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Publisher: Elsevier   (Total: 3042 journals)

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Showing 1 - 200 of 3042 Journals sorted alphabetically
AASRI Procedia     Open Access   (Followers: 15)
Academic Pediatrics     Hybrid Journal   (Followers: 19, SJR: 1.402, h-index: 51)
Academic Radiology     Hybrid Journal   (Followers: 16, SJR: 1.008, h-index: 75)
Accident Analysis & Prevention     Partially Free   (Followers: 81, SJR: 1.109, h-index: 94)
Accounting Forum     Hybrid Journal   (Followers: 23, SJR: 0.612, h-index: 27)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 27, 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: 328, 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  
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: 205, 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: 9, 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: 2)
Acta Poética     Open Access   (Followers: 4)
Acta Psychologica     Hybrid Journal   (Followers: 22, SJR: 1.365, h-index: 73)
Acta Sociológica     Open Access  
Acta Tropica     Hybrid Journal   (Followers: 5, 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)
Actas Urológicas Españolas (English Edition)     Full-text available via subscription   (Followers: 2)
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: 3)
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: 5)
Additive Manufacturing     Hybrid Journal   (Followers: 7, SJR: 1.039, h-index: 5)
Additives for Polymers     Full-text available via subscription   (Followers: 20)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 124, 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: 16, 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: 25, 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: 10, SJR: 0.801, h-index: 26)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 21, 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 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: 24, 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: 8, SJR: 1.268, h-index: 45)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 28, 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 Developmental Biology     Full-text available via subscription   (Followers: 11)
Advances in Digestive Medicine     Open Access   (Followers: 4)
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: 39, SJR: 3.25, h-index: 43)
Advances in Engineering Software     Hybrid Journal   (Followers: 25, 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: 40, 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: 45, SJR: 0.674, h-index: 38)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 14)
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: 12)
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: 20, SJR: 0.906, h-index: 24)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 0.497, h-index: 31)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 24)
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: 34, 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: 4)
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: 5, 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: 7, 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 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: 21, 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: 7, 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: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 19, SJR: 1.5, h-index: 62)
Advances in Psychology     Full-text available via subscription   (Followers: 58)
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 Research     Full-text available via subscription   (Followers: 339, 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: 6, SJR: 0.823, h-index: 27)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 29, SJR: 1.321, h-index: 56)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 15)
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: 43, 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: 308, 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: 7, SJR: 3.289, h-index: 78)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 422, SJR: 1.385, h-index: 72)
Agri Gene     Hybrid Journal  
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 15, SJR: 2.18, h-index: 116)
Agricultural Systems     Hybrid Journal   (Followers: 30, SJR: 1.275, h-index: 74)
Agricultural Water Management     Hybrid Journal   (Followers: 38, SJR: 1.546, h-index: 79)
Agriculture and Agricultural Science Procedia     Open Access  
Agriculture and Natural Resources     Open Access   (Followers: 1)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 50, 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: 10, SJR: 0.922, h-index: 66)
Alcoholism and Drug Addiction     Open Access   (Followers: 6)
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  
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: 5, SJR: 0.776, h-index: 35)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 6, 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: 5)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 3)
American Heart J.     Hybrid Journal   (Followers: 47, SJR: 3.157, h-index: 153)
American J. of Cardiology     Hybrid Journal   (Followers: 44, SJR: 2.063, h-index: 186)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 34, SJR: 0.574, h-index: 65)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 6, SJR: 1.091, h-index: 45)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 15, SJR: 1.653, h-index: 93)
American J. of Human Genetics     Hybrid Journal   (Followers: 30, SJR: 8.769, h-index: 256)
American J. of Infection Control     Hybrid Journal   (Followers: 24, 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: 44, 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: 179, SJR: 2.255, h-index: 171)
American J. of Ophthalmology     Hybrid Journal   (Followers: 54, SJR: 2.803, h-index: 148)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 2)
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: 23, SJR: 0.59, h-index: 45)
American J. of Pathology     Hybrid Journal   (Followers: 23, SJR: 2.653, h-index: 228)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 21, SJR: 2.764, h-index: 154)
American J. of Surgery     Hybrid Journal   (Followers: 33, 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: 5)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.066, h-index: 51)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 53, SJR: 0.124, h-index: 9)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 5)
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: 2, SJR: 2.577, h-index: 7)
Analytica Chimica Acta     Hybrid Journal   (Followers: 38, SJR: 1.548, h-index: 152)
Analytical Biochemistry     Hybrid Journal   (Followers: 160, 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: 10)
Anesthésie & Réanimation     Full-text available via subscription  
Anesthesiology Clinics     Full-text available via subscription   (Followers: 21, SJR: 0.421, h-index: 40)
Angiología     Full-text available via subscription   (SJR: 0.124, h-index: 9)
Angiologia e Cirurgia Vascular     Open Access  
Animal Behaviour     Hybrid Journal   (Followers: 153, SJR: 1.907, h-index: 126)
Animal Feed Science and Technology     Hybrid Journal   (Followers: 5, SJR: 1.151, h-index: 83)
Animal Reproduction Science     Hybrid Journal   (Followers: 5, SJR: 0.711, h-index: 78)
Annales d'Endocrinologie     Full-text available via subscription   (SJR: 0.394, h-index: 30)
Annales d'Urologie     Full-text available via subscription  
Annales de Cardiologie et d'Angéiologie     Full-text available via subscription   (SJR: 0.177, h-index: 13)
Annales de Chirurgie de la Main et du Membre Supérieur     Full-text available via subscription  
Annales de Chirurgie Plastique Esthétique     Full-text available via subscription   (Followers: 2, SJR: 0.354, h-index: 22)
Annales de Chirurgie Vasculaire     Full-text available via subscription   (Followers: 1)

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Journal Cover American Journal of Human Genetics
  [SJR: 8.769]   [H-I: 256]   [30 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0002-9297 - ISSN (Online) 1537-6605
   Published by Elsevier Homepage  [3042 journals]
  • Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with
           Multiple Morphological Abnormalities of the Sperm Flagella
    • Authors: Shuyan Tang; Xiong Wang; Weiyu Li; Xiaoyu Yang; Zheng Li; Wangjie Liu; Caihua Li; Zijue Zhu; Lingxiang Wang; Jiaxiong Wang; Ling Zhang; Xiaoling Sun; Erlei Zhi; Hongyan Wang; Hong Li; Li Jin; Yang Luo; Jian Wang; Shenmin Yang; Feng Zhang
      Pages: 854 - 864
      Abstract: Publication date: 1 June 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 6
      Author(s): Shuyan Tang, Xiong Wang, Weiyu Li, Xiaoyu Yang, Zheng Li, Wangjie Liu, Caihua Li, Zijue Zhu, Lingxiang Wang, Jiaxiong Wang, Ling Zhang, Xiaoling Sun, Erlei Zhi, Hongyan Wang, Hong Li, Li Jin, Yang Luo, Jian Wang, Shenmin Yang, Feng Zhang
      Sperm motility is vital to human reproduction. Malformations of sperm flagella can cause male infertility. Men with multiple morphological abnormalities of the flagella (MMAF) have abnormal spermatozoa with absent, short, coiled, bent, and/or irregular-caliber flagella, which impair sperm motility. The known human MMAF-associated genes, such as DNAH1, only account for fewer than 45% of affected individuals. Pathogenic mechanisms in the genetically unexplained MMAF remain to be elucidated. Here, we conducted genetic analyses by using whole-exome sequencing and genome-wide comparative genomic hybridization microarrays in a multi-center cohort of 30 Han Chinese men affected by MMAF. Among them, 12 subjects could not be genetically explained by any known MMAF-associated genes. Intriguingly, we identified compound-heterozygous mutations in CFAP43 in three subjects and a homozygous frameshift mutation in CFAP44 in one subject. All of these recessive mutations were parentally inherited from heterozygous carriers but were absent in 984 individuals from three Han Chinese control populations. CFAP43 and CFAP44, encoding two cilia- and flagella-associated proteins (CFAPs), are specifically or preferentially expressed in the testis. Using CRISPR/Cas9 technology, we generated two knockout models each deficient in mouse ortholog Cfap43 or Cfap44. Notably, both Cfap43- and Cfap44-deficient male mice presented with MMAF phenotypes, whereas the corresponding female mice were fertile. Our experimental observations on human subjects and animal models strongly suggest that biallelic mutations in either CFAP43 or CFAP44 can cause sperm flagellar abnormalities and impair sperm motility. Further investigations on other CFAP-encoding genes in more genetically unexplained MMAF-affected individuals could uncover novel mechanisms underlying sperm flagellar formation.

      PubDate: 2017-06-02T04:46:06Z
      DOI: 10.1016/j.ajhg.2017.04.012
  • Large-Scale Identification of Common Trait and Disease Variants Affecting
           Gene Expression
    • Authors: Mads Engel Hauberg; Wen Zhang; Claudia Giambartolomei; Oscar Franzén; David L. Morris; Timothy J. Vyse; Arno Ruusalepp; Pamela Sklar; Eric E. Schadt; Johan L.M. Björkegren; Panos Roussos; Menachem Fromer; Solveig K. Sieberts; Jessica S. Johnson; Douglas M. Ruderfer; Hardik R. Shah; Lambertus L. Klei; Kristen K. Dang; Thanneer M. Perumal; Benjamin A. Logsdon; Milind C. Mahajan; Lara M. Mangravite; Laurent Essioux; Hiroyoshi Toyoshiba; Raquel E. Gur; Chang-Gyu Hahn; David A. Lewis; Vahram Haroutunian; Mette A. Peters; Barbara K. Lipska; Joseph D. Buxbaum; Keisuke Hirai; Enrico Domenici; Bernie Devlin
      Pages: 885 - 894
      Abstract: Publication date: 1 June 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 6
      Author(s): Mads Engel Hauberg, Wen Zhang, Claudia Giambartolomei, Oscar Franzén, David L. Morris, Timothy J. Vyse, Arno Ruusalepp, Pamela Sklar, Eric E. Schadt, Johan L.M. Björkegren, Panos Roussos
      Genome-wide association studies (GWASs) have identified a multitude of genetic loci involved with traits and diseases. However, it is often unclear which genes are affected in such loci and whether the associated genetic variants lead to increased or decreased gene function. To mitigate this, we integrated associations of common genetic variants in 57 GWASs with 24 studies of expression quantitative trait loci (eQTLs) from a broad range of tissues by using a Mendelian randomization approach. We discovered a total of 3,484 instances of gene-trait-associated changes in expression at a false-discovery rate < 0.05. These genes were often not closest to the genetic variant and were primarily identified in eQTLs derived from pathophysiologically relevant tissues. For instance, genes with expression changes associated with lipid traits were mostly identified in the liver, and those associated with cardiovascular disease were identified in arterial tissue. The affected genes additionally point to biological processes implicated in the interrogated traits, such as the interleukin-27 pathway in rheumatoid arthritis. Further, comparing trait-associated gene expression changes across traits suggests that pleiotropy is a widespread phenomenon and points to specific instances of both agonistic and antagonistic pleiotropy. For instance, expression of SNX19 and ABCB9 is positively correlated with both the risk of schizophrenia and educational attainment. To facilitate interpretation, we provide this lexicon of how common trait-associated genetic variants alter gene expression in various tissues as the online database GWAS2Genes.

      PubDate: 2017-06-02T04:46:06Z
      DOI: 10.1016/j.ajhg.2017.04.016
  • YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome
           Featuring Transcriptional and Chromatin Dysfunction
    • Authors: Michele Gabriele; Anneke T. Vulto-van Silfhout; Pierre-Luc Germain; Alessandro Vitriolo; Raman Kumar; Evelyn Douglas; Eric Haan; Kenjiro Kosaki; Toshiki Takenouchi; Anita Rauch; Katharina Steindl; Eirik Frengen; Doriana Misceo; Christeen Ramane J. Pedurupillay; Petter Stromme; Jill A. Rosenfeld; Yunru Shao; William J. Craigen; Christian P. Schaaf; David Rodriguez-Buritica; Laura Farach; Jennifer Friedman; Perla Thulin; Scott D. McLean; Kimberly M. Nugent; Jenny Morton; Jillian Nicholl; Joris Andrieux; Asbjørg Stray-Pedersen; Pascal Chambon; Sophie Patrier; Sally A. Lynch; Susanne Kjaergaard; Pernille M. Tørring; Charlotte Brasch-Andersen; Anne Ronan; Arie van Haeringen; Peter J. Anderson; Zöe Powis; Han G. Brunner; Rolph Pfundt; Janneke H.M. Schuurs-Hoeijmakers; Bregje W.M. van Bon; Stefan Lelieveld; Christian Gilissen; Willy M. Nillesen; Lisenka E.L.M. Vissers; Jozef Gecz; David A. Koolen; Giuseppe Testa; Bert B.A. de Vries
      Pages: 907 - 925
      Abstract: Publication date: 1 June 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 6
      Author(s): Michele Gabriele, Anneke T. Vulto-van Silfhout, Pierre-Luc Germain, Alessandro Vitriolo, Raman Kumar, Evelyn Douglas, Eric Haan, Kenjiro Kosaki, Toshiki Takenouchi, Anita Rauch, Katharina Steindl, Eirik Frengen, Doriana Misceo, Christeen Ramane J. Pedurupillay, Petter Stromme, Jill A. Rosenfeld, Yunru Shao, William J. Craigen, Christian P. Schaaf, David Rodriguez-Buritica, Laura Farach, Jennifer Friedman, Perla Thulin, Scott D. McLean, Kimberly M. Nugent, Jenny Morton, Jillian Nicholl, Joris Andrieux, Asbjørg Stray-Pedersen, Pascal Chambon, Sophie Patrier, Sally A. Lynch, Susanne Kjaergaard, Pernille M. Tørring, Charlotte Brasch-Andersen, Anne Ronan, Arie van Haeringen, Peter J. Anderson, Zöe Powis, Han G. Brunner, Rolph Pfundt, Janneke H.M. Schuurs-Hoeijmakers, Bregje W.M. van Bon, Stefan Lelieveld, Christian Gilissen, Willy M. Nillesen, Lisenka E.L.M. Vissers, Jozef Gecz, David A. Koolen, Giuseppe Testa, Bert B.A. de Vries
      Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define “YY1 syndrome” as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals’ cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators.

      PubDate: 2017-06-02T04:46:06Z
      DOI: 10.1016/j.ajhg.2017.05.006
  • Mutations in SULT2B1 Cause Autosomal-Recessive Congenital Ichthyosis in
    • Authors: Lisa Heinz; Gwang-Jin Kim; Slaheddine Marrakchi; Julie Christiansen; Hamida Turki; Marc-Alexander Rauschendorf; Mark Lathrop; Ingrid Hausser; Andreas D. Zimmer; Judith Fischer
      Pages: 926 - 939
      Abstract: Publication date: 1 June 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 6
      Author(s): Lisa Heinz, Gwang-Jin Kim, Slaheddine Marrakchi, Julie Christiansen, Hamida Turki, Marc-Alexander Rauschendorf, Mark Lathrop, Ingrid Hausser, Andreas D. Zimmer, Judith Fischer
      Ichthyoses are a clinically and genetically heterogeneous group of genodermatoses associated with abnormal scaling of the skin over the whole body. Mutations in nine genes are known to cause non-syndromic forms of autosomal-recessive congenital ichthyosis (ARCI). However, not all genetic causes for ARCI have been discovered to date. Using whole-exome sequencing (WES) and multigene panel screening, we identified 6 ARCI-affected individuals from three unrelated families with mutations in Sulfotransferase family 2B member 1 (SULT2B1), showing their causative association with ARCI. Cytosolic sulfotransferases form a large family of enzymes that are involved in the synthesis and metabolism of several steroids in humans. We identified four distinct mutations including missense, nonsense, and splice site mutations. We demonstrated the loss of SULT2B1 expression at RNA and protein levels in keratinocytes from individuals with ARCI by functional analyses. Furthermore, we succeeded in reconstructing the morphologic skin alterations in a 3D organotypic tissue culture model with SULT2B1-deficient keratinocytes and fibroblasts. By thin layer chromatography (TLC) of extracts from these organotypic cultures, we could show the absence of cholesterol sulfate, the metabolite of SULT2B1, and an increased level of cholesterol, indicating a disturbed cholesterol metabolism of the skin upon loss-of-function mutation in SULT2B1. In conclusion, our study reveals an essential role for SULT2B1 in the proper development of healthy human skin. Mutation in SULT2B1 leads to an ARCI phenotype via increased proliferation of human keratinocytes, thickening of epithelial layers, and altered epidermal cholesterol metabolism.

      PubDate: 2017-06-02T04:46:06Z
      DOI: 10.1016/j.ajhg.2017.05.007
  • Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with
           Important Functions for Kidney Disease
    • Authors: Yi-An Ko; Huiguang Yi; Chengxiang Qiu; Shizheng Huang; Jihwan Park; Nora Ledo; Anna Köttgen; Hongzhe Li; Daniel J. Rader; Michael A. Pack; Christopher D. Brown; Katalin Susztak
      Pages: 940 - 953
      Abstract: Publication date: 1 June 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 6
      Author(s): Yi-An Ko, Huiguang Yi, Chengxiang Qiu, Shizheng Huang, Jihwan Park, Nora Ledo, Anna Köttgen, Hongzhe Li, Daniel J. Rader, Michael A. Pack, Christopher D. Brown, Katalin Susztak
      Chronic kidney disease (CKD) is a complex gene-environmental disease affecting close to 10% of the US population. Genome-wide association studies (GWASs) have identified sequence variants, localized to non-coding genomic regions, associated with kidney function. Despite these robust observations, the mechanism by which variants lead to CKD remains a critical unanswered question. Expression quantitative trait loci (eQTL) analysis is a method to identify genetic variation associated with gene expression changes in specific tissue types. We hypothesized that an integrative analysis combining CKD GWAS and kidney eQTL results can identify candidate genes for CKD. We performed eQTL analysis by correlating genotype with RNA-seq-based gene expression levels in 96 human kidney samples. Applying stringent statistical criteria, we detected 1,886 genes whose expression differs with the sequence variants. Using direct overlap and Bayesian methods, we identified new potential target genes for CKD. With respect to one of the target genes, lysosomal beta A mannosidase (MANBA), we observed that genetic variants associated with MANBA expression in the kidney showed statistically significant colocalization with variants identified in CKD GWASs, indicating that MANBA is a potential target gene for CKD. The expression of MANBA was significantly lower in kidneys of subjects with risk alleles. Suppressing manba expression in zebrafish resulted in renal tubule defects and pericardial edema, phenotypes typically induced by kidney dysfunction. Our analysis shows that gene-expression changes driven by genetic variation in the kidney can highlight potential new target genes for CKD development.

      PubDate: 2017-06-02T04:46:06Z
      DOI: 10.1016/j.ajhg.2017.05.004
  • Defects in the Cell Signaling Mediator β-Catenin Cause the Retinal
           Vascular Condition FEVR
    • Authors: Evangelia S. Panagiotou; Carla Sanjurjo Soriano; James A. Poulter; Emma C. Lord; Denisa Dzulova; Hiroyuki Kondo; Atsushi Hiyoshi; Brian Hon-Yin Chung; Yoyo Wing-Yiu Chu; Connie H.Y. Lai; Mark E. Tafoya; Dyah Karjosukarso; Rob W.J. Collin; Joanne Topping; Louise M. Downey; Manir Ali; Chris F. Inglehearn; Carmel Toomes
      Pages: 960 - 968
      Abstract: Publication date: 1 June 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 6
      Author(s): Evangelia S. Panagiotou, Carla Sanjurjo Soriano, James A. Poulter, Emma C. Lord, Denisa Dzulova, Hiroyuki Kondo, Atsushi Hiyoshi, Brian Hon-Yin Chung, Yoyo Wing-Yiu Chu, Connie H.Y. Lai, Mark E. Tafoya, Dyah Karjosukarso, Rob W.J. Collin, Joanne Topping, Louise M. Downey, Manir Ali, Chris F. Inglehearn, Carmel Toomes
      Familial exudative vitreoretinopathy (FEVR) is an inherited blinding disorder characterized by the abnormal development of the retinal vasculature. The majority of mutations identified in FEVR are found within four genes that encode the receptor complex (FZD4, LRP5, and TSPAN12) and ligand (NDP) of a molecular pathway that controls angiogenesis, the Norrin-β-catenin signaling pathway. However, half of all FEVR-affected case subjects do not harbor mutations in these genes, indicating that further mutated genes remain to be identified. Here we report the identification of mutations in CTNNB1, the gene encoding β-catenin, as a cause of FEVR. We describe heterozygous mutations (c.2142_2157dup [p.His720∗] and c.2128C>T [p.Arg710Cys]) in two dominant FEVR-affected families and a de novo mutation (c.1434_1435insC [p.Glu479Argfs∗18]) in a simplex case subject. Previous studies have reported heterozygous de novo CTNNB1 mutations as a cause of syndromic intellectual disability (ID) and autism spectrum disorder, and somatic mutations are linked to many cancers. However, in this study we show that Mendelian inherited CTNNB1 mutations can cause non-syndromic FEVR and that FEVR can be a part of the syndromic ID phenotype, further establishing the role that β-catenin signaling plays in the development of the retinal vasculature.

      PubDate: 2017-06-02T04:46:06Z
      DOI: 10.1016/j.ajhg.2017.05.001
  • Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination
    • Authors: Viorica Chelban; Nisha Patel; Jana Vandrovcova; M. Natalia Zanetti; David S. Lynch; Mina Ryten; Juan A. Botía; Oscar Bello; Eloise Tribollet; Stephanie Efthymiou; Indran Davagnanam; Fahad A. Bashiri; Nicholas W. Wood; James E. Rothman; Fowzan S. Alkuraya; Henry Houlden
      Pages: 969 - 977
      Abstract: Publication date: 1 June 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 6
      Author(s): Viorica Chelban, Nisha Patel, Jana Vandrovcova, M. Natalia Zanetti, David S. Lynch, Mina Ryten, Juan A. Botía, Oscar Bello, Eloise Tribollet, Stephanie Efthymiou, Indran Davagnanam, Fahad A. Bashiri, Nicholas W. Wood, James E. Rothman, Fowzan S. Alkuraya, Henry Houlden
      Progressive limb spasticity and cerebellar ataxia are frequently found together in clinical practice and form a heterogeneous group of degenerative disorders that are classified either as pure spastic ataxia or as complex spastic ataxia with additional neurological signs. Inheritance is either autosomal dominant or autosomal recessive. Hypomyelinating features on MRI are sometimes seen with spastic ataxia, but this is usually mild in adults and severe and life limiting in children. We report seven individuals with an early-onset spastic-ataxia phenotype. The individuals come from three families of different ethnic backgrounds. Affected members of two families had childhood onset disease with very slow progression. They are still alive in their 30s and 40s and show predominant ataxia and cerebellar atrophy features on imaging. Affected members of the third family had a similar but earlier-onset presentation associated with brain hypomyelination. Using a combination of homozygozity mapping and exome sequencing, we mapped this phenotype to deleterious nonsense or homeobox domain missense mutations in NKX6-2. NKX6-2 encodes a transcriptional repressor with early high general and late focused CNS expression. Deficiency of its mouse ortholog results in widespread hypomyelination in the brain and optic nerve, as well as in poor motor coordination in a pattern consistent with the observed human phenotype. In-silico analysis of human brain expression and network data provides evidence that NKX6-2 is involved in oligodendrocyte maturation and might act within the same pathways of genes already associated with central hypomyelination. Our results support a non-redundant developmental role of NKX6-2 in humans and imply that NKX6-2 mutations should be considered in the differential diagnosis of spastic ataxia and hypomyelination.

      PubDate: 2017-06-02T04:46:06Z
      DOI: 10.1016/j.ajhg.2017.05.009
  • Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma
    • Authors: Lynn M. Boyden; Nicholas G. Vincent; Jing Zhou; Ronghua Hu; Brittany G. Craiglow; Susan J. Bayliss; Ilana S. Rosman; Anne W. Lucky; Luis A. Diaz; Lowell A. Goldsmith; Amy S. Paller; Richard P. Lifton; Susan J. Baserga; Keith A. Choate
      Pages: 978 - 984
      Abstract: Publication date: 1 June 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 6
      Author(s): Lynn M. Boyden, Nicholas G. Vincent, Jing Zhou, Ronghua Hu, Brittany G. Craiglow, Susan J. Bayliss, Ilana S. Rosman, Anne W. Lucky, Luis A. Diaz, Lowell A. Goldsmith, Amy S. Paller, Richard P. Lifton, Susan J. Baserga, Keith A. Choate
      The discovery of new genetic determinants of inherited skin disorders has been instrumental to the understanding of epidermal function, differentiation, and renewal. Here, we show that mutations in KDSR (3-ketodihydrosphingosine reductase), encoding an enzyme in the ceramide synthesis pathway, lead to a previously undescribed recessive Mendelian disorder in the progressive symmetric erythrokeratoderma spectrum. This disorder is characterized by severe lesions of thick scaly skin on the face and genitals and thickened, red, and scaly skin on the hands and feet. Although exome sequencing revealed several of the KDSR mutations, we employed genome sequencing to discover a pathogenic 346 kb inversion in multiple probands, and cDNA sequencing and a splicing assay established that two mutations, including a recurrent silent third base change, cause exon skipping. Immunohistochemistry and yeast complementation studies demonstrated that the mutations cause defects in KDSR function. Systemic isotretinoin therapy has achieved nearly complete resolution in the two probands in whom it has been applied, consistent with the effects of retinoic acid on alternative pathways for ceramide generation.

      PubDate: 2017-06-02T04:46:06Z
      DOI: 10.1016/j.ajhg.2017.05.003
  • Dynamic Role of trans Regulation of Gene Expression in Relation to Complex
    • Authors: Chen Yao; Roby Joehanes; Andrew D. Johnson; Tianxiao Huan; Chunyu Liu; Jane E. Freedman; Peter J. Munson; David E. Hill; Marc Vidal; Daniel Levy
      Pages: 985 - 986
      Abstract: Publication date: 1 June 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 6
      Author(s): Chen Yao, Roby Joehanes, Andrew D. Johnson, Tianxiao Huan, Chunyu Liu, Jane E. Freedman, Peter J. Munson, David E. Hill, Marc Vidal, Daniel Levy

      PubDate: 2017-06-02T04:46:06Z
      DOI: 10.1016/j.ajhg.2017.05.002
  • International Cooperation to Enable the Diagnosis of All Rare Genetic
    • Authors: Kym M. Boycott; Ana Rath; Jessica X. Chong; Taila Hartley; Fowzan S. Alkuraya; Gareth Baynam; Anthony J. Brookes; Michael Brudno; Angel Carracedo; Johan T. den Dunnen; Stephanie O.M. Dyke; Xavier Estivill; Jack Goldblatt; Catherine Gonthier; Stephen C. Groft; Ivo Gut; Ada Hamosh; Philip Hieter; Sophie Höhn; Matthew E. Hurles; Petra Kaufmann; Bartha M. Knoppers; Jeffrey P. Krischer; Milan Macek; Gert Matthijs; Annie Olry; Samantha Parker; Justin Paschall; Anthony A. Philippakis; Heidi L. Rehm; Peter N. Robinson; Pak-Chung Sham; Rumen Stefanov; Domenica Taruscio; Divya Unni; Megan R. Vanstone; Feng Zhang; Han Brunner; Michael J. Bamshad; Hanns Lochmüller
      Pages: 695 - 705
      Abstract: Publication date: 4 May 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 5
      Author(s): Kym M. Boycott, Ana Rath, Jessica X. Chong, Taila Hartley, Fowzan S. Alkuraya, Gareth Baynam, Anthony J. Brookes, Michael Brudno, Angel Carracedo, Johan T. den Dunnen, Stephanie O.M. Dyke, Xavier Estivill, Jack Goldblatt, Catherine Gonthier, Stephen C. Groft, Ivo Gut, Ada Hamosh, Philip Hieter, Sophie Höhn, Matthew E. Hurles, Petra Kaufmann, Bartha M. Knoppers, Jeffrey P. Krischer, Milan Macek, Gert Matthijs, Annie Olry, Samantha Parker, Justin Paschall, Anthony A. Philippakis, Heidi L. Rehm, Peter N. Robinson, Pak-Chung Sham, Rumen Stefanov, Domenica Taruscio, Divya Unni, Megan R. Vanstone, Feng Zhang, Han Brunner, Michael J. Bamshad, Hanns Lochmüller
      Provision of a molecularly confirmed diagnosis in a timely manner for children and adults with rare genetic diseases shortens their “diagnostic odyssey,” improves disease management, and fosters genetic counseling with respect to recurrence risks while assuring reproductive choices. In a general clinical genetics setting, the current diagnostic rate is approximately 50%, but for those who do not receive a molecular diagnosis after the initial genetics evaluation, that rate is much lower. Diagnostic success for these more challenging affected individuals depends to a large extent on progress in the discovery of genes associated with, and mechanisms underlying, rare diseases. Thus, continued research is required for moving toward a more complete catalog of disease-related genes and variants. The International Rare Diseases Research Consortium (IRDiRC) was established in 2011 to bring together researchers and organizations invested in rare disease research to develop a means of achieving molecular diagnosis for all rare diseases. Here, we review the current and future bottlenecks to gene discovery and suggest strategies for enabling progress in this regard. Each successful discovery will define potential diagnostic, preventive, and therapeutic opportunities for the corresponding rare disease, enabling precision medicine for this patient population.

      PubDate: 2017-05-08T02:27:18Z
      DOI: 10.1016/j.ajhg.2017.04.003
  • Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth
           with Intellectual Disability
    • Authors: Katrina Tatton-Brown; Chey Loveday; Shawn Yost; Matthew Clarke; Emma Ramsay; Anna Zachariou; Anna Elliott; Harriet Wylie; Anna Ardissone; Olaf Rittinger; Fiona Stewart; I. Karen Temple; Trevor Cole; Shazia Mahamdallie; Sheila Seal; Elise Ruark; Nazneen Rahman
      Pages: 725 - 736
      Abstract: Publication date: 4 May 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 5
      Author(s): Katrina Tatton-Brown, Chey Loveday, Shawn Yost, Matthew Clarke, Emma Ramsay, Anna Zachariou, Anna Elliott, Harriet Wylie, Anna Ardissone, Olaf Rittinger, Fiona Stewart, I. Karen Temple, Trevor Cole, Shazia Mahamdallie, Sheila Seal, Elise Ruark, Nazneen Rahman
      To explore the genetic architecture of human overgrowth syndromes and human growth control, we performed experimental and bioinformatic analyses of 710 individuals with overgrowth (height and/or head circumference ≥+2 SD) and intellectual disability (OGID). We identified a causal mutation in 1 of 14 genes in 50% (353/710). This includes HIST1H1E, encoding histone H1.4, which has not been associated with a developmental disorder previously. The pathogenic HIST1H1E mutations are predicted to result in a product that is less effective in neutralizing negatively charged linker DNA because it has a reduced net charge, and in DNA binding and protein-protein interactions because key residues are truncated. Functional network analyses demonstrated that epigenetic regulation is a prominent biological process dysregulated in individuals with OGID. Mutations in six epigenetic regulation genes—NSD1, EZH2, DNMT3A, CHD8, HIST1H1E, and EED—accounted for 44% of individuals (311/710). There was significant overlap between the 14 genes involved in OGID and 611 genes in regions identified in GWASs to be associated with height (p = 6.84 × 10−8), suggesting that a common variation impacting function of genes involved in OGID influences height at a population level. Increased cellular growth is a hallmark of cancer and there was striking overlap between the genes involved in OGID and 260 somatically mutated cancer driver genes (p = 1.75 × 10−14). However, the mutation spectra of genes involved in OGID and cancer differ, suggesting complex genotype-phenotype relationships. These data reveal insights into the genetic control of human growth and demonstrate that exome sequencing in OGID has a high diagnostic yield.

      PubDate: 2017-05-08T02:27:18Z
      DOI: 10.1016/j.ajhg.2017.03.010
  • Systematic Computational Identification of Variants That Activate Exonic
           and Intronic Cryptic Splice Sites
    • Authors: Melissa Lee; Patrick Roos; Neeraj Sharma; Melis Atalar; Taylor A. Evans; Matthew J. Pellicore; Emily Davis; Anh-Thu N. Lam; Susan E. Stanley; Sara E. Khalil; George M. Solomon; Doug Walker; Karen S. Raraigh; Briana Vecchio-Pagan; Mary Armanios; Garry R. Cutting
      Pages: 751 - 765
      Abstract: Publication date: 4 May 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 5
      Author(s): Melissa Lee, Patrick Roos, Neeraj Sharma, Melis Atalar, Taylor A. Evans, Matthew J. Pellicore, Emily Davis, Anh-Thu N. Lam, Susan E. Stanley, Sara E. Khalil, George M. Solomon, Doug Walker, Karen S. Raraigh, Briana Vecchio-Pagan, Mary Armanios, Garry R. Cutting
      We developed a variant-annotation method that combines sequence-based machine-learning classification with a context-dependent algorithm for selecting splice variants. Our approach is distinctive in that it compares the splice potential of a sequence bearing a variant with the splice potential of the reference sequence. After training, classification accurately identified 168 of 180 (93.3%) canonical splice sites of five genes. The combined method, CryptSplice, identified and correctly predicted the effect of 18 of 21 (86%) known splice-altering variants in CFTR, a well-studied gene whose loss-of-function variants cause cystic fibrosis (CF). Among 1,423 unannotated CFTR disease-associated variants, the method identified 32 potential exonic cryptic splice variants, two of which were experimentally evaluated and confirmed. After complete CFTR sequencing, the method found three cryptic intronic splice variants (one known and two experimentally verified) that completed the molecular diagnosis of CF in 6 of 14 individuals. CryptSplice interrogation of sequence data from six individuals with X-linked dyskeratosis congenita caused by an unknown disease-causing variant in DKC1 identified two splice-altering variants that were experimentally verified. To assess the extent to which disease-associated variants might activate cryptic splicing, we selected 458 pathogenic variants and 348 variants of uncertain significance (VUSs) classified as high confidence from ClinVar. Splice-site activation was predicted for 129 (28%) of the pathogenic variants and 75 (22%) of the VUSs. Our findings suggest that cryptic splice-site activation is more common than previously thought and should be routinely considered for all variants within the transcribed regions of genes.

      PubDate: 2017-05-08T02:27:18Z
      DOI: 10.1016/j.ajhg.2017.04.001
  • Inferring Human Demographic Histories of Non-African Populations from
           Patterns of Allele Sharing
    • Authors: Jeffrey D. Wall
      Pages: 766 - 772
      Abstract: Publication date: 4 May 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 5
      Author(s): Jeffrey D. Wall
      Recent human-genetics studies have come to different conclusions regarding how and when modern humans spread out of Africa and into the rest of the world. I present here a simple parsimony-based analysis that suggests that East Asians and Melanesians are sister groups, and I discuss what implications this has for recent claims made about the demographic histories of non-African populations.

      PubDate: 2017-05-08T02:27:18Z
      DOI: 10.1016/j.ajhg.2017.04.002
  • CHARGE and Kabuki Syndromes: Gene-Specific DNA Methylation Signatures
           Identify Epigenetic Mechanisms Linking These Clinically Overlapping
    • Authors: Darci T. Butcher; Cheryl Cytrynbaum; Andrei L. Turinsky; Michelle T. Siu; Michal Inbar-Feigenberg; Roberto Mendoza-Londono; David Chitayat; Susan Walker; Jerry Machado; Oana Caluseriu; Lucie Dupuis; Daria Grafodatskaya; William Reardon; Brigitte Gilbert-Dussardier; Alain Verloes; Frederic Bilan; Jeff M. Milunsky; Raveen Basran; Blake Papsin; Tracy L. Stockley; Stephen W. Scherer; Sanaa Choufani; Michael Brudno; Rosanna Weksberg
      Pages: 773 - 788
      Abstract: Publication date: 4 May 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 5
      Author(s): Darci T. Butcher, Cheryl Cytrynbaum, Andrei L. Turinsky, Michelle T. Siu, Michal Inbar-Feigenberg, Roberto Mendoza-Londono, David Chitayat, Susan Walker, Jerry Machado, Oana Caluseriu, Lucie Dupuis, Daria Grafodatskaya, William Reardon, Brigitte Gilbert-Dussardier, Alain Verloes, Frederic Bilan, Jeff M. Milunsky, Raveen Basran, Blake Papsin, Tracy L. Stockley, Stephen W. Scherer, Sanaa Choufani, Michael Brudno, Rosanna Weksberg
      Epigenetic dysregulation has emerged as a recurring mechanism in the etiology of neurodevelopmental disorders. Two such disorders, CHARGE and Kabuki syndromes, result from loss of function mutations in chromodomain helicase DNA-binding protein 7 (CHD7 LOF) and lysine (K) methyltransferase 2D (KMT2D LOF), respectively. Although these two syndromes are clinically distinct, there is significant phenotypic overlap. We therefore expected that epigenetically driven developmental pathways regulated by CHD7 and KMT2D would overlap and that DNA methylation (DNAm) alterations downstream of the mutations in these genes would identify common target genes, elucidating a mechanistic link between these two conditions, as well as specific target genes for each disorder. Genome-wide DNAm profiles in individuals with CHARGE and Kabuki syndromes with CHD7 LOF or KMT2D LOF identified distinct sets of DNAm differences in each of the disorders, which were used to generate two unique, highly specific and sensitive DNAm signatures. These DNAm signatures were able to differentiate pathogenic mutations in these two genes from controls and from each other. Analysis of the DNAm targets in each gene-specific signature identified both common gene targets, including homeobox A5 (HOXA5), which could account for some of the clinical overlap in CHARGE and Kabuki syndromes, as well as distinct gene targets. Our findings demonstrate how characterization of the epigenome can contribute to our understanding of disease pathophysiology for epigenetic disorders, paving the way for explorations of novel therapeutics.

      PubDate: 2017-05-08T02:27:18Z
      DOI: 10.1016/j.ajhg.2017.04.004
  • Widespread Allelic Heterogeneity in Complex Traits
    • Authors: Farhad Hormozdiari; Anthony Zhu; Gleb Kichaev; Chelsea J.-T. Ju; Ayellet V. Segrè; Jong Wha J. Joo; Hyejung Won; Sriram Sankararaman; Bogdan Pasaniuc; Sagiv Shifman; Eleazar Eskin
      Pages: 789 - 802
      Abstract: Publication date: 4 May 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 5
      Author(s): Farhad Hormozdiari, Anthony Zhu, Gleb Kichaev, Chelsea J.-T. Ju, Ayellet V. Segrè, Jong Wha J. Joo, Hyejung Won, Sriram Sankararaman, Bogdan Pasaniuc, Sagiv Shifman, Eleazar Eskin
      Recent successes in genome-wide association studies (GWASs) make it possible to address important questions about the genetic architecture of complex traits, such as allele frequency and effect size. One lesser-known aspect of complex traits is the extent of allelic heterogeneity (AH) arising from multiple causal variants at a locus. We developed a computational method to infer the probability of AH and applied it to three GWASs and four expression quantitative trait loci (eQTL) datasets. We identified a total of 4,152 loci with strong evidence of AH. The proportion of all loci with identified AH is 4%–23% in eQTLs, 35% in GWASs of high-density lipoprotein (HDL), and 23% in GWASs of schizophrenia. For eQTLs, we observed a strong correlation between sample size and the proportion of loci with AH (R 2 = 0.85, p = 2.2 × 10−16), indicating that statistical power prevents identification of AH in other loci. Understanding the extent of AH may guide the development of new methods for fine mapping and association mapping of complex traits.

      PubDate: 2017-05-08T02:27:18Z
      DOI: 10.1016/j.ajhg.2017.04.005
  • High-Resolution Genetic Maps Identify Multiple Type 2 Diabetes Loci at
           Regulatory Hotspots in African Americans and Europeans
    • Authors: Winston Lau; Toby Andrew; Nikolas Maniatis
      Pages: 803 - 816
      Abstract: Publication date: 4 May 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 5
      Author(s): Winston Lau, Toby Andrew, Nikolas Maniatis
      Interpretation of results from genome-wide association studies for T2D is challenging. Only very few loci have been replicated in African ancestry populations and the identification of the implicated functional genes remain largely undefined. We used genetic maps that capture detailed linkage disequilibrium information in European and African Americans and applied these to large T2D case-control samples in order to estimate locations for putative functional variants in both populations. Replicated T2D locations were tested for evidence of being regulatory hotspots using adipose expression. We validated a sample of our co-location intervals using next generation sequencing and functional annotation, including enhancers, transcription, and chromatin modifications. We identified 111 additional disease-susceptibility locations, 93 of which are cosmopolitan and 18 of which are European specific. We show that many previously known signals are also risk loci in African Americans. The majority of the disease locations appear to confer risk of T2D via the regulation of expression levels for a large number (266) of cis-regulated genes, the majority of which are not the nearest genes to the disease loci. Sequencing three cosmopolitan locations provided candidate functional variants that precisely co-locate with cell-specific chromatin domains and pancreatic islet enhancers. These variants have large effect sizes and are common across populations. Results show that disease-associated loci in different populations, gene expression, and cell-specific regulatory annotation can be effectively integrated by localizing these effects on high-resolution genetic maps. The cis-regulated genes provide insights into the complex molecular pathways involved and can be used as targets for sequencing and functional molecular studies.

      PubDate: 2017-05-08T02:27:18Z
      DOI: 10.1016/j.ajhg.2017.04.007
  • GZF1 Mutations Expand the Genetic Heterogeneity of Larsen Syndrome
    • Authors: Nisha Patel; Hanan E. Shamseldin; Nadia Sakati; Arif O. Khan; Ameen Softa; Fatima M. Al-Fadhli; Mais Hashem; Firdous M. Abdulwahab; Tarfa Alshidi; Rana Alomar; Eman Alobeid; Salma M. Wakil; Dilek Colak; Fowzan S. Alkuraya
      Pages: 831 - 836
      Abstract: Publication date: 4 May 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 5
      Author(s): Nisha Patel, Hanan E. Shamseldin, Nadia Sakati, Arif O. Khan, Ameen Softa, Fatima M. Al-Fadhli, Mais Hashem, Firdous M. Abdulwahab, Tarfa Alshidi, Rana Alomar, Eman Alobeid, Salma M. Wakil, Dilek Colak, Fowzan S. Alkuraya
      Larsen syndrome is characterized by the dislocation of large joints and other less consistent clinical findings. Heterozygous FLNB mutations account for the majority of Larsen syndrome cases, but biallelic mutations in CHST3 and B4GALT7 have been more recently described, thus confirming the existence of recessive forms of the disease. In a multiplex consanguineous Saudi family affected by severe and recurrent large joint dislocation and severe myopia, we identified a homozygous truncating variant in GZF1 through a combined autozygome and exome approach. Independently, the same approach identified a second homozygous truncating GZF1 variant in another multiplex consanguineous family affected by severe myopia, retinal detachment, and milder skeletal involvement. GZF1 encodes GDNF-inducible zinc finger protein 1, a transcription factor of unknown developmental function, which we found to be expressed in the eyes and limbs of developing mice. Global transcriptional profiling of cells from affected individuals revealed a shared pattern of gene dysregulation and significant enrichment of genes encoding matrix proteins, including P3H2, which hints at a potential disease mechanism. Our results suggest that GZF1 mutations cause a phenotype of severe myopia and significant articular involvement not previously described in Larsen syndrome.

      PubDate: 2017-05-08T02:27:18Z
      DOI: 10.1016/j.ajhg.2017.04.008
  • Retraction Notice to: A BLOC-1 Mutation Screen Reveals that PLDN Is
           Mutated in Hermansky-Pudlak Syndrome Type 9
    • Authors: Andrew R. Cullinane; James A. Curry; Carmelo Carmona-Rivera; C. Gail Summers; Carla Ciccone; Nicholas D. Cardillo; Heidi Dorward; Richard A. Hess; James G. White; David Adams; Marjan Huizing; William A. Gahl
      First page: 837
      Abstract: Publication date: 4 May 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 5
      Author(s): Andrew R. Cullinane, James A. Curry, Carmelo Carmona-Rivera, C. Gail Summers, Carla Ciccone, Nicholas D. Cardillo, Heidi Dorward, Richard A. Hess, James G. White, David Adams, Marjan Huizing, William A. Gahl

      PubDate: 2017-05-08T02:27:18Z
      DOI: 10.1016/j.ajhg.2017.04.011
  • This Month in The Journal
    • Authors: Sarah Ratzel; Sara B. Cullinan
      Pages: 567 - 568
      Abstract: Publication date: 4 May 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 5
      Author(s): Sarah Ratzel, Sara B. Cullinan

      PubDate: 2017-05-08T02:27:18Z
      DOI: 10.1016/j.ajhg.2017.03.007
  • This Month in Genetics
    • Authors: Kathryn B. Garber
      Pages: 569 - 570
      Abstract: Publication date: 4 May 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 5
      Author(s): Kathryn B. Garber

      PubDate: 2017-05-08T02:27:18Z
      DOI: 10.1016/j.ajhg.2017.03.006
  • 2016 Presidential Address: Let’s Make Human Genetics Great (Again): The
           Importance of Beauty in Science1
    • Authors: Harry C. Dietz
      Pages: 379 - 384
      Abstract: Publication date: 2 March 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 3
      Author(s): Harry C. Dietz

      PubDate: 2017-03-08T16:01:27Z
      DOI: 10.1016/j.ajhg.2017.01.009
  • This Month in The Journal
    • Authors: Sarah Ratzel; Sara B. Cullinan
      Pages: 181 - 182
      Abstract: Publication date: 6 April 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 4
      Author(s): Sarah Ratzel, Sara B. Cullinan

      PubDate: 2017-04-11T01:08:12Z
      DOI: 10.1016/j.ajhg.2016.12.007
  • This Month in The Journal
    • Authors: Sarah Ratzel; Sara B. Cullinan
      Pages: 181 - 182
      Abstract: Publication date: 2 March 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 3
      Author(s): Sarah Ratzel, Sara B. Cullinan

      PubDate: 2017-03-08T16:01:27Z
      DOI: 10.1016/j.ajhg.2016.12.007
  • This Month in Genetics
    • Authors: Kathryn B. Garber
      Pages: 183 - 184
      Abstract: Publication date: 6 April 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 4
      Author(s): Kathryn B. Garber

      PubDate: 2017-04-11T01:08:12Z
      DOI: 10.1016/j.ajhg.2017.01.015
  • This Month in Genetics
    • Authors: Kathryn B. Garber
      Pages: 183 - 184
      Abstract: Publication date: 2 March 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 3
      Author(s): Kathryn B. Garber

      PubDate: 2017-03-08T16:01:27Z
      DOI: 10.1016/j.ajhg.2017.01.015
  • De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a
           Syndromic Neurodevelopmental Disorder
    • Authors: Sébastien Küry; Thomas Besnard; Frédéric Ebstein; Tahir N. Khan; Tomasz Gambin; Jessica Douglas; Carlos A. Bacino; William J. Craigen; Stephan J. Sanders; Andrea Lehmann; Xénia Latypova; Kamal Khan; Mathilde Pacault; Stephanie Sacharow; Kimberly Glaser; Eric Bieth; Laurence Perrin-Sabourin; Marie-Line Jacquemont; Megan T. Cho; Elizabeth Roeder; Anne-Sophie Denommé-Pichon; Kristin G. Monaghan; Bo Yuan; Fan Xia; Sylvain Simon; Dominique Bonneau; Philippe Parent; Brigitte Gilbert-Dussardier; Sylvie Odent; Annick Toutain; Laurent Pasquier; Deborah Barbouth; Chad A. Shaw; Ankita Patel; Janice L. Smith; Weimin Bi; Sébastien Schmitt; Wallid Deb; Mathilde Nizon; Sandra Mercier; Marie Vincent; Caroline Rooryck; Valérie Malan; Ignacio Briceño; Alberto Gómez; Kimberly M. Nugent; James B. Gibson; Benjamin Cogné; James R. Lupski; Holly A.F. Stessman; Evan E. Eichler; Kyle Retterer; Yaping Yang; Richard Redon; Nicholas Katsanis; Jill A. Rosenfeld; Peter-Michael Kloetzel; Christelle Golzio; Stéphane Bézieau; Paweł Stankiewicz; Bertrand Isidor
      Pages: 352 - 363
      Abstract: Publication date: 6 April 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 4
      Author(s): Sébastien Küry, Thomas Besnard, Frédéric Ebstein, Tahir N. Khan, Tomasz Gambin, Jessica Douglas, Carlos A. Bacino, William J. Craigen, Stephan J. Sanders, Andrea Lehmann, Xénia Latypova, Kamal Khan, Mathilde Pacault, Stephanie Sacharow, Kimberly Glaser, Eric Bieth, Laurence Perrin-Sabourin, Marie-Line Jacquemont, Megan T. Cho, Elizabeth Roeder, Anne-Sophie Denommé-Pichon, Kristin G. Monaghan, Bo Yuan, Fan Xia, Sylvain Simon, Dominique Bonneau, Philippe Parent, Brigitte Gilbert-Dussardier, Sylvie Odent, Annick Toutain, Laurent Pasquier, Deborah Barbouth, Chad A. Shaw, Ankita Patel, Janice L. Smith, Weimin Bi, Sébastien Schmitt, Wallid Deb, Mathilde Nizon, Sandra Mercier, Marie Vincent, Caroline Rooryck, Valérie Malan, Ignacio Briceño, Alberto Gómez, Kimberly M. Nugent, James B. Gibson, Benjamin Cogné, James R. Lupski, Holly A.F. Stessman, Evan E. Eichler, Kyle Retterer, Yaping Yang, Richard Redon, Nicholas Katsanis, Jill A. Rosenfeld, Peter-Michael Kloetzel, Christelle Golzio, Stéphane Bézieau, Paweł Stankiewicz, Bertrand Isidor

      PubDate: 2017-04-11T01:08:12Z
      DOI: 10.1016/j.ajhg.2017.01.003
  • This Month in The Journal
    • Authors: Sarah Ratzel; Sara B. Cullinan
      Pages: 1 - 2
      Abstract: Publication date: 1 June 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 6
      Author(s): Sarah Ratzel, Sara B. Cullinan

      PubDate: 2017-06-02T04:46:06Z
      DOI: 10.1016/j.ajhg.2016.12.006
  • This Month in Genetics
    • Authors: Kathryn B. Garber
      Pages: 3 - 4
      Abstract: Publication date: 1 June 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 6
      Author(s): Kathryn B. Garber

      PubDate: 2017-06-02T04:46:06Z
      DOI: 10.1016/j.ajhg.2016.12.005
  • Mutations in ARMC9, which Encodes a Basal Body Protein, Cause Joubert
           Syndrome in Humans and Ciliopathy Phenotypes in Zebrafish
    • Authors: Julie C. Van De Weghe; Tamara D.S. Rusterholz; Brooke Latour; Megan E. Grout; Kimberly A. Aldinger; Ranad Shaheen; Jennifer C. Dempsey; Sateesh Maddirevula; Yong-Han H. Cheng; Ian G. Phelps; Matthias Gesemann; Himanshu Goel; Ohad S. Birk; Talal Alanzi; Rifaat Rawashdeh; Arif O. Khan; Michael J. Bamshad; Deborah A. Nickerson; Stephan C.F. Neuhauss; William B. Dobyns; Fowzan S. Alkuraya; Ronald Roepman; Ruxandra Bachmann-Gagescu; Dan Doherty
      Abstract: Publication date: Available online 15 June 2017
      Source:The American Journal of Human Genetics
      Author(s): Julie C. Van De Weghe, Tamara D.S. Rusterholz, Brooke Latour, Megan E. Grout, Kimberly A. Aldinger, Ranad Shaheen, Jennifer C. Dempsey, Sateesh Maddirevula, Yong-Han H. Cheng, Ian G. Phelps, Matthias Gesemann, Himanshu Goel, Ohad S. Birk, Talal Alanzi, Rifaat Rawashdeh, Arif O. Khan, Michael J. Bamshad, Deborah A. Nickerson, Stephan C.F. Neuhauss, William B. Dobyns, Fowzan S. Alkuraya, Ronald Roepman, Ruxandra Bachmann-Gagescu, Dan Doherty
      Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by hypotonia, ataxia, abnormal eye movements, and variable cognitive impairment. It is defined by a distinctive brain malformation known as the “molar tooth sign” on axial MRI. Subsets of affected individuals have malformations such as coloboma, polydactyly, and encephalocele, as well as progressive retinal dystrophy, fibrocystic kidney disease, and liver fibrosis. More than 35 genes have been associated with JS, but in a subset of families the genetic cause remains unknown. All of the gene products localize in and around the primary cilium, making JS a canonical ciliopathy. Ciliopathies are unified by their overlapping clinical features and underlying mechanisms involving ciliary dysfunction. In this work, we identify biallelic rare, predicted-deleterious ARMC9 variants (stop-gain, missense, splice-site, and single-exon deletion) in 11 individuals with JS from 8 families, accounting for approximately 1% of the disorder. The associated phenotypes range from isolated neurological involvement to JS with retinal dystrophy, additional brain abnormalities (e.g., heterotopia, Dandy-Walker malformation), pituitary insufficiency, and/or synpolydactyly. We show that ARMC9 localizes to the basal body of the cilium and is upregulated during ciliogenesis. Typical ciliopathy phenotypes (curved body shape, retinal dystrophy, coloboma, and decreased cilia) in a CRISPR/Cas9-engineered zebrafish mutant model provide additional support for ARMC9 as a ciliopathy-associated gene. Identifying ARMC9 mutations as a cause of JS takes us one step closer to a full genetic understanding of this important disorder and enables future functional work to define the central biological mechanisms underlying JS and other ciliopathies.

      PubDate: 2017-06-17T06:37:25Z
      DOI: 10.1016/j.ajhg.2017.05.010
  • Loss-of-Function Variants in MYLK Cause Recessive Megacystis Microcolon
           Intestinal Hypoperistalsis Syndrome
    • Authors: Danny Halim; Erwin Brosens; Françoise Muller; Michael F. Wangler; Arthur L. Beaudet; James R. Lupski; Zeynep H. Coban Akdemir; Michael Doukas; Hans J. Stoop; Bianca M. de Graaf; Rutger W.W. Brouwer; Wilfred F.J. van Ijcken; Jean-François Oury; Jonathan Rosenblatt; Alan J. Burns; Dick Tibboel; Robert M.W. Hofstra; Maria M. Alves
      Abstract: Publication date: Available online 8 June 2017
      Source:The American Journal of Human Genetics
      Author(s): Danny Halim, Erwin Brosens, Françoise Muller, Michael F. Wangler, Arthur L. Beaudet, James R. Lupski, Zeynep H. Coban Akdemir, Michael Doukas, Hans J. Stoop, Bianca M. de Graaf, Rutger W.W. Brouwer, Wilfred F.J. van Ijcken, Jean-François Oury, Jonathan Rosenblatt, Alan J. Burns, Dick Tibboel, Robert M.W. Hofstra, Maria M. Alves
      Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a congenital disorder characterized by loss of smooth muscle contraction in the bladder and intestine. To date, three genes are known to be involved in MMIHS pathogenesis: ACTG2, MYH11, and LMOD1. However, for approximately 10% of affected individuals, the genetic cause of the disease is unknown, suggesting that other loci are most likely involved. Here, we report on three MMIHS-affected subjects from two consanguineous families with no variants in the known MMIHS-associated genes. By performing homozygosity mapping and whole-exome sequencing, we found homozygous variants in myosin light chain kinase (MYLK) in both families. We identified a 7 bp duplication (c.3838_3844dupGAAAGCG [p.Glu1282_Glyfs∗51]) in one family and a putative splice-site variant (c.3985+5C>A) in the other. Expression studies and splicing assays indicated that both variants affect normal MYLK expression. Because MYLK encodes an important kinase required for myosin activation and subsequent interaction with actin filaments, it is likely that in its absence, contraction of smooth muscle cells is impaired. The existence of a conditional-Mylk-knockout mouse model with severe gut dysmotility and abnormal function of the bladder supports the involvement of this gene in MMIHS pathogenesis. In aggregate, our findings implicate MYLK as a gene involved in the recessive form of MMIHS, confirming that this disease of the visceral organs is heterogeneous with a myopathic origin.

      PubDate: 2017-06-17T06:37:25Z
      DOI: 10.1016/j.ajhg.2017.05.011
  • A Fast and Accurate Algorithm to Test for Binary Phenotypes and Its
           Application to PheWAS
    • Authors: Rounak Dey; Ellen Schmidt Goncalo Abecasis Seunggeun Lee
      Abstract: Publication date: Available online 8 June 2017
      Source:The American Journal of Human Genetics
      Author(s): Rounak Dey, Ellen M. Schmidt, Goncalo R. Abecasis, Seunggeun Lee
      The availability of electronic health record (EHR)-based phenotypes allows for genome-wide association analyses in thousands of traits and has great potential to enable identification of genetic variants associated with clinical phenotypes. We can interpret the phenome-wide association study (PheWAS) result for a single genetic variant by observing its association across a landscape of phenotypes. Because a PheWAS can test thousands of binary phenotypes, and most of them have unbalanced or often extremely unbalanced case-control ratios (1:10 or 1:600, respectively), existing methods cannot provide an accurate and scalable way to test for associations. Here, we propose a computationally fast score-test-based method that estimates the distribution of the test statistic by using the saddlepoint approximation. Our method is much (∼100 times) faster than the state-of-the-art Firth’s test. It can also adjust for covariates and control type I error rates even when the case-control ratio is extremely unbalanced. Through application to PheWAS data from the Michigan Genomics Initiative, we show that the proposed method can control type I error rates while replicating previously known association signals even for traits with a very small number of cases and a large number of controls.

      PubDate: 2017-06-17T06:37:25Z
  • Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals
           for Anthropometric Traits
    • Authors: Ioanna Tachmazidou; Josine Min Graham R.S. Ritchie Julia Steinberg Klaudia
      Abstract: Publication date: 1 June 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 6
      Author(s): Ioanna Tachmazidou, Dániel Süveges, Josine L. Min, Graham R.S. Ritchie, Julia Steinberg, Klaudia Walter, Valentina Iotchkova, Jeremy Schwartzentruber, Jie Huang, Yasin Memari, Shane McCarthy, Andrew A. Crawford, Cristina Bombieri, Massimiliano Cocca, Aliki-Eleni Farmaki, Tom R. Gaunt, Pekka Jousilahti, Marjolein N. Kooijman, Benjamin Lehne, Giovanni Malerba, Satu Männistö, Angela Matchan, Carolina Medina-Gomez, Sarah J. Metrustry, Abhishek Nag, Ioanna Ntalla, Lavinia Paternoster, Nigel W. Rayner, Cinzia Sala, William R. Scott, Hashem A. Shihab, Lorraine Southam, Beate St Pourcain, Michela Traglia, Katerina Trajanoska, Gialuigi Zaza, Weihua Zhang, María S. Artigas, Narinder Bansal, Marianne Benn, Zhongsheng Chen, Petr Danecek, Wei-Yu Lin, Adam Locke, Jian’an Luan, Alisa K. Manning, Antonella Mulas, Carlo Sidore, Anne Tybjaerg-Hansen, Anette Varbo, Magdalena Zoledziewska, Chris Finan, Konstantinos Hatzikotoulas, Audrey E. Hendricks, John P. Kemp, Alireza Moayyeri, Kalliope Panoutsopoulou, Michal Szpak, Scott G. Wilson, Michael Boehnke, Francesco Cucca, Emanuele Di Angelantonio, Claudia Langenberg, Cecilia Lindgren, Mark I. McCarthy, Andrew P. Morris, Børge G. Nordestgaard, Robert A. Scott, Martin D. Tobin, Nicholas J. Wareham, Paul Burton, John C. Chambers, George Davey Smith, George Dedoussis, Janine F. Felix, Oscar H. Franco, Giovanni Gambaro, Paolo Gasparini, Christopher J. Hammond, Albert Hofman, Vincent W.V. Jaddoe, Marcus Kleber, Jaspal S. Kooner, Markus Perola, Caroline Relton, Susan M. Ring, Fernando Rivadeneira, Veikko Salomaa, Timothy D. Spector, Oliver Stegle, Daniela Toniolo, André G. Uitterlinden, Inês Barroso, Celia M.T. Greenwood, John R.B. Perry, Brian R. Walker, Adam S. Butterworth, Yali Xue, Richard Durbin, Kerrin S. Small, Nicole Soranzo, Nicholas J. Timpson, Eleftheria Zeggini
      Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.

      PubDate: 2017-06-02T04:46:06Z
  • Evaluating the Clinical Validity of Gene-Disease Associations: An
           Evidence-Based Framework Developed by the Clinical Genome Resource
    • Authors: Natasha Strande; Erin Rooney Riggs Adam Buchanan Ozge Ceyhan-Birsoy Marina
      Abstract: Publication date: 1 June 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 6
      Author(s): Natasha T. Strande, Erin Rooney Riggs, Adam H. Buchanan, Ozge Ceyhan-Birsoy, Marina DiStefano, Selina S. Dwight, Jenny Goldstein, Rajarshi Ghosh, Bryce A. Seifert, Tam P. Sneddon, Matt W. Wright, Laura V. Milko, J. Michael Cherry, Monica A. Giovanni, Michael F. Murray, Julianne M. O’Daniel, Erin M. Ramos, Avni B. Santani, Alan F. Scott, Sharon E. Plon, Heidi L. Rehm, Christa L. Martin, Jonathan S. Berg
      With advances in genomic sequencing technology, the number of reported gene-disease relationships has rapidly expanded. However, the evidence supporting these claims varies widely, confounding accurate evaluation of genomic variation in a clinical setting. Despite the critical need to differentiate clinically valid relationships from less well-substantiated relationships, standard guidelines for such evaluation do not currently exist. The NIH-funded Clinical Genome Resource (ClinGen) has developed a framework to define and evaluate the clinical validity of gene-disease pairs across a variety of Mendelian disorders. In this manuscript we describe a proposed framework to evaluate relevant genetic and experimental evidence supporting or contradicting a gene-disease relationship and the subsequent validation of this framework using a set of representative gene-disease pairs. The framework provides a semiquantitative measurement for the strength of evidence of a gene-disease relationship that correlates to a qualitative classification: “Definitive,” “Strong,” “Moderate,” “Limited,” “No Reported Evidence,” or “Conflicting Evidence.” Within the ClinGen structure, classifications derived with this framework are reviewed and confirmed or adjusted based on clinical expertise of appropriate disease experts. Detailed guidance for utilizing this framework and access to the curation interface is available on our website. This evidence-based, systematic method to assess the strength of gene-disease relationships will facilitate more knowledgeable utilization of genomic variants in clinical and research settings.

      PubDate: 2017-06-02T04:46:06Z
  • Pleiotropic Effects of Trait-Associated Genetic Variation on DNA
           Methylation: Utility for Refining GWAS Loci
    • Authors: Eilis Hannon; Mike Weedon; Nicholas Bray; Michael O’Donovan; Jonathan Mill
      Abstract: Publication date: Available online 18 May 2017
      Source:The American Journal of Human Genetics
      Author(s): Eilis Hannon, Mike Weedon, Nicholas Bray, Michael O’Donovan, Jonathan Mill
      Most genetic variants identified in genome-wide association studies (GWASs) of complex traits are thought to act by affecting gene regulation rather than directly altering the protein product. As a consequence, the actual genes involved in disease are not necessarily the most proximal to the associated variants. By integrating data from GWAS analyses with those from genetic studies of regulatory variation, it is possible to identify variants pleiotropically associated with both a complex trait and measures of gene regulation. In this study, we used summary-data-based Mendelian randomization (SMR), a method developed to identify variants pleiotropically associated with both complex traits and gene expression, to identify variants associated with complex traits and DNA methylation. We used large DNA methylation quantitative trait locus (mQTL) datasets generated from two different tissues (blood and fetal brain) to prioritize genes for >40 complex traits with robust GWAS data and found considerable overlap with the results of SMR analyses performed with expression QTL (eQTL) data. We identified multiple examples of variable DNA methylation associated with GWAS variants for a range of complex traits, demonstrating the utility of this approach for refining genetic association signals.

      PubDate: 2017-05-23T02:36:34Z
      DOI: 10.1016/j.ajhg.2017.04.013
  • MARRVEL: Integration of Human and Model Organism Genetic Resources to
           Facilitate Functional Annotation of the Human Genome
    • Authors: Julia Wang; Rami Al-Ouran Yanhui Seon-Young Kim Ying-Wooi Wan Michael
      Abstract: Publication date: Available online 11 May 2017
      Source:The American Journal of Human Genetics
      Author(s): Julia Wang, Rami Al-Ouran, Yanhui Hu, Seon-Young Kim, Ying-Wooi Wan, Michael F. Wangler, Shinya Yamamoto, Hsiao-Tuan Chao, Aram Comjean, Stephanie E. Mohr, Norbert Perrimon, Zhandong Liu, Hugo J. Bellen
      One major challenge encountered with interpreting human genetic variants is the limited understanding of the functional impact of genetic alterations on biological processes. Furthermore, there remains an unmet demand for an efficient survey of the wealth of information on human homologs in model organisms across numerous databases. To efficiently assess the large volume of publically available information, it is important to provide a concise summary of the most relevant information in a rapid user-friendly format. To this end, we created MARRVEL (model organism aggregated resources for rare variant exploration). MARRVEL is a publicly available website that integrates information from six human genetic databases and seven model organism databases. For any given variant or gene, MARRVEL displays information from OMIM, ExAC, ClinVar, Geno2MP, DGV, and DECIPHER. Importantly, it curates model organism-specific databases to concurrently display a concise summary regarding the human gene homologs in budding and fission yeast, worm, fly, fish, mouse, and rat on a single webpage. Experiment-based information on tissue expression, protein subcellular localization, biological process, and molecular function for the human gene and homologs in the seven model organisms are arranged into a concise output. Hence, rather than visiting multiple separate databases for variant and gene analysis, users can obtain important information by searching once through MARRVEL. Altogether, MARRVEL dramatically improves efficiency and accessibility to data collection and facilitates analysis of human genes and variants by cross-disciplinary integration of 18 million records available in public databases to facilitate clinical diagnosis and basic research.

      PubDate: 2017-05-13T01:59:00Z
  • Duplicated Enhancer Region Increases Expression of CTSB and Segregates
           with Keratolytic Winter Erythema in South African and Norwegian Families
    • Authors: Thandiswa Ngcungcu; Martin Oti; Jan C. Sitek; Bjørn I. Haukanes; Bolan Linghu; Robert Bruccoleri; Tomasz Stokowy; Edward J. Oakeley; Fan Yang; Jiang Zhu; Marc Sultan; Joost Schalkwijk; Ivonne M.J.J. van Vlijmen-Willems; Charlotte von der Lippe; Han G. Brunner; Kari M. Ersland; Wayne Grayson; Stine Buechmann-Moller; Olav Sundnes; Nanguneri Nirmala; Thomas M. Morgan; Hans van Bokhoven; Vidar M. Steen; Peter R. Hull; Joseph Szustakowski; Frank Staedtler; Huiqing Zhou; Torunn Fiskerstrand; Michele Ramsay
      Abstract: Publication date: Available online 27 April 2017
      Source:The American Journal of Human Genetics
      Author(s): Thandiswa Ngcungcu, Martin Oti, Jan C. Sitek, Bjørn I. Haukanes, Bolan Linghu, Robert Bruccoleri, Tomasz Stokowy, Edward J. Oakeley, Fan Yang, Jiang Zhu, Marc Sultan, Joost Schalkwijk, Ivonne M.J.J. van Vlijmen-Willems, Charlotte von der Lippe, Han G. Brunner, Kari M. Ersland, Wayne Grayson, Stine Buechmann-Moller, Olav Sundnes, Nanguneri Nirmala, Thomas M. Morgan, Hans van Bokhoven, Vidar M. Steen, Peter R. Hull, Joseph Szustakowski, Frank Staedtler, Huiqing Zhou, Torunn Fiskerstrand, Michele Ramsay
      Keratolytic winter erythema (KWE) is a rare autosomal-dominant skin disorder characterized by recurrent episodes of palmoplantar erythema and epidermal peeling. KWE was previously mapped to 8p23.1–p22 (KWE critical region) in South African families. Using targeted resequencing of the KWE critical region in five South African families and SNP array and whole-genome sequencing in two Norwegian families, we identified two overlapping tandem duplications of 7.67 kb (South Africans) and 15.93 kb (Norwegians). The duplications segregated with the disease and were located upstream of CTSB, a gene encoding cathepsin B, a cysteine protease involved in keratinocyte homeostasis. Included in the 2.62 kb overlapping region of these duplications is an enhancer element that is active in epidermal keratinocytes. The activity of this enhancer correlated with CTSB expression in normal differentiating keratinocytes and other cell lines, but not with FDFT1 or NEIL2 expression. Gene expression (qPCR) analysis and immunohistochemistry of the palmar epidermis demonstrated significantly increased expression of CTSB, as well as stronger staining of cathepsin B in the stratum granulosum of affected individuals than in that of control individuals. Analysis of higher-order chromatin structure data and RNA polymerase II ChIA-PET data from MCF-7 cells did not suggest remote effects of the enhancer. In conclusion, KWE in South African and Norwegian families is caused by tandem duplications in a non-coding genomic region containing an active enhancer element for CTSB, resulting in upregulation of this gene in affected individuals.

      PubDate: 2017-05-02T02:23:36Z
      DOI: 10.1016/j.ajhg.2017.03.012
  • Dysfunction of the Cerebral Glucose Transporter SLC45A1 in Individuals
           with Intellectual Disability and Epilepsy
    • Authors: Myriam Srour; Noriaki Shimokawa; Fadi F. Hamdan; Christina Nassif; Chantal Poulin; Lihadh Al Gazali; Jill A. Rosenfeld; Noriyuki Koibuchi; Guy A. Rouleau; Aisha Al Shamsi; Jacques L. Michaud
      Abstract: Publication date: Available online 20 April 2017
      Source:The American Journal of Human Genetics
      Author(s): Myriam Srour, Noriaki Shimokawa, Fadi F. Hamdan, Christina Nassif, Chantal Poulin, Lihadh Al Gazali, Jill A. Rosenfeld, Noriyuki Koibuchi, Guy A. Rouleau, Aisha Al Shamsi, Jacques L. Michaud
      Glucose transport across the blood brain barrier and into neural cells is critical for normal cerebral physiologic function. Dysfunction of the cerebral glucose transporter GLUT1 (encoded by SLC2A1) is known to result in epilepsy, intellectual disability (ID), and movement disorder. Using whole-exome sequencing, we identified rare homozygous missense variants (c.526C>T [p.Arg176Trp] and c.629C>T [p.Ala210Val]) in SLC45A1, encoding another cerebral glucose transporter, in two consanguineous multiplex families with moderate to severe ID, epilepsy, and variable neuropsychiatric features. The variants segregate with the phenotype in these families, affect well-conserved amino acids, and are predicted to be damaging by in silico programs. Intracellular glucose transport activity of the p.Arg176Trp and p.Ala210Val SLC45A1 variants, measured in transfected COS-7 cells, was approximately 50% (p = 0.013) and 33% (p = 0.008) lower, respectively, than that of intact SLC45A1. These results indicate that residues at positions 176 and 210 are critical for the glucose transport activity of SLC45A1. All together, our data strongly suggest that recessive mutations in SLC45A1 cause ID and epilepsy. SLC45A1 thus represents the second cerebral glucose transporter, in addition to GLUT1, to be involved in neurodevelopmental disability. Identification of additional individuals with mutations in SLC45A1 will allow better definition of the associated phenotypic spectrum and the exploration of potential targeted treatment options.

      PubDate: 2017-04-25T01:33:29Z
      DOI: 10.1016/j.ajhg.2017.03.009
  • PLAA Mutations Cause a Lethal Infantile Epileptic Encephalopathy by
           Disrupting Ubiquitin-Mediated Endolysosomal Degradation of Synaptic
    • Authors: Emma A. Hall; Michael S. Nahorski; Lyndsay M. Murray; Ranad Shaheen; Emma Perkins; Kosala N. Dissanayake; Yosua Kristaryanto; Ross A. Jones; Julie Vogt; Manon Rivagorda; Mark T. Handley; Girish R. Mali; Tooba Quidwai; Dinesh C. Soares; Margaret A. Keighren; Lisa McKie; Richard L. Mort; Noor Gammoh; Amaya Garcia-Munoz; Tracey Davey; Matthieu Vermeren; Diana Walsh; Peter Budd; Irene A. Aligianis; Eissa Faqeih; Alan J. Quigley; Ian J. Jackson; Yogesh Kulathu; Mandy Jackson; Richard R. Ribchester; Alex von Kriegsheim; Fowzan S. Alkuraya; C. Geoffrey Woods; Eamonn R. Maher; Pleasantine Mill
      Abstract: Publication date: Available online 13 April 2017
      Source:The American Journal of Human Genetics
      Author(s): Emma A. Hall, Michael S. Nahorski, Lyndsay M. Murray, Ranad Shaheen, Emma Perkins, Kosala N. Dissanayake, Yosua Kristaryanto, Ross A. Jones, Julie Vogt, Manon Rivagorda, Mark T. Handley, Girish R. Mali, Tooba Quidwai, Dinesh C. Soares, Margaret A. Keighren, Lisa McKie, Richard L. Mort, Noor Gammoh, Amaya Garcia-Munoz, Tracey Davey, Matthieu Vermeren, Diana Walsh, Peter Budd, Irene A. Aligianis, Eissa Faqeih, Alan J. Quigley, Ian J. Jackson, Yogesh Kulathu, Mandy Jackson, Richard R. Ribchester, Alex von Kriegsheim, Fowzan S. Alkuraya, C. Geoffrey Woods, Eamonn R. Maher, Pleasantine Mill
      During neurotransmission, synaptic vesicles undergo multiple rounds of exo-endocytosis, involving recycling and/or degradation of synaptic proteins. While ubiquitin signaling at synapses is essential for neural function, it has been assumed that synaptic proteostasis requires the ubiquitin-proteasome system (UPS). We demonstrate here that turnover of synaptic membrane proteins via the endolysosomal pathway is essential for synaptic function. In both human and mouse, hypomorphic mutations in the ubiquitin adaptor protein PLAA cause an infantile-lethal neurodysfunction syndrome with seizures. Resulting from perturbed endolysosomal degradation, Plaa mutant neurons accumulate K63-polyubiquitylated proteins and synaptic membrane proteins, disrupting synaptic vesicle recycling and neurotransmission. Through characterization of this neurological intracellular trafficking disorder, we establish the importance of ubiquitin-mediated endolysosomal trafficking at the synapse.

      PubDate: 2017-04-18T01:12:23Z
      DOI: 10.1016/j.ajhg.2017.03.008
  • Germline Mutations in CDH23, Encoding Cadherin-Related 23, Are Associated
           with Both Familial and Sporadic Pituitary Adenomas
    • Authors: Qilin Zhang; Cheng Peng; Jianping Song; Yichao Zhang; Jianhua Chen; Zhijian Song; Xuefei Shou; Zengyi Ma; Hong Peng; Xuemin Jian; Wenqiang He; Zhao Ye; Zhiqiang Li; Yongfei Wang; Hongying Ye; Zhaoyun Zhang; Ming Shen; Feng Tang; Hong Chen; Zhifeng Shi; Chunjui Chen; Zhengyuan Chen; Yue Shen; Ye Wang; Shaoyong Lu; Jian Zhang; Yiming Li; Shiqi Li; Ying Mao; Liangfu Zhou; Hai Yan; Yongyong Shi; Chuanxin Huang; Yao Zhao
      Abstract: Publication date: Available online 13 April 2017
      Source:The American Journal of Human Genetics
      Author(s): Qilin Zhang, Cheng Peng, Jianping Song, Yichao Zhang, Jianhua Chen, Zhijian Song, Xuefei Shou, Zengyi Ma, Hong Peng, Xuemin Jian, Wenqiang He, Zhao Ye, Zhiqiang Li, Yongfei Wang, Hongying Ye, Zhaoyun Zhang, Ming Shen, Feng Tang, Hong Chen, Zhifeng Shi, Chunjui Chen, Zhengyuan Chen, Yue Shen, Ye Wang, Shaoyong Lu, Jian Zhang, Yiming Li, Shiqi Li, Ying Mao, Liangfu Zhou, Hai Yan, Yongyong Shi, Chuanxin Huang, Yao Zhao
      Pituitary adenoma (PA) is one of the most common intracranial neoplasms. Several genetic predisposing factors for PA have been identified, but they account for a small portion of cases. In this study, we sought to identify the PA genetic risk factors by focusing on causative mutations for PAs. Among the 4 affected and 17 asymptomatic members from one family with familial PA, whole-exome sequencing identified cosegregation of the PA phenotype with the heterozygous missense mutation c.4136G>T (p.Arg1379Leu) in cadherin-related 23 (CDH23). This mutation causes an amino acid substitution in the calcium-binding motif of the extracellular cadherin (EC) domains of CDH23 and is predicted to impair cell-cell adhesion. Genomic screening in a total of 12 families with familial PA (20 individuals), 125 individuals with sporadic PA, and 260 control individuals showed that 33% of the families with familial PA (4/12) and 12% of individuals with sporadic PA (15/125) harbored functional CDH23 variants. In contrast, 0.8% of the healthy control individuals (2/260) carried functional CDH23 variants. Gene-based analysis also revealed a significant association between CDH23 genotype and PA (p = 5.54 × 10−7). Moreover, PA individuals who did not harbor functional CDH23 variants displayed tumors that were larger in size (p = 0.005) and more invasive (p < 0.001). Therefore, mutations in CDH23 are linked with familial and sporadic PA and could play important roles in the pathogenesis of PA.

      PubDate: 2017-04-18T01:12:23Z
      DOI: 10.1016/j.ajhg.2017.03.011
  • Human Demographic History Impacts Genetic Risk Prediction across Diverse
    • Authors: Alicia R. Martin; Christopher R. Gignoux; Raymond K. Walters; Genevieve L. Wojcik; Benjamin M. Neale; Simon Gravel; Mark J. Daly; Carlos D. Bustamante; Eimear E. Kenny
      Abstract: Publication date: Available online 30 March 2017
      Source:The American Journal of Human Genetics
      Author(s): Alicia R. Martin, Christopher R. Gignoux, Raymond K. Walters, Genevieve L. Wojcik, Benjamin M. Neale, Simon Gravel, Mark J. Daly, Carlos D. Bustamante, Eimear E. Kenny
      The vast majority of genome-wide association studies (GWASs) are performed in Europeans, and their transferability to other populations is dependent on many factors (e.g., linkage disequilibrium, allele frequencies, genetic architecture). As medical genomics studies become increasingly large and diverse, gaining insights into population history and consequently the transferability of disease risk measurement is critical. Here, we disentangle recent population history in the widely used 1000 Genomes Project reference panel, with an emphasis on populations underrepresented in medical studies. To examine the transferability of single-ancestry GWASs, we used published summary statistics to calculate polygenic risk scores for eight well-studied phenotypes. We identify directional inconsistencies in all scores; for example, height is predicted to decrease with genetic distance from Europeans, despite robust anthropological evidence that West Africans are as tall as Europeans on average. To gain deeper quantitative insights into GWAS transferability, we developed a complex trait coalescent-based simulation framework considering effects of polygenicity, causal allele frequency divergence, and heritability. As expected, correlations between true and inferred risk are typically highest in the population from which summary statistics were derived. We demonstrate that scores inferred from European GWASs are biased by genetic drift in other populations even when choosing the same causal variants and that biases in any direction are possible and unpredictable. This work cautions that summarizing findings from large-scale GWASs may have limited portability to other populations using standard approaches and highlights the need for generalized risk prediction methods and the inclusion of more diverse individuals in medical genomics.

      PubDate: 2017-04-04T00:28:01Z
      DOI: 10.1016/j.ajhg.2017.03.004
  • Modeling the Mutational and Phenotypic Landscapes of Pelizaeus-Merzbacher
           Disease with Human iPSC-Derived Oligodendrocytes
    • Authors: Zachary S. Nevin; Daniel C. Factor; Robert T. Karl; Panagiotis Douvaras; Jeremy Laukka; Martha S. Windrem; Steven A. Goldman; Valentina Fossati; Grace M. Hobson; Paul J. Tesar
      Abstract: Publication date: Available online 30 March 2017
      Source:The American Journal of Human Genetics
      Author(s): Zachary S. Nevin, Daniel C. Factor, Robert T. Karl, Panagiotis Douvaras, Jeremy Laukka, Martha S. Windrem, Steven A. Goldman, Valentina Fossati, Grace M. Hobson, Paul J. Tesar
      Pelizaeus-Merzbacher disease (PMD) is a pediatric disease of myelin in the central nervous system and manifests with a wide spectrum of clinical severities. Although PMD is a rare monogenic disease, hundreds of mutations in the X-linked myelin gene proteolipid protein 1 (PLP1) have been identified in humans. Attempts to identify a common pathogenic process underlying PMD have been complicated by an incomplete understanding of PLP1 dysfunction and limited access to primary human oligodendrocytes. To address this, we generated panels of human induced pluripotent stem cells (hiPSCs) and hiPSC-derived oligodendrocytes from 12 individuals with mutations spanning the genetic and clinical diversity of PMD—including point mutations and duplication, triplication, and deletion of PLP1—and developed an in vitro platform for molecular and cellular characterization of all 12 mutations simultaneously. We identified individual and shared defects in PLP1 mRNA expression and splicing, oligodendrocyte progenitor development, and oligodendrocyte morphology and capacity for myelination. These observations enabled classification of PMD subgroups by cell-intrinsic phenotypes and identified a subset of mutations for targeted testing of small-molecule modulators of the endoplasmic reticulum stress response, which improved both morphologic and myelination defects. Collectively, these data provide insights into the pathogeneses of a variety of PLP1 mutations and suggest that disparate etiologies of PMD could require specific treatment approaches for subsets of individuals. More broadly, this study demonstrates the versatility of a hiPSC-based panel spanning the mutational heterogeneity within a single disease and establishes a widely applicable platform for genotype-phenotype correlation and drug screening in any human myelin disorder.

      PubDate: 2017-04-04T00:28:01Z
      DOI: 10.1016/j.ajhg.2017.03.005
  • Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome
           Associated with Seizures and Dysmorphic Features
    • Authors: Teresa Santiago-Sim; Lindsay C. Burrage; Frédéric Ebstein; Mari J. Tokita; Marcus Miller; Weimin Bi; Alicia A. Braxton; Jill A. Rosenfeld; Maher Shahrour; Andrea Lehmann; Benjamin Cogné; Sébastien Küry; Thomas Besnard; Bertrand Isidor; Stéphane Bézieau; Isabelle Hazart; Honey Nagakura; LaDonna L. Immken; Rebecca O. Littlejohn; Elizabeth Roeder; Bulent Kara; Katia Hardies; Sarah Weckhuysen; Patrick May; Johannes R. Lemke; Orly Elpeleg; Bassam Abu-Libdeh; Kiely N. James; Jennifer L. Silhavy; Mahmoud Y. Issa; Maha S. Zaki; Joseph G. Gleeson; John R. Seavitt; Mary E. Dickinson; M. Cecilia Ljungberg; Sara Wells; Sara J. Johnson; Lydia Teboul; Christine M. Eng; Yaping Yang; Peter-Michael Kloetzel; Jason D. Heaney; Magdalena A. Walkiewicz; Zaid Afawi; Rudi Balling; Nina Barisic; Stéphanie Baulac; Dana Craiu; Peter De Jonghe; Rosa Guerrero-Lopez; Renzo Guerrini; Ingo Helbig; Helle Hjalgrim; Johanna Jähn; Karl Martin Klein; Eric Leguern; Holger Lerche; Carla Marini; Hiltrud Muhle; Felix Rosenow; José Serratosa; Katalin Sterbová; Arvid Suls; Rikke S. Moller; Pasquale Striano; Yvonne Weber; Federico Zara
      Abstract: Publication date: Available online 23 March 2017
      Source:The American Journal of Human Genetics
      Author(s): Teresa Santiago-Sim, Lindsay C. Burrage, Frédéric Ebstein, Mari J. Tokita, Marcus Miller, Weimin Bi, Alicia A. Braxton, Jill A. Rosenfeld, Maher Shahrour, Andrea Lehmann, Benjamin Cogné, Sébastien Küry, Thomas Besnard, Bertrand Isidor, Stéphane Bézieau, Isabelle Hazart, Honey Nagakura, LaDonna L. Immken, Rebecca O. Littlejohn, Elizabeth Roeder, Bulent Kara, Katia Hardies, Sarah Weckhuysen, Patrick May, Johannes R. Lemke, Orly Elpeleg, Bassam Abu-Libdeh, Kiely N. James, Jennifer L. Silhavy, Mahmoud Y. Issa, Maha S. Zaki, Joseph G. Gleeson, John R. Seavitt, Mary E. Dickinson, M. Cecilia Ljungberg, Sara Wells, Sara J. Johnson, Lydia Teboul, Christine M. Eng, Yaping Yang, Peter-Michael Kloetzel, Jason D. Heaney, Magdalena A. Walkiewicz
      Ubiquitination is a posttranslational modification that regulates many cellular processes including protein degradation, intracellular trafficking, cell signaling, and protein-protein interactions. Deubiquitinating enzymes (DUBs), which reverse the process of ubiquitination, are important regulators of the ubiquitin system. OTUD6B encodes a member of the ovarian tumor domain (OTU)-containing subfamily of deubiquitinating enzymes. Herein, we report biallelic pathogenic variants in OTUD6B in 12 individuals from 6 independent families with an intellectual disability syndrome associated with seizures and dysmorphic features. In subjects with predicted loss-of-function alleles, additional features include global developmental delay, microcephaly, absent speech, hypotonia, growth retardation with prenatal onset, feeding difficulties, structural brain abnormalities, congenital malformations including congenital heart disease, and musculoskeletal features. Homozygous Otud6b knockout mice were subviable, smaller in size, and had congenital heart defects, consistent with the severity of loss-of-function variants in humans. Analysis of peripheral blood mononuclear cells from an affected subject showed reduced incorporation of 19S subunits into 26S proteasomes, decreased chymotrypsin-like activity, and accumulation of ubiquitin-protein conjugates. Our findings suggest a role for OTUD6B in proteasome function, establish that defective OTUD6B function underlies a multisystemic human disorder, and provide additional evidence for the emerging relationship between the ubiquitin system and human disease.

      PubDate: 2017-03-28T00:57:48Z
      DOI: 10.1016/j.ajhg.2017.03.001
  • Functional Architectures of Local and Distal Regulation of Gene Expression
           in Multiple Human Tissues
    • Authors: Xuanyao Liu; Hilary K. Finucane; Alexander Gusev; Gaurav Bhatia; Steven Gazal; Luke O’Connor; Brendan Bulik-Sullivan; Fred A. Wright; Patrick F. Sullivan; Benjamin M. Neale; Alkes L. Price
      Abstract: Publication date: Available online 23 March 2017
      Source:The American Journal of Human Genetics
      Author(s): Xuanyao Liu, Hilary K. Finucane, Alexander Gusev, Gaurav Bhatia, Steven Gazal, Luke O’Connor, Brendan Bulik-Sullivan, Fred A. Wright, Patrick F. Sullivan, Benjamin M. Neale, Alkes L. Price
      Genetic variants that modulate gene expression levels play an important role in the etiology of human diseases and complex traits. Although large-scale eQTL mapping studies routinely identify many local eQTLs, the molecular mechanisms by which genetic variants regulate expression remain unclear, particularly for distal eQTLs, which these studies are not well powered to detect. Here, we leveraged all variants (not just those that pass stringent significance thresholds) to analyze the functional architecture of local and distal regulation of gene expression in 15 human tissues by employing an extension of stratified LD-score regression that produces robust results in simulations. The top enriched functional categories in local regulation of peripheral-blood gene expression included coding regions (11.41×), conserved regions (4.67×), and four histone marks (p < 5 × 10−5 for all enrichments); local enrichments were similar across the 15 tissues. We also observed substantial enrichments for distal regulation of peripheral-blood gene expression: coding regions (4.47×), conserved regions (4.51×), and two histone marks (p < 3 × 10−7 for all enrichments). Analyses of the genetic correlation of gene expression across tissues confirmed that local regulation of gene expression is largely shared across tissues but that distal regulation is highly tissue specific. Our results elucidate the functional components of the genetic architecture of local and distal regulation of gene expression.

      PubDate: 2017-03-28T00:57:48Z
      DOI: 10.1016/j.ajhg.2017.03.002
  • De Novo Truncating Mutations in the Last and Penultimate Exons of PPM1D
           Cause an Intellectual Disability Syndrome
    • Authors: Sandra Jansen; Sinje Geuer; Rolph Pfundt; Rachel Brough; Priyanka Ghongane; Johanna C. Herkert; Elysa J. Marco; Marjolein H. Willemsen; Tjitske Kleefstra; Mark Hannibal; Joseph T. Shieh; Sally Ann Lynch; Frances Flinter; David R. FitzPatrick; Alice Gardham; Birgitta Bernhard; Nicola Ragge; Ruth Newbury-Ecob; Raphael Bernier; Malin Kvarnung; E.A. Helena Magnusson; Marja W. Wessels; Marjon A. van Slegtenhorst; Kristin G. Monaghan; Petra de Vries; Joris A. Veltman; Christopher J. Lord; Lisenka E.L.M. Vissers; Bert B.A. de Vries
      Abstract: Publication date: Available online 23 March 2017
      Source:The American Journal of Human Genetics
      Author(s): Sandra Jansen, Sinje Geuer, Rolph Pfundt, Rachel Brough, Priyanka Ghongane, Johanna C. Herkert, Elysa J. Marco, Marjolein H. Willemsen, Tjitske Kleefstra, Mark Hannibal, Joseph T. Shieh, Sally Ann Lynch, Frances Flinter, David R. FitzPatrick, Alice Gardham, Birgitta Bernhard, Nicola Ragge, Ruth Newbury-Ecob, Raphael Bernier, Malin Kvarnung, E.A. Helena Magnusson, Marja W. Wessels, Marjon A. van Slegtenhorst, Kristin G. Monaghan, Petra de Vries, Joris A. Veltman, Christopher J. Lord, Lisenka E.L.M. Vissers, Bert B.A. de Vries
      Intellectual disability (ID) is a highly heterogeneous disorder involving at least 600 genes, yet a genetic diagnosis remains elusive in ∼35%–40% of individuals with moderate to severe ID. Recent meta-analyses statistically analyzing de novo mutations in >7,000 individuals with neurodevelopmental disorders highlighted mutations in PPM1D as a possible cause of ID. PPM1D is a type 2C phosphatase that functions as a negative regulator of cellular stress-response pathways by mediating a feedback loop of p38-p53 signaling, thereby contributing to growth inhibition and suppression of stress-induced apoptosis. We identified 14 individuals with mild to severe ID and/or developmental delay and de novo truncating PPM1D mutations. Additionally, deep phenotyping revealed overlapping behavioral problems (ASD, ADHD, and anxiety disorders), hypotonia, broad-based gait, facial dysmorphisms, and periods of fever and vomiting. PPM1D is expressed during fetal brain development and in the adult brain. All mutations were located in the last or penultimate exon, suggesting escape from nonsense-mediated mRNA decay. Both PPM1D expression analysis and cDNA sequencing in EBV LCLs of individuals support the presence of a stable truncated transcript, consistent with this hypothesis. Exposure of cells derived from individuals with PPM1D truncating mutations to ionizing radiation resulted in normal p53 activation, suggesting that p53 signaling is unaffected. However, a cell-growth disadvantage was observed, suggesting a possible effect on the stress-response pathway. Thus, we show that de novo truncating PPM1D mutations in the last and penultimate exons cause syndromic ID, which provides additional insight into the role of cell-cycle checkpoint genes in neurodevelopmental disorders.

      PubDate: 2017-03-28T00:57:48Z
      DOI: 10.1016/j.ajhg.2017.02.005
  • Loss-of-Function Mutations in LGI4, a Secreted Ligand Involved in Schwann
           Cell Myelination, Are Responsible for Arthrogryposis Multiplex Congenita
    • Authors: Shifeng Xue; Jérôme Maluenda; Florent Marguet; Mohammad Shboul; Loïc Quevarec; Carine Bonnard; Alvin Yu Jin Ng; Sumanty Tohari; Thong Teck Tan; Mung Kei Kong; Kristin G. Monaghan; Megan T. Cho; Carly E. Siskind; Jacinda B. Sampson; Carolina Tesi Rocha; Fawaz Alkazaleh; Marie Gonzales; Luc Rigonnot; Sandra Whalen; Marta Gut; Ivo Gut; Martine Bucourt; Byrappa Venkatesh; Annie Laquerrière; Bruno Reversade; Judith Melki
      Abstract: Publication date: Available online 16 March 2017
      Source:The American Journal of Human Genetics
      Author(s): Shifeng Xue, Jérôme Maluenda, Florent Marguet, Mohammad Shboul, Loïc Quevarec, Carine Bonnard, Alvin Yu Jin Ng, Sumanty Tohari, Thong Teck Tan, Mung Kei Kong, Kristin G. Monaghan, Megan T. Cho, Carly E. Siskind, Jacinda B. Sampson, Carolina Tesi Rocha, Fawaz Alkazaleh, Marie Gonzales, Luc Rigonnot, Sandra Whalen, Marta Gut, Ivo Gut, Martine Bucourt, Byrappa Venkatesh, Annie Laquerrière, Bruno Reversade, Judith Melki
      Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through genetic mapping of disease loci and whole-exome sequencing in four unrelated multiplex families presenting with severe AMC, we identified biallelic loss-of-function mutations in LGI4 (leucine-rich glioma-inactivated 4). LGI4 is a ligand secreted by Schwann cells that regulates peripheral nerve myelination via its cognate receptor ADAM22 expressed by neurons. Immunolabeling experiments and transmission electron microscopy of the sciatic nerve from one of the affected individuals revealed a lack of myelin. Functional tests using affected individual-derived iPSCs showed that these germline mutations caused aberrant splicing of the endogenous LGI4 transcript and in a cell-based assay impaired the secretion of truncated LGI4 protein. This is consistent with previous studies reporting arthrogryposis in Lgi4-deficient mice due to peripheral hypomyelination. This study adds to the recent reports implicating defective axoglial function as a key cause of AMC.

      PubDate: 2017-03-28T00:57:48Z
      DOI: 10.1016/j.ajhg.2017.02.006
  • Mutations in TMEM260 Cause a Pediatric Neurodevelopmental, Cardiac, and
           Renal Syndrome
    • Authors: Asaf Ta-Shma; Tahir N. Khan; Asaf Vivante; Jason R. Willer; Pavle Matak; Chaim Jalas; Ben Pode-Shakked; Yishay Salem; Yair Anikster; Friedhelm Hildebrandt; Nicholas Katsanis; Orly Elpeleg; Erica E. Davis
      Abstract: Publication date: Available online 16 March 2017
      Source:The American Journal of Human Genetics
      Author(s): Asaf Ta-Shma, Tahir N. Khan, Asaf Vivante, Jason R. Willer, Pavle Matak, Chaim Jalas, Ben Pode-Shakked, Yishay Salem, Yair Anikster, Friedhelm Hildebrandt, Nicholas Katsanis, Orly Elpeleg, Erica E. Davis
      Despite the accelerated discovery of genes associated with syndromic traits, the majority of families affected by such conditions remain undiagnosed. Here, we employed whole-exome sequencing in two unrelated consanguineous kindreds with central nervous system (CNS), cardiac, renal, and digit abnormalities. We identified homozygous truncating mutations in TMEM260, a locus predicted to encode numerous splice isoforms. Systematic expression analyses across tissues and developmental stages validated two such isoforms, which differ in the utilization of an internal exon. The mutations in both families map uniquely to the long isoform, raising the possibility of an isoform-specific disorder. Consistent with this notion, RT-PCR of lymphocyte cell lines from one of the kindreds showed reduced levels of only the long isoform, which could be ameliorated by emetine, suggesting that the mutation induces nonsense-mediated decay. Subsequent in vivo testing supported this hypothesis. First, either transient suppression or CRISPR/Cas9 genome editing of zebrafish tmem260 recapitulated key neurological phenotypes. Second, co-injection of morphants with the long human TMEM260 mRNA rescued CNS pathology, whereas the short isoform was significantly less efficient. Finally, immunocytochemical and biochemical studies showed preferential enrichment of the long TMEM260 isoform to the plasma membrane. Together, our data suggest that there is overall reduced, but not ablated, functionality of TMEM260 and that attenuation of the membrane-associated functions of this protein is a principal driver of pathology. These observations contribute to an appreciation of the roles of splice isoforms in genetic disorders and suggest that dissection of the functions of these transcripts will most likely inform pathomechanism.

      PubDate: 2017-03-28T00:57:48Z
      DOI: 10.1016/j.ajhg.2017.02.007
  • Large-Scale trans-eQTLs Affect Hundreds of Transcripts and Mediate
           Patterns of Transcriptional Co-regulation
    • Authors: Boel Brynedal; JinMyung Choi; Towfique Raj; Robert Bjornson; Barbara E. Stranger; Benjamin M. Neale; Benjamin F. Voight; Chris Cotsapas
      Abstract: Publication date: Available online 9 March 2017
      Source:The American Journal of Human Genetics
      Author(s): Boel Brynedal, JinMyung Choi, Towfique Raj, Robert Bjornson, Barbara E. Stranger, Benjamin M. Neale, Benjamin F. Voight, Chris Cotsapas
      Efforts to decipher the causal relationships between differences in gene regulation and corresponding differences in phenotype have been stymied by several basic technical challenges. Although detecting local, cis-eQTLs is now routine, trans-eQTLs, which are distant from the genes of origin, are far more difficult to find because millions of SNPs must currently be compared to thousands of transcripts. Here, we demonstrate an alternative approach: we looked for SNPs associated with the expression of many genes simultaneously and found that hundreds of trans-eQTLs each affect hundreds of transcripts in lymphoblastoid cell lines across three African populations. These trans-eQTLs target the same genes across the three populations and show the same direction of effect. We discovered that target transcripts of a high-confidence set of trans-eQTLs encode proteins that interact more frequently than expected by chance, are bound by the same transcription factors, and are enriched for pathway annotations indicative of roles in basic cell homeostasis. We thus demonstrate that our approach can uncover trans-acting transcriptional control circuits that affect co-regulated groups of genes: a key to understanding how cellular pathways and processes are orchestrated.

      PubDate: 2017-03-12T16:15:43Z
      DOI: 10.1016/j.ajhg.2017.02.004
  • Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration
           with or without Additional Developmental Anomalies
    • Authors: Mingchu Xu; Yajing (Angela) Xie; Hana Abouzeid; Christopher T. Gordon; Alessia Fiorentino; Zixi Sun; Anna Lehman; Ihab S. Osman; Rachayata Dharmat; Rosa Riveiro-Alvarez; Linda Bapst-Wicht; Darwin Babino; Gavin Arno; Virginia Busetto; Li Zhao; Hui Li; Miguel A. Lopez-Martinez; Liliana F. Azevedo; Laurence Hubert; Nikolas Pontikos; Aiden Eblimit; Isabel Lorda-Sanchez; Valeria Kheir; Vincent Plagnol; Myriam Oufadem; Zachry T. Soens; Lizhu Yang; Christine Bole-Feysot; Rolph Pfundt; Nathalie Allaman-Pillet; Patrick Nitschké; Michael E. Cheetham; Stanislas Lyonnet; Smriti A. Agrawal; Huajin Li; Gaëtan Pinton; Michel Michaelides; Claude Besmond; Yumei Li; Zhisheng Yuan; Johannes von Lintig; Andrew R. Webster; Hervé Le Hir; Peter Stoilov; Jeanne Amiel; Alison J. Hardcastle; Carmen Ayuso; Ruifang Sui; Rui Chen; Rando Allikmets; Daniel F. Schorderet; Graeme Black; Georgina Hall; Rachel Gillespie; Simon Ramsden; Forbes Manson; Panagiotis Sergouniotis; Chris Inglehearn; Carmel Toomes; Manir Ali; Martin McKibbin; James Poulter; Emma Lord; Andrea Nemeth; Stephanie Halford; Susan Downes; Jing Yu
      Abstract: Publication date: Available online 9 March 2017
      Source:The American Journal of Human Genetics
      Author(s): Mingchu Xu, Yajing (Angela) Xie, Hana Abouzeid, Christopher T. Gordon, Alessia Fiorentino, Zixi Sun, Anna Lehman, Ihab S. Osman, Rachayata Dharmat, Rosa Riveiro-Alvarez, Linda Bapst-Wicht, Darwin Babino, Gavin Arno, Virginia Busetto, Li Zhao, Hui Li, Miguel A. Lopez-Martinez, Liliana F. Azevedo, Laurence Hubert, Nikolas Pontikos, Aiden Eblimit, Isabel Lorda-Sanchez, Valeria Kheir, Vincent Plagnol, Myriam Oufadem, Zachry T. Soens, Lizhu Yang, Christine Bole-Feysot, Rolph Pfundt, Nathalie Allaman-Pillet, Patrick Nitschké, Michael E. Cheetham, Stanislas Lyonnet, Smriti A. Agrawal, Huajin Li, Gaëtan Pinton, Michel Michaelides, Claude Besmond, Yumei Li, Zhisheng Yuan, Johannes von Lintig, Andrew R. Webster, Hervé Le Hir, Peter Stoilov, Jeanne Amiel, Alison J. Hardcastle, Carmen Ayuso, Ruifang Sui, Rui Chen, Rando Allikmets, Daniel F. Schorderet
      Pre-mRNA splicing factors play a fundamental role in regulating transcript diversity both temporally and spatially. Genetic defects in several spliceosome components have been linked to a set of non-overlapping spliceosomopathy phenotypes in humans, among which skeletal developmental defects and non-syndromic retinitis pigmentosa (RP) are frequent findings. Here we report that defects in spliceosome-associated protein CWC27 are associated with a spectrum of disease phenotypes ranging from isolated RP to severe syndromic forms. By whole-exome sequencing, recessive protein-truncating mutations in CWC27 were found in seven unrelated families that show a range of clinical phenotypes, including retinal degeneration, brachydactyly, craniofacial abnormalities, short stature, and neurological defects. Remarkably, variable expressivity of the human phenotype can be recapitulated in Cwc27 mutant mouse models, with significant embryonic lethality and severe phenotypes in the complete knockout mice while mice with a partial loss-of-function allele mimic the isolated retinal degeneration phenotype. Our study describes a retinal dystrophy-related phenotype spectrum as well as its genetic etiology and highlights the complexity of the spliceosomal gene network.

      PubDate: 2017-03-12T16:15:43Z
      DOI: 10.1016/j.ajhg.2017.02.008
  • Dynamic Role of trans Regulation of Gene Expression in Relation to Complex
    • Authors: Chen Yao; Roby Joehanes; Andrew D. Johnson; Tianxiao Huan; Chunyu Liu; Jane E. Freedman; Peter J. Munson; David E. Hill; Marc Vidal; Daniel Levy
      Abstract: Publication date: Available online 9 March 2017
      Source:The American Journal of Human Genetics
      Author(s): Chen Yao, Roby Joehanes, Andrew D. Johnson, Tianxiao Huan, Chunyu Liu, Jane E. Freedman, Peter J. Munson, David E. Hill, Marc Vidal, Daniel Levy
      Identifying causal genetic variants and understanding their mechanisms of effect on traits remains a challenge in genome-wide association studies (GWASs). In particular, how genetic variants (i.e., trans-eQTLs) affect expression of remote genes (i.e., trans-eGenes) remains unknown. We hypothesized that some trans-eQTLs regulate expression of distant genes by altering the expression of nearby genes (cis-eGenes). Using published GWAS datasets with 39,165 single-nucleotide polymorphisms (SNPs) associated with 1,960 traits, we explored whole blood gene expression associations of trait-associated SNPs in 5,257 individuals from the Framingham Heart Study. We identified 2,350 trans-eQTLs (at p < 10−7); more than 80% of them were found to have cis-associated eGenes. Mediation testing suggested that for 35% of trans-eQTL-trans-eGene pairs in different chromosomes and 90% pairs in the same chromosome, the disease-associated SNP may alter expression of the trans-eGene via cis-eGene expression. In addition, we identified 13 trans-eQTL hotspots, affecting from ten to hundreds of genes, suggesting the existence of master genetic regulators. Using causal inference testing, we searched causal variants across eight cardiometabolic traits (BMI, systolic and diastolic blood pressure, LDL cholesterol, HDL cholesterol, total cholesterol, triglycerides, and fasting blood glucose) and identified several cis-eGenes (ALDH2 for systolic and diastolic blood pressure, MCM6 and DARS for total cholesterol, and TRIB1 for triglycerides) that were causal mediators for the corresponding traits, as well as examples of trans-mediators (TAGAP for LDL cholesterol). The finding of extensive evidence of genome-wide mediation effects suggests a critical role of cryptic gene regulation underlying many disease traits.

      PubDate: 2017-03-12T16:15:43Z
      DOI: 10.1016/j.ajhg.2017.02.003
  • 2016 ASHG Awards and Addresses
    • Abstract: Publication date: 2 March 2017
      Source:The American Journal of Human Genetics, Volume 100, Issue 3
      Each year at the annual meeting of the American Society of Human Genetics (ASHG), addresses are given in honor of the society and a number of award winners. A summary of each of these is given below. On the following pages, we have printed the presidential address and the addresses for the William Allan Award, Curt Stern Award, and Victor A. McKusick Leadership Award. Webcasts of these addresses, as well as those of many other presentations, can be found at

      PubDate: 2017-03-08T16:01:27Z
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
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Fax: +00 44 (0)131 4513327
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