few years, various novel statistical methods have been developed for fine-mapping with the use of summary statistics from genome-wide association studies (GWASs). Although these approaches require information about the linkage disequilibrium (LD) between variants, there has not been a comprehensive evaluation of how estimation of the LD structure from reference genotype panels performs in comparison with that from the original individual-level GWAS data. Using population genotype data from Finland and the UK Biobank, we show here that a reference panel of 1,000 individuals from the target population is adequate for a GWAS cohort of up to 10,000 individuals, whereas smaller panels, such as those from the 1000 Genomes Project, should be avoided. We also show, both theoretically and empirically, that the size of the reference panel needs to scale with the GWAS sample size; this has important consequences for the application of these methods in ongoing GWAS meta-analyses and large biobank studies. We conclude by providing software tools and by recommending practices for sharing LD information to more efficiently exploit summary statistics in genetics research.

      PubDate: 2017-10-29T09:27:30Z
      DOI: 10.1016/j.ajhg.2017.08.012
  • Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway
           and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects
    • Authors: Roberta De Mori; Marta Romani; Stefano D’Arrigo; Maha S. Zaki; Elisa Lorefice; Silvia Tardivo; Tommaso Biagini; Valentina Stanley; Damir Musaev; Joel Fluss; Alessia Micalizzi; Sara Nuovo; Barbara Illi; Luisa Chiapparini; Lucia Di Marcotullio; Mahmoud Y. Issa; Danila Anello; Antonella Casella; Monia Ginevrino; Autumn Sa’na Leggins; Susanne Roosing; Romina Alfonsi; Jessica Rosati; Rachel Schot; Grazia Maria Simonetta Mancini; Enrico Bertini; William B. Dobyns; Tommaso Mazza; Joseph G. Gleeson; Enza Maria Valente
      Pages: 552 - 563
      Abstract: Publication date: 5 October 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 4
      Author(s): Roberta De Mori, Marta Romani, Stefano D’Arrigo, Maha S. Zaki, Elisa Lorefice, Silvia Tardivo, Tommaso Biagini, Valentina Stanley, Damir Musaev, Joel Fluss, Alessia Micalizzi, Sara Nuovo, Barbara Illi, Luisa Chiapparini, Lucia Di Marcotullio, Mahmoud Y. Issa, Danila Anello, Antonella Casella, Monia Ginevrino, Autumn Sa’na Leggins, Susanne Roosing, Romina Alfonsi, Jessica Rosati, Rachel Schot, Grazia Maria Simonetta Mancini, Enrico Bertini, William B. Dobyns, Tommaso Mazza, Joseph G. Gleeson, Enza Maria Valente
      The Sonic Hedgehog (SHH) pathway is a key signaling pathway orchestrating embryonic development, mainly of the CNS and limbs. In vertebrates, SHH signaling is mediated by the primary cilium, and genetic defects affecting either SHH pathway members or ciliary proteins cause a spectrum of developmental disorders. SUFU is the main negative regulator of the SHH pathway and is essential during development. Indeed, Sufu knock-out is lethal in mice, and recessive pathogenic variants of this gene have never been reported in humans. Through whole-exome sequencing in subjects with Joubert syndrome, we identified four children from two unrelated families carrying homozygous missense variants in SUFU. The children presented congenital ataxia and cerebellar vermis hypoplasia with elongated superior cerebellar peduncles (mild “molar tooth sign”), typical cranio-facial dysmorphisms (hypertelorism, depressed nasal bridge, frontal bossing), and postaxial polydactyly. Two siblings also showed polymicrogyria. Molecular dynamics simulation predicted random movements of the mutated residues, with loss of the native enveloping movement of the binding site around its ligand GLI3. Functional studies on cellular models and fibroblasts showed that both variants significantly reduced SUFU stability and its capacity to bind GLI3 and promote its cleavage into the repressor form GLI3R. In turn, this impaired SUFU-mediated repression of the SHH pathway, as shown by altered expression levels of several target genes. We demonstrate that germline hypomorphic variants of SUFU cause deregulation of SHH signaling, resulting in recessive developmental defects of the CNS and limbs which share features with both SHH-related disorders and ciliopathies.

      PubDate: 2017-10-29T09:27:30Z
      DOI: 10.1016/j.ajhg.2017.08.017
  • The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical
           Phenotype of 16p11.2 BP2-BP3 CNVs
    • Authors: Maria Nicla Loviglio; Thomas Arbogast; Aia Elise Jønch; Stephan C. Collins; Konstantin Popadin; Camille S. Bonnet; Giuliana Giannuzzi; Anne M. Maillard; Sébastien Jacquemont; Binnaz Yalcin; Nicholas Katsanis; Christelle Golzio; Alexandre Reymond; Maria Nicla Loviglio; Aia Elise Jønch; Konstantin Popadin; Giuliana Giannuzzi; Anne M. Maillard; Christina Fagerberg; Charlotte Brasch Andersen; Martine Doco-Fenzy; Marie-Ange Delrue; Laurence Faivre; Benoit Arveiler; David Geneviève; Anouck Schneider; Marion Gerard; Joris Andrieux; Salima El Chehadeh; Elise Schaefer; Christel Depienne; Mieke Van Haelst; Eva H. Brilstra; Ellen Van Binsbergen; Jeske van Harssel; Lars T. van der Veken; James F. Gusella; Yiping Shen; Elyse Mitchell; Usha Kini; Lara Hawkes; Carolyn Campbell; Florence Niel Butschi; Marie-Claude Addor; Jacques S. Beckmann; Sébastien Jacquemont; Alexandre Reymond
      Pages: 564 - 577
      Abstract: Publication date: 5 October 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 4
      Author(s): Maria Nicla Loviglio, Thomas Arbogast, Aia Elise Jønch, Stephan C. Collins, Konstantin Popadin, Camille S. Bonnet, Giuliana Giannuzzi, Anne M. Maillard, Sébastien Jacquemont, Binnaz Yalcin, Nicholas Katsanis, Christelle Golzio, Alexandre Reymond
      Copy-number changes in 16p11.2 contribute significantly to neuropsychiatric traits. Besides the 600 kb BP4-BP5 CNV found in 0.5%–1% of individuals with autism spectrum disorders and schizophrenia and whose rearrangement causes reciprocal defects in head size and body weight, a second distal 220 kb BP2-BP3 CNV is likewise a potent driver of neuropsychiatric, anatomical, and metabolic pathologies. These two CNVs are engaged in complex reciprocal chromatin looping, intimating a functional relationship between genes in these regions that might be relevant to pathomechanism. We assessed the drivers of the distal 16p11.2 duplication by overexpressing each of the nine encompassed genes in zebrafish. Only overexpression of LAT induced a reduction of brain proliferating cells and concomitant microcephaly. Consistently, suppression of the zebrafish ortholog induced an increase of proliferation and macrocephaly. These phenotypes were not unique to zebrafish; Lat knockout mice show brain volumetric changes. Consistent with the hypothesis that LAT dosage is relevant to the CNV pathology, we observed similar effects upon overexpression of CD247 and ZAP70, encoding members of the LAT signalosome. We also evaluated whether LAT was interacting with KCTD13, MVP, and MAPK3, major driver and modifiers of the proximal 16p11.2 600 kb BP4-BP5 syndromes, respectively. Co-injected embryos exhibited an increased microcephaly, suggesting the presence of genetic interaction. Correspondingly, carriers of 1.7 Mb BP1-BP5 rearrangements that encompass both the BP2-BP3 and BP4-BP5 loci showed more severe phenotypes. Taken together, our results suggest that LAT, besides its well-recognized function in T cell development, is a major contributor of the 16p11.2 220 kb BP2-BP3 CNV-associated neurodevelopmental phenotypes.

      PubDate: 2017-10-29T09:27:30Z
      DOI: 10.1016/j.ajhg.2017.08.016
  • The Contribution of Neanderthals to Phenotypic Variation in Modern Humans
    • Authors: Michael Dannemann; Janet Kelso
      Pages: 578 - 589
      Abstract: Publication date: 5 October 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 4
      Author(s): Michael Dannemann, Janet Kelso
      Assessing the genetic contribution of Neanderthals to non-disease phenotypes in modern humans has been difficult because of the absence of large cohorts for which common phenotype information is available. Using baseline phenotypes collected for 112,000 individuals by the UK Biobank, we can now elaborate on previous findings that identified associations between signatures of positive selection on Neanderthal DNA and various modern human traits but not any specific phenotypic consequences. Here, we show that Neanderthal DNA affects skin tone and hair color, height, sleeping patterns, mood, and smoking status in present-day Europeans. Interestingly, multiple Neanderthal alleles at different loci contribute to skin and hair color in present-day Europeans, and these Neanderthal alleles contribute to both lighter and darker skin tones and hair color, suggesting that Neanderthals themselves were most likely variable in these traits.

      PubDate: 2017-10-29T09:27:30Z
      DOI: 10.1016/j.ajhg.2017.09.010
  • Female Infertility Caused by Mutations in the Oocyte-Specific
           Translational Repressor PATL2
    • Authors: Sateesh Maddirevula; Serdar Coskun; Saad Alhassan; Atif Elnour; Hessa S. Alsaif; Niema Ibrahim; Firdous Abdulwahab; Stefan T. Arold; Fowzan S. Alkuraya
      Pages: 603 - 608
      Abstract: Publication date: 5 October 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 4
      Author(s): Sateesh Maddirevula, Serdar Coskun, Saad Alhassan, Atif Elnour, Hessa S. Alsaif, Niema Ibrahim, Firdous Abdulwahab, Stefan T. Arold, Fowzan S. Alkuraya
      Infertility is a relatively common disorder of the reproductive system and remains unexplained in many cases. In vitro fertilization techniques have uncovered previously unrecognized infertility phenotypes, including oocyte maturation arrest, the molecular etiology of which remains largely unknown. We report two families affected by female-limited infertility caused by oocyte maturation failure. Positional mapping and whole-exome sequencing revealed two homozygous, likely deleterious variants in PATL2, each of which fully segregates with the phenotype within the respective family. PATL2 encodes a highly conserved oocyte-specific mRNP repressor of translation. Previous data have shown the strict requirement for PATL2 in oocyte-maturation in model organisms. Data gathered from the families in this study suggest that the role of PATL2 is conserved in humans and expand our knowledge of the factors that are necessary for female meiosis.

      PubDate: 2017-10-29T09:27:30Z
      DOI: 10.1016/j.ajhg.2017.08.009
  • Biallelic Mutations in PATL2 Cause Female Infertility Characterized by
           Oocyte Maturation Arrest
    • Authors: Biaobang Chen; Zhihua Zhang; Xiaoxi Sun; Yanping Kuang; Xiaoyan Mao; Xueqian Wang; Zheng Yan; Bin Li; Yao Xu; Min Yu; Jing Fu; Jian Mu; Zhou Zhou; Qiaoli Li; Li Jin; Lin He; Qing Sang; Lei Wang
      Pages: 609 - 615
      Abstract: Publication date: 5 October 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 4
      Author(s): Biaobang Chen, Zhihua Zhang, Xiaoxi Sun, Yanping Kuang, Xiaoyan Mao, Xueqian Wang, Zheng Yan, Bin Li, Yao Xu, Min Yu, Jing Fu, Jian Mu, Zhou Zhou, Qiaoli Li, Li Jin, Lin He, Qing Sang, Lei Wang
      Oocyte maturation arrest results in female infertility, but the genetic determinants of human oocyte maturation arrest remain largely unknown. Previously, we identified TUBB8 mutations responsible for human oocyte maturation arrest, indicating the important role of genetic factors in the disorder. However, TUBB8 mutations account for only around 30% of individuals with oocyte maturation arrest; thus, the disorder is likely to involve other genetic factors that are as yet unknown. Here, we initially identified a homozygous nonsense mutation of PATL2 (c.784C>T [p.Arg262∗]) in a consanguineous family with a phenotype characterized by human oocyte germinal vesicle (GV) arrest. Subsequent mutation screening of PATL2 in a cohort of 179 individuals identified four additional independent individuals with compound-heterozygous PATL2 mutations with slight phenotypic variability. A genetic burden test further confirmed the genetic contribution of PATL2 to human oocyte maturation arrest. By western blot in HeLa cells, identification of splicing events in affected individuals’ granulosa cells, and immunostaining in affected individuals’ oocytes, we provide evidence that mutations in PATL2 lead to decreased amounts of protein. These findings suggest an important role for PATL2 mutations in oocyte maturation arrest and expand our understanding of the genetic basis of female infertility.

      PubDate: 2017-10-29T09:27:30Z
      DOI: 10.1016/j.ajhg.2017.08.018
  • Nested Inversion Polymorphisms Predispose Chromosome 22q11.2 to Meiotic
    • Authors: Wolfram Demaerel; Matthew S. Hestand; Elfi Vergaelen; Ann Swillen; Marcos López-Sánchez; Luis A. Pérez-Jurado; Donna M. McDonald-McGinn; Elaine Zackai; Beverly S. Emanuel; Bernice E. Morrow; Jeroen Breckpot; Koenraad Devriendt; Joris R. Vermeesch; Kevin Antshel; Celso Arango; Marco Armando; Anne Bassett; Carrie Bearden; Erik Boot; Marta Bravo-Sanchez; Elemi Breetvelt; Tiffany Busa; Nancy Butcher; Linda Campbell; Miri Carmel; Eva Chow; T. Blaine Crowley; Joseph Cubells; David Cutler; Wolfram Demaerel; Maria Cristina Digilio; Sasja Duijff; Stephan Eliez; Beverly Emanuel; Michael Epstein; Rens Evers; Luis Fernandez Garcia-Moya; Ania Fiksinski; David Fraguas; Wanda Fremont; Rosemarie Fritsch; Sixto Garcia-Minaur; Aaron Golden; Doron Gothelf; Tingwei Guo; Ruben Gur; Raquel Gur; Damian Heine-Suner; Matthew Hestand; Stephen Hooper; Wendy Kates; Leila Kushan; Alejandra Laorden-Nieto; Johanna Maeder; Bruno Marino; Christian Marshall; Kathryn McCabe; Donna McDonald-McGinn; Elena Michaelovosky; Bernice Morrow; Edward Moss; Jennifer Mulle; Declan Murphy; Kieran Murphy; Clodagh Murphy; Maria Niarchou; Claudia Ornstein; Michael Owen; Nicole Philip; Gabriela Repetto; Maude Schneider; Vandana Shashi; Tony Simon; Ann Swillen; Flora Tassone; Marta Unolt; Therese van Amelsvoort; Marianne van den Bree; Esther Van Duin; Elfi Vergaelen; Joris Vermeesch; Stefano Vicari; Claudia Vingerhoets; Jacob Vorstman; Steve Warren; Ronnie Weinberger; Omri Weisman; Abraham Weizman; Elaine Zackai; Zhengdong Zhang; Michael Zwick
      Pages: 616 - 622
      Abstract: Publication date: 5 October 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 4
      Author(s): Wolfram Demaerel, Matthew S. Hestand, Elfi Vergaelen, Ann Swillen, Marcos López-Sánchez, Luis A. Pérez-Jurado, Donna M. McDonald-McGinn, Elaine Zackai, Beverly S. Emanuel, Bernice E. Morrow, Jeroen Breckpot, Koenraad Devriendt, Joris R. Vermeesch
      Inversion polymorphisms between low-copy repeats (LCRs) might predispose chromosomes to meiotic non-allelic homologous recombination (NAHR) events and thus lead to genomic disorders. However, for the 22q11.2 deletion syndrome (22q11.2DS), the most common genomic disorder, no such inversions have been uncovered as of yet. Using fiber-FISH, we demonstrate that parents transmitting the de novo 3 Mb LCR22A–D 22q11.2 deletion, the reciprocal duplication, and the smaller 1.5 Mb LCR22A–B 22q11.2 deletion carry inversions of LCR22B–D or LCR22C–D. Hence, the inversions predispose chromosome 22q11.2 to meiotic rearrangements and increase the individual risk for transmitting rearrangements. Interestingly, the inversions are nested or flanking rather than coinciding with the deletion or duplication sizes. This finding raises the possibility that inversions are a prerequisite not only for 22q11.2 rearrangements but also for all NAHR-mediated genomic disorders.

      PubDate: 2017-10-29T09:27:30Z
      DOI: 10.1016/j.ajhg.2017.09.002
  • Dominant Mutations in GRM1 Cause Spinocerebellar Ataxia Type 44
    • Authors: Lauren M. Watson; Elizabeth Bamber; Ricardo Parolin Schnekenberg; Jonathan Williams; Conceição Bettencourt; Sandeep Jayawant; Jennifer Lickiss; Katherine Fawcett; Samuel Clokie; Yvonne Wallis; Penny Clouston; David Sims; Henry Houlden; Esther B.E. Becker; Andrea H. Németh
      First page: 638
      Abstract: Publication date: 2 November 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 5
      Author(s): Lauren M. Watson, Elizabeth Bamber, Ricardo Parolin Schnekenberg, Jonathan Williams, Conceição Bettencourt, Jennifer Lickiss, Sandeep Jayawant, Katherine Fawcett, Samuel Clokie, Yvonne Wallis, Penny Clouston, David Sims, Henry Houlden, Esther B.E. Becker, Andrea H. Németh

      PubDate: 2017-11-05T10:27:28Z
      DOI: 10.1016/j.ajhg.2017.09.006
  • This Month in The Journal
    • Authors: Sarah Ratzel; Sara B. Cullinan
      Pages: 691 - 692
      Abstract: Publication date: 7 December 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 6
      Author(s): Sarah Ratzel, Sara B. Cullinan

      PubDate: 2017-12-12T05:02:50Z
      DOI: 10.1016/j.ajhg.2017.04.009
  • This Month in The Journal
    • Authors: Sarah Ratzel; Sara B. Cullinan
      Pages: 691 - 692
      Abstract: Publication date: 5 October 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 4
      Author(s): Sarah Ratzel, Sara B. Cullinan

      PubDate: 2017-10-29T09:27:30Z
      DOI: 10.1016/j.ajhg.2017.04.009
  • This Month in Genetics
    • Authors: Kathryn B. Garber
      Pages: 693 - 694
      Abstract: Publication date: 7 December 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 6
      Author(s): Kathryn B. Garber

      PubDate: 2017-12-12T05:02:50Z
      DOI: 10.1016/j.ajhg.2017.04.006
  • This Month in Genetics
    • Authors: Kathryn B. Garber
      Pages: 693 - 694
      Abstract: Publication date: 5 October 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 4
      Author(s): Kathryn B. Garber

      PubDate: 2017-10-29T09:27:30Z
      DOI: 10.1016/j.ajhg.2017.04.006
  • This Month in The Journal
    • Authors: Sarah Ratzel; Sara B. Cullinan
      Pages: 1 - 2
      Abstract: Publication date: 2 November 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 5
      Author(s): Sarah Ratzel, Sara B. Cullinan

      PubDate: 2017-11-05T10:27:28Z
      DOI: 10.1016/j.ajhg.2016.12.006
  • This Month in Genetics
    • Authors: Kathryn B. Garber
      Pages: 3 - 4
      Abstract: Publication date: 2 November 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 5
      Author(s): Kathryn B. Garber

      PubDate: 2017-11-05T10:27:28Z
      DOI: 10.1016/j.ajhg.2016.12.005
  • A Powerful Approach to Estimating Annotation-Stratified Genetic Covariance
           via GWAS Summary Statistics
    • Authors: Qiongshi Boyang; Derek Margret Erlendsdottir Ryan Powles Tony Jiang Yiming
      Abstract: Publication date: 7 December 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 6
      Author(s): Qiongshi Lu, Boyang Li, Derek Ou, Margret Erlendsdottir, Ryan L. Powles, Tony Jiang, Yiming Hu, David Chang, Chentian Jin, Wei Dai, Qidu He, Zefeng Liu, Shubhabrata Mukherjee, Paul K. Crane, Hongyu Zhao
      Despite the success of large-scale genome-wide association studies (GWASs) on complex traits, our understanding of their genetic architecture is far from complete. Jointly modeling multiple traits’ genetic profiles has provided insights into the shared genetic basis of many complex traits. However, large-scale inference sets a high bar for both statistical power and biological interpretability. Here we introduce a principled framework to estimate annotation-stratified genetic covariance between traits using GWAS summary statistics. Through theoretical and numerical analyses, we demonstrate that our method provides accurate covariance estimates, thereby enabling researchers to dissect both the shared and distinct genetic architecture across traits to better understand their etiologies. Among 50 complex traits with publicly accessible GWAS summary statistics (Ntotal ≈ 4.5 million), we identified more than 170 pairs with statistically significant genetic covariance. In particular, we found strong genetic covariance between late-onset Alzheimer disease (LOAD) and amyotrophic lateral sclerosis (ALS), two major neurodegenerative diseases, in single-nucleotide polymorphisms (SNPs) with high minor allele frequencies and in SNPs located in the predicted functional genome. Joint analysis of LOAD, ALS, and other traits highlights LOAD’s correlation with cognitive traits and hints at an autoimmune component for ALS.

      PubDate: 2017-12-12T05:02:50Z
  • Mutations in TUBB4B Cause a Distinctive Sensorineural Disease
    • Authors: Romain Luscan; Sabrina Mechaussier; Antoine Paul; Guoling Tian; Xavier Gérard; Sabine Defoort-Dellhemmes; Natalie Loundon; Isabelle Audo; Sophie Bonnin; Jean-François LeGargasson; Julien Dumont; Nicolas Goudin; Meriem Garfa-Traoré; Marc Bras; Aurore Pouliet; Bettina Bessières; Nathalie Boddaert; José-Alain Sahel; Stanislas Lyonnet; Josseline Kaplan; Nicholas J. Cowan; Jean-Michel Rozet; Sandrine Marlin; Isabelle Perrault
      Abstract: Publication date: Available online 30 November 2017
      Source:The American Journal of Human Genetics
      Author(s): Romain Luscan, Sabrina Mechaussier, Antoine Paul, Guoling Tian, Xavier Gérard, Sabine Defoort-Dellhemmes, Natalie Loundon, Isabelle Audo, Sophie Bonnin, Jean-François LeGargasson, Julien Dumont, Nicolas Goudin, Meriem Garfa-Traoré, Marc Bras, Aurore Pouliet, Bettina Bessières, Nathalie Boddaert, José-Alain Sahel, Stanislas Lyonnet, Josseline Kaplan, Nicholas J. Cowan, Jean-Michel Rozet, Sandrine Marlin, Isabelle Perrault
      Leber congenital amaurosis (LCA) is a neurodegenerative disease of photoreceptor cells that causes blindness within the first year of life. It occasionally occurs in syndromic metabolic diseases and plurisystemic ciliopathies. Using exome sequencing in a multiplex family and three simplex case subjects with an atypical association of LCA with early-onset hearing loss, we identified two heterozygous mutations affecting Arg391 in β-tubulin 4B isotype-encoding (TUBB4B). Inspection of the atomic structure of the microtubule (MT) protofilament reveals that the β-tubulin Arg391 residue contributes to a binding pocket that interacts with α-tubulin contained in the longitudinally adjacent αβ-heterodimer, consistent with a role in maintaining MT stability. Functional analysis in cultured cells overexpressing FLAG-tagged wild-type or mutant TUBB4B as well as in primary skin-derived fibroblasts showed that the mutant TUBB4B is able to fold, form αβ-heterodimers, and co-assemble into the endogenous MT lattice. However, the dynamics of growing MTs were consistently altered, showing that the mutations have a significant dampening impact on normal MT growth. Our findings provide a link between sensorineural disease and anomalies in MT behavior and describe a syndromic LCA unrelated to ciliary dysfunction.

      PubDate: 2017-12-01T04:54:22Z
      DOI: 10.1016/j.ajhg.2017.10.010
  • A Recurrent De Novo Nonsense Variant in ZSWIM6 Results in Severe
           Intellectual Disability without Frontonasal or Limb Malformations
    • Authors: Elizabeth E. Palmer; Raman Kumar; Christopher T. Gordon; Marie Shaw; Laurence Hubert; Renee Carroll; Marlène Rio; Lucinda Murray; Melanie Leffler; Tracy Dudding-Byth; Myriam Oufadem; Seema R. Lalani; Andrea M. Lewis; Fan Xia; Allison Tam; Richard Webster; Susan Brammah; Francesca Filippini; John Pollard; Judy Spies; Andre E. Minoche; Mark J. Cowley; Sarah Risen; Nina N. Powell-Hamilton; Jessica E. Tusi; LaDonna Immken; Honey Nagakura; Christine Bole-Feysot; Patrick Nitschké; Alexandrine Garrigue; Geneviève de Saint Basile; Emma Kivuva; Richard H. Scott; Augusto Rendon; Arnold Munnich; William Newman; Bronwyn Kerr; Claude Besmond; Jill A. Rosenfeld; Jeanne Amiel; Michael Field; Jozef Gecz
      Abstract: Publication date: Available online 30 November 2017
      Source:The American Journal of Human Genetics
      Author(s): Elizabeth E. Palmer, Raman Kumar, Christopher T. Gordon, Marie Shaw, Laurence Hubert, Renee Carroll, Marlène Rio, Lucinda Murray, Melanie Leffler, Tracy Dudding-Byth, Myriam Oufadem, Seema R. Lalani, Andrea M. Lewis, Fan Xia, Allison Tam, Richard Webster, Susan Brammah, Francesca Filippini, John Pollard, Judy Spies, Andre E. Minoche, Mark J. Cowley, Sarah Risen, Nina N. Powell-Hamilton, Jessica E. Tusi, LaDonna Immken, Honey Nagakura, Christine Bole-Feysot, Patrick Nitschké, Alexandrine Garrigue, Geneviève de Saint Basile, Emma Kivuva, Richard H. Scott, Augusto Rendon, Arnold Munnich, William Newman, Bronwyn Kerr, Claude Besmond, Jill A. Rosenfeld, Jeanne Amiel, Michael Field, Jozef Gecz
      A recurrent de novo missense variant within the C-terminal Sin3-like domain of ZSWIM6 was previously reported to cause acromelic frontonasal dysostosis (AFND), an autosomal-dominant severe frontonasal and limb malformation syndrome, associated with neurocognitive and motor delay, via a proposed gain-of-function effect. We present detailed phenotypic information on seven unrelated individuals with a recurrent de novo nonsense variant (c.2737C>T [p.Arg913Ter]) in the penultimate exon of ZSWIM6 who have severe-profound intellectual disability and additional central and peripheral nervous system symptoms but an absence of frontonasal or limb malformations. We show that the c.2737C>T variant does not trigger nonsense-mediated decay of the ZSWIM6 mRNA in affected individual-derived cells. This finding supports the existence of a truncated ZSWIM6 protein lacking the Sin3-like domain, which could have a dominant-negative effect. This study builds support for a key role for ZSWIM6 in neuronal development and function, in addition to its putative roles in limb and craniofacial development, and provides a striking example of different variants in the same gene leading to distinct phenotypes.

      PubDate: 2017-12-01T04:54:22Z
      DOI: 10.1016/j.ajhg.2017.10.009
  • DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation
    • Authors: Melissa A. Richard; Tianxiao Huan; Symen Ligthart; Rahul Gondalia; Min A. Jhun; Jennifer A. Brody; Marguerite R. Irvin; Riccardo Marioni; Jincheng Shen; Pei-Chien Tsai; May E. Montasser; Yucheng Jia; Catriona Syme; Elias L. Salfati; Eric Boerwinkle; Weihua Guan; Thomas H. Mosley; Jan Bressler; Alanna C. Morrison; Chunyu Liu; Michael M. Mendelson; André G. Uitterlinden; Joyce B. van Meurs; Oscar H. Franco; Guosheng Zhang; Yun Li; James D. Stewart; Joshua C. Bis; Bruce M. Psaty; Yii-Der Ida Chen; Sharon L.R. Kardia; Wei Zhao; Stephen T. Turner; Devin Absher; Stella Aslibekyan; John M. Starr; Allan F. McRae; Lifang Hou; Allan C. Just; Joel D. Schwartz; Pantel S. Vokonas; Cristina Menni; Tim D. Spector; Alan Shuldiner; Coleen M. Damcott; Jerome I. Rotter; Walter Palmas; Yongmei Liu; Tomáš Paus; Steve Horvath; Jeffrey R. O’Connell; Xiuqing Guo; Zdenka Pausova; Themistocles L. Assimes; Nona Sotoodehnia; Jennifer A. Smith; Donna K. Arnett; Ian J. Deary; Andrea A. Baccarelli; Jordana T. Bell; Eric Whitsel; Abbas Dehghan; Daniel Levy; Myriam Fornage; Bastiaan T. Heijmans; Peter A.C. ’t Hoen; Joyce van Meurs; Aaron Isaacs; Rick Jansen; Lude Franke; Dorret I. Boomsma; René Pool; Jenny van Dongen; Jouke J. Hottenga; Marleen M.J. van Greevenbroek; Coen D.A. Stehouwer; Carla J.H. van der Kallen; Casper G. Schalkwijk; Cisca Wijmenga; Alexandra Zhernakova; Ettje F. Tigchelaar; P. Eline Slagboom; Marian Beekman; Joris Deelen; Diana van Heemst; Jan H. Veldink; Leonard H. van den Berg; Cornelia M. van Duijn; Albert Hofman; André G. Uitterlinden; P. Mila Jhamai; Michael Verbiest; H. Eka D. Suchiman; Marijn Verkerk; Ruud van der Breggen; Jeroen van Rooij; Nico Lakenberg; Hailiang Mei; Maarten van Iterson; Michiel van Galen; Jan Bot; Peter van ’t Hof; Patrick Deelen; Irene Nooren; Matthijs Moed; Martijn Vermaat; Dasha V. Zhernakova; René Luijk; Marc Jan Bonder; Freerk van Dijk; Wibowo Arindrarto; Szymon M. Kielbasa; Morris A. Swertz; Erik W. van Zwet
      Abstract: Publication date: Available online 30 November 2017
      Source:The American Journal of Human Genetics
      Author(s): Melissa A. Richard, Tianxiao Huan, Symen Ligthart, Rahul Gondalia, Min A. Jhun, Jennifer A. Brody, Marguerite R. Irvin, Riccardo Marioni, Jincheng Shen, Pei-Chien Tsai, May E. Montasser, Yucheng Jia, Catriona Syme, Elias L. Salfati, Eric Boerwinkle, Weihua Guan, Thomas H. Mosley, Jan Bressler, Alanna C. Morrison, Chunyu Liu, Michael M. Mendelson, André G. Uitterlinden, Joyce B. van Meurs, Oscar H. Franco, Guosheng Zhang, Yun Li, James D. Stewart, Joshua C. Bis, Bruce M. Psaty, Yii-Der Ida Chen, Sharon L.R. Kardia, Wei Zhao, Stephen T. Turner, Devin Absher, Stella Aslibekyan, John M. Starr, Allan F. McRae, Lifang Hou, Allan C. Just, Joel D. Schwartz, Pantel S. Vokonas, Cristina Menni, Tim D. Spector, Alan Shuldiner, Coleen M. Damcott, Jerome I. Rotter, Walter Palmas, Yongmei Liu, Tomáš Paus, Steve Horvath, Jeffrey R. O’Connell, Xiuqing Guo, Zdenka Pausova, Themistocles L. Assimes, Nona Sotoodehnia, Jennifer A. Smith, Donna K. Arnett, Ian J. Deary, Andrea A. Baccarelli, Jordana T. Bell, Eric Whitsel, Abbas Dehghan, Daniel Levy, Myriam Fornage
      Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10−7; replication: N = 7,182, p < 1.6 × 10−3). The replicated methylation sites are heritable (h2 > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.

      PubDate: 2017-12-01T04:54:22Z
      DOI: 10.1016/j.ajhg.2017.09.028
  • Multiethnic GWAS Reveals Polygenic Architecture of Earlobe Attachment
    • Authors: John R. Shaffer; Jinxi Li; Myoung Keun Lee; Jasmien Roosenboom; Ekaterina Orlova; Kaustabh Adhikari; Carla Gallo; Giovanni Poletti; Lavinia Schuler-Faccini; Maria-Cátira Bortolini; Samuel Canizales-Quinteros; Francisco Rothhammer; Gabriel Bedoya; Rolando González-José; Paige E. Pfeffer; Christopher A. Wollenschlaeger; Jacqueline T. Hecht; George L. Wehby; Lina M. Moreno; Anan Ding; Li Jin; Yajun Yang; Jenna C. Carlson; Elizabeth J. Leslie; Eleanor Feingold; Mary L. Marazita; David A. Hinds; Timothy C. Cox; Sijia Wang; Andrés Ruiz-Linares; Seth M. Weinberg; Michelle Agee; Babak Alipanahi; Adam Auton; Robert K. Bell; Katarzyna Bryc; Sarah L. Elson; Pierre Fontanillas; Nicholas A. Furlotte; David A. Hinds; Bethann S. Hromatka; Karen E. Huber; Aaron Kleinman; Nadia K. Litterman; Matthew H. McIntyre; Joanna L. Mountain; Elizabeth S. Noblin; Carrie A.M. Northover; Steven J. Pitts; J. Fah Sathirapongsasuti; Olga V. Sazonova; Janie F. Shelton; Suyash Shringarpure; Chao Tian; Joyce Y. Tung; Vladimir Vacic; Catherine H. Wilson
      Abstract: Publication date: Available online 30 November 2017
      Source:The American Journal of Human Genetics
      Author(s): John R. Shaffer, Jinxi Li, Myoung Keun Lee, Jasmien Roosenboom, Ekaterina Orlova, Kaustabh Adhikari, Carla Gallo, Giovanni Poletti, Lavinia Schuler-Faccini, Maria-Cátira Bortolini, Samuel Canizales-Quinteros, Francisco Rothhammer, Gabriel Bedoya, Rolando González-José, Paige E. Pfeffer, Christopher A. Wollenschlaeger, Jacqueline T. Hecht, George L. Wehby, Lina M. Moreno, Anan Ding, Li Jin, Yajun Yang, Jenna C. Carlson, Elizabeth J. Leslie, Eleanor Feingold, Mary L. Marazita, David A. Hinds, Timothy C. Cox, Sijia Wang, Andrés Ruiz-Linares, Seth M. Weinberg
      The genetic basis of earlobe attachment has been a matter of debate since the early 20th century, such that geneticists argue both for and against polygenic inheritance. Recent genetic studies have identified a few loci associated with the trait, but large-scale analyses are still lacking. Here, we performed a genome-wide association study of lobe attachment in a multiethnic sample of 74,660 individuals from four cohorts (three with the trait scored by an expert rater and one with the trait self-reported). Meta-analysis of the three expert-rater-scored cohorts revealed six associated loci harboring numerous candidate genes, including EDAR, SP5, MRPS22, ADGRG6 (GPR126), KIAA1217, and PAX9. The large self-reported 23andMe cohort recapitulated each of these six loci. Moreover, meta-analysis across all four cohorts revealed a total of 49 significant (p < 5 × 10−8) loci. Annotation and enrichment analyses of these 49 loci showed strong evidence of genes involved in ear development and syndromes with auricular phenotypes. RNA sequencing data from both human fetal ear and mouse second branchial arch tissue confirmed that genes located among associated loci showed evidence of expression. These results provide strong evidence for the polygenic nature of earlobe attachment and offer insights into the biological basis of normal and abnormal ear development.

      PubDate: 2017-12-01T04:54:22Z
      DOI: 10.1016/j.ajhg.2017.10.001
  • Monoallelic BMP2 Variants Predicted to Result in Haploinsufficiency Cause
           Craniofacial, Skeletal, and Cardiac Features Overlapping Those of 20p12
    • Authors: Tiong Yang Tan; Claudia Gonzaga-Jauregui; Elizabeth J. Bhoj; Kevin A. Strauss; Karlla Brigatti; Erik Puffenberger; Dong Li; LiQin Xie; Nanditha Das; Ioanna Skubas; Ron A. Deckelbaum; Virginia Hughes; Susannah Brydges; Sarah Hatsell; Chia-Jen Siao; Melissa G. Dominguez; Aris Economides; John D. Overton; Valerie Mayne; Peter J. Simm; Bryn O. Jones; Stefanie Eggers; Gwenaël Le Guyader; Fanny Pelluard; Tobias B. Haack; Marc Sturm; Angelika Riess; Stephan Waldmueller; Michael Hofbeck; Katharina Steindl; Pascal Joset; Anita Rauch; Hakon Hakonarson; Naomi L. Baker; Peter G. Farlie
      Abstract: Publication date: Available online 30 November 2017
      Source:The American Journal of Human Genetics
      Author(s): Tiong Yang Tan, Claudia Gonzaga-Jauregui, Elizabeth J. Bhoj, Kevin A. Strauss, Karlla Brigatti, Erik Puffenberger, Dong Li, LiQin Xie, Nanditha Das, Ioanna Skubas, Ron A. Deckelbaum, Virginia Hughes, Susannah Brydges, Sarah Hatsell, Chia-Jen Siao, Melissa G. Dominguez, Aris Economides, John D. Overton, Valerie Mayne, Peter J. Simm, Bryn O. Jones, Stefanie Eggers, Gwenaël Le Guyader, Fanny Pelluard, Tobias B. Haack, Marc Sturm, Angelika Riess, Stephan Waldmueller, Michael Hofbeck, Katharina Steindl, Pascal Joset, Anita Rauch, Hakon Hakonarson, Naomi L. Baker, Peter G. Farlie
      Bone morphogenetic protein 2 (BMP2) in chromosomal region 20p12 belongs to a gene superfamily encoding TGF-β-signaling proteins involved in bone and cartilage biology. Monoallelic deletions of 20p12 are variably associated with cleft palate, short stature, and developmental delay. Here, we report a cranioskeletal phenotype due to monoallelic truncating and frameshift BMP2 variants and deletions in 12 individuals from eight unrelated families that share features of short stature, a recognizable craniofacial gestalt, skeletal anomalies, and congenital heart disease. De novo occurrence and autosomal-dominant inheritance of variants, including paternal mosaicism in two affected sisters who inherited a BMP2 splice-altering variant, were observed across all reported families. Additionally, we observed similarity to the human phenotype of short stature and skeletal anomalies in a heterozygous Bmp2-knockout mouse model, suggesting that haploinsufficiency of BMP2 could be the primary phenotypic determinant in individuals with predicted truncating variants and deletions encompassing BMP2. These findings demonstrate the important role of BMP2 in human craniofacial, skeletal, and cardiac development and confirm that individuals heterozygous for BMP2 truncating sequence variants or deletions display a consistent distinct phenotype characterized by short stature and skeletal and cardiac anomalies without neurological deficits.

      PubDate: 2017-12-01T04:54:22Z
      DOI: 10.1016/j.ajhg.2017.10.006
  • The Genetic Legacy of the Indian Ocean Slave Trade: Recent Admixture and
           Post-admixture Selection in the Makranis of Pakistan
    • Authors: Romuald Laso-Jadart; Christine Harmant; Hélène Quach; Nora Zidane; Chris Tyler-Smith; Qasim Mehdi; Qasim Ayub; Lluis Quintana-Murci; Etienne Patin
      Abstract: Publication date: Available online 9 November 2017
      Source:The American Journal of Human Genetics
      Author(s): Romuald Laso-Jadart, Christine Harmant, Hélène Quach, Nora Zidane, Chris Tyler-Smith, Qasim Mehdi, Qasim Ayub, Lluis Quintana-Murci, Etienne Patin
      From the eighth century onward, the Indian Ocean was the scene of extensive trade of sub-Saharan African slaves via sea routes controlled by Muslim Arab and Swahili traders. Several populations in present-day Pakistan and India are thought to be the descendants of such slaves, yet their history of admixture and natural selection remains largely undefined. Here, we studied the genome-wide diversity of the African-descent Makranis, who reside on the Arabian Sea coast of Pakistan, as well that of four neighboring Pakistani populations, to investigate the genetic legacy, population dynamics, and tempo of the Indian Ocean slave trade. We show that the Makranis are the result of an admixture event between local Baluch tribes and Bantu-speaking populations from eastern or southeastern Africa; we dated this event to ∼300 years ago during the Omani Empire domination. Levels of parental relatedness, measured through runs of homozygosity, were found to be similar across Pakistani populations, suggesting that the Makranis rapidly adopted the traditional practice of endogamous marriages. Finally, we searched for signatures of post-admixture selection at traits evolving under positive selection, including skin color, lactase persistence, and resistance to malaria. We demonstrate that the African-specific Duffy-null blood group—believed to confer resistance against Plasmodium vivax infection—was recently introduced to Pakistan through the slave trade and evolved adaptively in this P. vivax malaria-endemic region. Our study reconstructs the genetic and adaptive history of a neglected episode of the African Diaspora and illustrates the impact of recent admixture on the diffusion of adaptive traits across human populations.

      PubDate: 2017-11-11T11:09:35Z
      DOI: 10.1016/j.ajhg.2017.09.025
  • Functional Consequences of CHRNA7 Copy-Number Alterations in Induced
           Pluripotent Stem Cells and Neural Progenitor Cells
    • Authors: Madelyn A. Gillentine; Jiani Yin; Aleksandar Bajic; Ping Zhang; Steven Cummock; Jean J. Kim; Christian P. Schaaf
      Abstract: Publication date: Available online 9 November 2017
      Source:The American Journal of Human Genetics
      Author(s): Madelyn A. Gillentine, Jiani Yin, Aleksandar Bajic, Ping Zhang, Steven Cummock, Jean J. Kim, Christian P. Schaaf
      Copy-number variants (CNVs) of chromosome 15q13.3 manifest clinically as neuropsychiatric disorders with variable expressivity. CHRNA7, encoding for the α7 nicotinic acetylcholine receptor (nAChR), has been suggested as a candidate gene for the phenotypes observed. Here, we used induced pluripotent stem cells (iPSCs) and neural progenitor cells (NPCs) derived from individuals with heterozygous 15q13.3 deletions and heterozygous 15q13.3 duplications to investigate the CHRNA7-dependent molecular consequences of the respective CNVs. Unexpectedly, both deletions and duplications lead to decreased α7 nAChR-associated calcium flux. For deletions, this decrease in α7 nAChR-dependent calcium flux is expected due to haploinsufficiency of CHRNA7. For duplications, we found that increased expression of CHRNA7 mRNA is associated with higher expression of nAChR-specific and resident ER chaperones, indicating increased ER stress. This is likely a consequence of inefficient chaperoning and accumulation of α7 subunits in the ER, as opposed to being incorporated into functional α7 nAChRs at the cell membrane. Here, we showed that α7 nAChR-dependent calcium signal cascades are downregulated in both 15q13.3 deletion and duplication NPCs. While it may seem surprising that genomic changes in opposite direction have consequences on downstream pathways that are in similar direction, it aligns with clinical data, which suggest that both individuals with deletions and duplications of 15q13.3 manifest neuropsychiatric disease and cognitive deficits.

      PubDate: 2017-11-11T11:09:35Z
      DOI: 10.1016/j.ajhg.2017.09.024
  • High Rate of Recurrent De Novo Mutations in Developmental and Epileptic
    • Authors: Fadi Hamdan; Candace Myers Patrick Cossette Philippe Lemay Dan Spiegelman
      Abstract: Publication date: 2 November 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 5
      Author(s): Fadi F. Hamdan, Candace T. Myers, Patrick Cossette, Philippe Lemay, Dan Spiegelman, Alexandre Dionne Laporte, Christina Nassif, Ousmane Diallo, Jean Monlong, Maxime Cadieux-Dion, Sylvia Dobrzeniecka, Caroline Meloche, Kyle Retterer, Megan T. Cho, Jill A. Rosenfeld, Weimin Bi, Christine Massicotte, Marguerite Miguet, Ledia Brunga, Brigid M. Regan, Kelly Mo, Cory Tam, Amy Schneider, Georgie Hollingsworth, David R. FitzPatrick, Alan Donaldson, Natalie Canham, Edward Blair, Bronwyn Kerr, Andrew E. Fry, Rhys H. Thomas, Joss Shelagh, Jane A. Hurst, Helen Brittain, Moira Blyth, Robert Roger Lebel, Erica H. Gerkes, Laura Davis-Keppen, Quinn Stein, Wendy K. Chung, Sara J. Dorison, Paul J. Benke, Emily Fassi, Nicole Corsten-Janssen, Erik-Jan Kamsteeg, Frederic T. Mau-Them, Ange-Line Bruel, Alain Verloes, Katrin Õunap, Monica H. Wojcik, Dara V.F. Albert, Sunita Venkateswaran, Tyson Ware, Dean Jones, Yu-Chi Liu, Shekeeb S. Mohammad, Peyman Bizargity, Carlos A. Bacino, Vincenzo Leuzzi, Simone Martinelli, Bruno Dallapiccola, Marco Tartaglia, Lubov Blumkin, Klaas J. Wierenga, Gabriela Purcarin, James J. O’Byrne, Sylvia Stockler, Anna Lehman, Boris Keren, Marie-Christine Nougues, Cyril Mignot, Stéphane Auvin, Caroline Nava, Susan M. Hiatt, Martina Bebin, Yunru Shao, Fernando Scaglia, Seema R. Lalani, Richard E. Frye, Imad T. Jarjour, Stéphanie Jacques, Renee-Myriam Boucher, Emilie Riou, Myriam Srour, Lionel Carmant, Anne Lortie, Philippe Major, Paola Diadori, François Dubeau, Guy D’Anjou, Guillaume Bourque, Samuel F. Berkovic, Lynette G. Sadleir, Philippe M. Campeau, Zoha Kibar, Ronald G. Lafrenière, Simon L. Girard, Saadet Mercimek-Mahmutoglu, Cyrus Boelman, Guy A. Rouleau, Ingrid E. Scheffer, Heather C. Mefford, Danielle M. Andrade, Elsa Rossignol, Berge A. Minassian, Jacques L. Michaud
      Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy.

      PubDate: 2017-11-05T10:27:28Z
  • Recurrent De Novo Mutations Disturbing the GTP/GDP Binding Pocket of
           RAB11B Cause Intellectual Disability and a Distinctive Brain Phenotype
    • Authors: Ideke J.C. Lamers; Margot R.F. Reijnders; Hanka Venselaar; Alison Kraus; Sandra Jansen; Bert B.A. de Vries; Gunnar Houge; Gyri Aasland Gradek; Jieun Seo; Murim Choi; Jong-Hee Chae; Ineke van der Burgt; Rolph Pfundt; Stef J.F. Letteboer; Sylvia E.C. van Beersum; Simone Dusseljee; Han G. Brunner; Dan Doherty; Tjitske Kleefstra; Ronald Roepman
      Abstract: Publication date: Available online 26 October 2017
      Source:The American Journal of Human Genetics
      Author(s): Ideke J.C. Lamers, Margot R.F. Reijnders, Hanka Venselaar, Alison Kraus, Sandra Jansen, Bert B.A. de Vries, Gunnar Houge, Gyri Aasland Gradek, Jieun Seo, Murim Choi, Jong-Hee Chae, Ineke van der Burgt, Rolph Pfundt, Stef J.F. Letteboer, Sylvia E.C. van Beersum, Simone Dusseljee, Han G. Brunner, Dan Doherty, Tjitske Kleefstra, Ronald Roepman
      The Rab GTPase family comprises ∼70 GTP-binding proteins, functioning in vesicle formation, transport and fusion. They are activated by a conformational change induced by GTP-binding, allowing interactions with downstream effectors. Here, we report five individuals with two recurrent de novo missense mutations in RAB11B; c.64G>A; p.Val22Met in three individuals and c.202G>A; p.Ala68Thr in two individuals. An overlapping neurodevelopmental phenotype, including severe intellectual disability with absent speech, epilepsy, and hypotonia was observed in all affected individuals. Additionally, visual problems, musculoskeletal abnormalities, and microcephaly were present in the majority of cases. Re-evaluation of brain MRI images of four individuals showed a shared distinct brain phenotype, consisting of abnormal white matter (severely decreased volume and abnormal signal), thin corpus callosum, cerebellar vermis hypoplasia, optic nerve hypoplasia and mild ventriculomegaly. To compare the effects of both variants with known inactive GDP- and active GTP-bound RAB11B mutants, we modeled the variants on the three-dimensional protein structure and performed subcellular localization studies. We predicted that both variants alter the GTP/GDP binding pocket and show that they both have localization patterns similar to inactive RAB11B. Evaluation of their influence on the affinity of RAB11B to a series of binary interactors, both effectors and guanine nucleotide exchange factors (GEFs), showed induction of RAB11B binding to the GEF SH3BP5, again similar to inactive RAB11B. In conclusion, we report two recurrent dominant mutations in RAB11B leading to a neurodevelopmental syndrome, likely caused by altered GDP/GTP binding that inactivate the protein and induce GEF binding and protein mislocalization.

      PubDate: 2017-10-29T09:27:30Z
      DOI: 10.1016/j.ajhg.2017.09.015
  • Inferring Relevant Cell Types for Complex Traits by Using Single-Cell Gene
    • Authors: Diego Calderon; Anand Bhaskar David Knowles David Golan Towfique Raj
      Abstract: Publication date: Available online 26 October 2017
      Source:The American Journal of Human Genetics
      Author(s): Diego Calderon, Anand Bhaskar, David A. Knowles, David Golan, Towfique Raj, Audrey Q. Fu, Jonathan K. Pritchard
      Previous studies have prioritized trait-relevant cell types by looking for an enrichment of genome-wide association study (GWAS) signal within functional regions. However, these studies are limited in cell resolution by the lack of functional annotations from difficult-to-characterize or rare cell populations. Measurement of single-cell gene expression has become a popular method for characterizing novel cell types, and yet limited work has linked single-cell RNA sequencing (RNA-seq) to phenotypes of interest. To address this deficiency, we present RolyPoly, a regression-based polygenic model that can prioritize trait-relevant cell types and genes from GWAS summary statistics and gene expression data. RolyPoly is designed to use expression data from either bulk tissue or single-cell RNA-seq. In this study, we demonstrated RolyPoly’s accuracy through simulation and validated previously known tissue-trait associations. We discovered a significant association between microglia and late-onset Alzheimer disease and an association between schizophrenia and oligodendrocytes and replicating fetal cortical cells. Additionally, RolyPoly computes a trait-relevance score for each gene to reflect the importance of expression specific to a cell type. We found that differentially expressed genes in the prefrontal cortex of individuals with Alzheimer disease were significantly enriched with genes ranked highly by RolyPoly gene scores. Overall, our method represents a powerful framework for understanding the effect of common variants on cell types contributing to complex traits.

      PubDate: 2017-10-29T09:27:30Z
  • A Dementia-Associated Risk Variant near TMEM106B Alters Chromatin
           Architecture and Gene Expression
    • Authors: Michael Gallagher; Marijan Posavi Peng Huang Travis Unger Yosef Berlyand
      Abstract: Publication date: Available online 19 October 2017
      Source:The American Journal of Human Genetics
      Author(s): Michael D. Gallagher, Marijan Posavi, Peng Huang, Travis L. Unger, Yosef Berlyand, Analise L. Gruenewald, Alessandra Chesi, Elisabetta Manduchi, Andrew D. Wells, Struan F.A. Grant, Gerd A. Blobel, Christopher D. Brown, Alice S. Chen-Plotkin
      Neurodegenerative diseases pose an extraordinary threat to the world’s aging population, yet no disease-modifying therapies are available. Although genome-wide association studies (GWASs) have identified hundreds of risk loci for neurodegeneration, the mechanisms by which these loci influence disease risk are largely unknown. Here, we investigated the association between common genetic variants at the 7p21 locus and risk of the neurodegenerative disease frontotemporal lobar degeneration. We showed that variants associated with disease risk correlate with increased expression of the 7p21 gene TMEM106B and no other genes; co-localization analyses implicated a common causal variant underlying both association with disease and association with TMEM106B expression in lymphoblastoid cell lines and human brain. Furthermore, increases in the amount of TMEM106B resulted in increases in abnormal lysosomal phenotypes and cell toxicity in both immortalized cell lines and neurons. We then combined fine-mapping, bioinformatics, and bench-based approaches to functionally characterize all candidate causal variants at this locus. This approach identified a noncoding variant, rs1990620, that differentially recruits CTCF in lymphoblastoid cell lines and human brain to influence CTCF-mediated long-range chromatin-looping interactions between multiple cis-regulatory elements, including the TMEM106B promoter. Our findings thus provide an in-depth analysis of the 7p21 locus linked by GWASs to frontotemporal lobar degeneration, nominating a causal variant and causal mechanism for allele-specific expression and disease association at this locus. Finally, we show that genetic variants associated with risk of neurodegenerative diseases beyond frontotemporal lobar degeneration are enriched in CTCF-binding sites found in brain-relevant tissues, implicating CTCF-mediated gene regulation in risk of neurodegeneration more generally.

      PubDate: 2017-10-29T09:27:30Z
  • Mendelian Randomization Analysis Identifies CpG Sites as Putative
           Mediators for Genetic Influences on Cardiovascular Disease Risk
    • Authors: Tom Richardson; Jie Zheng George Davey Smith Nicholas Timpson Tom
      Abstract: Publication date: 5 October 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 4
      Author(s): Tom G. Richardson, Jie Zheng, George Davey Smith, Nicholas J. Timpson, Tom R. Gaunt, Caroline L. Relton, Gibran Hemani
      The extent to which genetic influences on cardiovascular disease risk are mediated by changes in DNA methylation levels has not been systematically explored. We developed an analytical framework that integrates genetic fine mapping and Mendelian randomization with epigenome-wide association studies to evaluate the causal relationships between methylation levels and 14 cardiovascular disease traits. We identified ten genetic loci known to influence proximal DNA methylation which were also associated with cardiovascular traits after multiple-testing correction. Bivariate fine mapping provided evidence that the individual variants responsible for the observed effects on cardiovascular traits at the ADCY3 and ADIPOQ loci were potentially mediated through changes in DNA methylation, although we highlight that we are unable to reliably separate causality from horizontal pleiotropy. Estimates of causal effects were replicated with results from large-scale consortia. Genetic variants and CpG sites identified in this study were enriched for histone mark peaks in relevant tissue types and gene promoter regions. Integrating our results with expression quantitative trait loci data, we provide evidence that variation at these regulatory regions is likely to also influence gene expression levels at these loci.

      PubDate: 2017-10-29T09:27:30Z
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