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Publisher: Elsevier   (Total: 3043 journals)

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Showing 1 - 200 of 3043 Journals sorted alphabetically
AASRI Procedia     Open Access   (Followers: 15)
Academic Pediatrics     Hybrid Journal   (Followers: 20, SJR: 1.402, h-index: 51)
Academic Radiology     Hybrid Journal   (Followers: 18, SJR: 1.008, h-index: 75)
Accident Analysis & Prevention     Partially Free   (Followers: 83, 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: 333, SJR: 0.726, h-index: 43)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 3)
Acta Biomaterialia     Hybrid Journal   (Followers: 25, SJR: 2.02, h-index: 104)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription   (Followers: 1)
Acta de Investigación Psicológica     Open Access   (Followers: 2)
Acta Ecologica Sinica     Open Access   (Followers: 8, SJR: 0.172, h-index: 29)
Acta Haematologica Polonica     Free   (SJR: 0.123, h-index: 8)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.604, h-index: 38)
Acta Materialia     Hybrid Journal   (Followers: 225, 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: 23, SJR: 1.365, h-index: 73)
Acta Sociológica     Open Access  
Acta Tropica     Hybrid Journal   (Followers: 6, SJR: 1.059, h-index: 77)
Acta Urológica Portuguesa     Open Access  
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 4)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 3)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 4, SJR: 0.383, h-index: 19)
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: 8, SJR: 1.039, h-index: 5)
Additives for Polymers     Full-text available via subscription   (Followers: 20)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 134, 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: 22, SJR: 1.286, h-index: 49)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 16, SJR: 3.31, h-index: 42)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.277, h-index: 43)
Advances in Botanical Research     Full-text available via subscription   (Followers: 3, SJR: 0.619, h-index: 48)
Advances in Cancer Research     Full-text available via subscription   (Followers: 25, SJR: 2.215, h-index: 78)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 9, SJR: 0.9, h-index: 30)
Advances in Catalysis     Full-text available via subscription   (Followers: 5, SJR: 2.139, h-index: 42)
Advances in 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: 10, 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: 42, 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: 47, SJR: 0.674, h-index: 38)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 15)
Advances in Genetics     Full-text available via subscription   (Followers: 15, SJR: 2.558, h-index: 54)
Advances in Genome Biology     Full-text available via subscription   (Followers: 11)
Advances in Geophysics     Full-text available via subscription   (Followers: 6, SJR: 2.325, h-index: 20)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 21, 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: 26)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 2, SJR: 0.396, h-index: 27)
Advances in Immunology     Full-text available via subscription   (Followers: 35, 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: 5)
Advances in Intl. Accounting     Full-text available via subscription   (Followers: 4)
Advances in Life Course Research     Hybrid Journal   (Followers: 8, SJR: 0.764, h-index: 15)
Advances in Lipobiology     Full-text available via subscription   (Followers: 2)
Advances in Magnetic and Optical Resonance     Full-text available via subscription   (Followers: 9)
Advances in Marine Biology     Full-text available via subscription   (Followers: 16, SJR: 1.645, h-index: 45)
Advances in Mathematics     Full-text available via subscription   (Followers: 10, SJR: 3.261, h-index: 65)
Advances in Medical Sciences     Hybrid Journal   (Followers: 6, SJR: 0.489, h-index: 25)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 4, SJR: 1.44, h-index: 51)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 22)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 10)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 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: 24, SJR: 0.4, h-index: 28)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 13)
Advances in Pharmacology     Full-text available via subscription   (Followers: 15, SJR: 1.718, h-index: 58)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 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: 60)
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: 345, SJR: 0.606, h-index: 65)
Advances in Structural Biology     Full-text available via subscription   (Followers: 8)
Advances in Surgery     Full-text available via subscription   (Followers: 7, SJR: 0.823, h-index: 27)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 30, SJR: 1.321, h-index: 56)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 16)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 13)
Advances in Virus Research     Full-text available via subscription   (Followers: 5, SJR: 1.878, h-index: 68)
Advances in Water Resources     Hybrid Journal   (Followers: 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: 310, SJR: 0.816, h-index: 49)
AEU - Intl. J. of Electronics and Communications     Hybrid Journal   (Followers: 8, SJR: 0.318, h-index: 36)
African J. of Emergency Medicine     Open Access   (Followers: 5, SJR: 0.344, h-index: 6)
Ageing Research Reviews     Hybrid Journal   (Followers: 8, SJR: 3.289, h-index: 78)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 408, 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: 53, 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: 9, 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: 4, 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: 7, SJR: 0.158, h-index: 9)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 48, 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: 48, SJR: 3.157, h-index: 153)
American J. of Cardiology     Hybrid Journal   (Followers: 45, SJR: 2.063, h-index: 186)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 38, 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: 16, SJR: 1.653, h-index: 93)
American J. of Human Genetics     Hybrid Journal   (Followers: 31, 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: 33, SJR: 2.313, h-index: 172)
American J. of Medicine     Hybrid Journal   (Followers: 46, SJR: 2.023, h-index: 189)
American J. of Medicine Supplements     Full-text available via subscription   (Followers: 3)
American J. of Obstetrics and Gynecology     Hybrid Journal   (Followers: 187, 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: 3)
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: 26, 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: 34, 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: 55, SJR: 0.124, h-index: 9)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 9)
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: 164, 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: 11)
Anesthésie & Réanimation     Full-text available via subscription   (Followers: 1)
Anesthesiology Clinics     Full-text available via subscription   (Followers: 22, SJR: 0.421, h-index: 40)
Angiología     Full-text available via subscription   (SJR: 0.124, h-index: 9)
Angiologia e Cirurgia Vascular     Open Access  
Animal Behaviour     Hybrid Journal   (Followers: 158, 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   (Followers: 1, 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]   [31 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0002-9297 - ISSN (Online) 1537-6605
   Published by Elsevier Homepage  [3043 journals]
  • This Month in The Journal
    • Authors: Sarah Ratzel; Sara B. Cullinan
      Pages: 159 - 160
      Abstract: Publication date: 3 August 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 2
      Author(s): Sarah Ratzel, Sara B. Cullinan

      PubDate: 2017-08-05T22:39:11Z
      DOI: 10.1016/j.ajhg.2017.07.008
  • This Month in Genetics
    • Authors: Kathryn B. Garber
      Pages: 161 - 162
      Abstract: Publication date: 3 August 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 2
      Author(s): Kathryn B. Garber

      PubDate: 2017-08-05T22:39:11Z
      DOI: 10.1016/j.ajhg.2017.07.009
  • William J. “Jack” Schull (1922–2017): Gentleman,
    • Authors: Kenneth M. Weiss
      Pages: 163 - 166
      Abstract: Publication date: 3 August 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 2
      Author(s): Kenneth M. Weiss

      PubDate: 2017-08-05T22:39:11Z
      DOI: 10.1016/j.ajhg.2017.07.003
  • Human Germline Genome Editing
    • Authors: Kelly E. Ormond; Douglas P. Mortlock; Derek T. Scholes; Yvonne Bombard; Lawrence C. Brody; W. Andrew Faucett; Nanibaa’ A. Garrison; Laura Hercher; Rosario Isasi; Anna Middleton; Kiran Musunuru; Daniel Shriner; Alice Virani; Caroline E. Young
      Pages: 167 - 176
      Abstract: Publication date: 3 August 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 2
      Author(s): Kelly E. Ormond, Douglas P. Mortlock, Derek T. Scholes, Yvonne Bombard, Lawrence C. Brody, W. Andrew Faucett, Nanibaa’ A. Garrison, Laura Hercher, Rosario Isasi, Anna Middleton, Kiran Musunuru, Daniel Shriner, Alice Virani, Caroline E. Young
      With CRISPR/Cas9 and other genome-editing technologies, successful somatic and germline genome editing are becoming feasible. To respond, an American Society of Human Genetics (ASHG) workgroup developed this position statement, which was approved by the ASHG Board in March 2017. The workgroup included representatives from the UK Association of Genetic Nurses and Counsellors, Canadian Association of Genetic Counsellors, International Genetic Epidemiology Society, and US National Society of Genetic Counselors. These groups, as well as the American Society for Reproductive Medicine, Asia Pacific Society of Human Genetics, British Society for Genetic Medicine, Human Genetics Society of Australasia, Professional Society of Genetic Counselors in Asia, and Southern African Society for Human Genetics, endorsed the final statement. The statement includes the following positions. (1) At this time, given the nature and number of unanswered scientific, ethical, and policy questions, it is inappropriate to perform germline gene editing that culminates in human pregnancy. (2) Currently, there is no reason to prohibit in vitro germline genome editing on human embryos and gametes, with appropriate oversight and consent from donors, to facilitate research on the possible future clinical applications of gene editing. There should be no prohibition on making public funds available to support this research. (3) Future clinical application of human germline genome editing should not proceed unless, at a minimum, there is (a) a compelling medical rationale, (b) an evidence base that supports its clinical use, (c) an ethical justification, and (d) a transparent public process to solicit and incorporate stakeholder input.

      PubDate: 2017-08-05T22:39:11Z
      DOI: 10.1016/j.ajhg.2017.06.012
  • From Peas to Disease: Modifier Genes, Network Resilience, and the Genetics
           of Health
    • Authors: Jesse D. Riordan; Joseph H. Nadeau
      Pages: 177 - 191
      Abstract: Publication date: 3 August 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 2
      Author(s): Jesse D. Riordan, Joseph H. Nadeau
      Phenotypes are rarely consistent across genetic backgrounds and environments, but instead vary in many ways depending on allelic variants, unlinked genes, epigenetic factors, and environmental exposures. In the extreme, individuals carrying the same causal DNA sequence variant but on different backgrounds can be classified as having distinct conditions. Similarly, some individuals that carry disease alleles are nevertheless healthy despite affected family members in the same environment. These genetic background effects often result from the action of so-called “modifier genes” that modulate the phenotypic manifestation of target genes in an epistatic manner. While complicating the prospects for gene discovery and the feasibility of mechanistic studies, such effects are opportunities to gain a deeper understanding of gene interaction networks that provide organismal form and function as well as resilience to perturbation. Here, we review the principles of modifier genetics and assess progress in studies of modifier genes and their targets in both simple and complex traits. We propose that modifier effects emerge from gene interaction networks whose structure and function vary with genetic background and argue that these effects can be exploited as safe and effective ways to prevent, stabilize, and reverse disease and dysfunction.

      PubDate: 2017-08-05T22:39:11Z
      DOI: 10.1016/j.ajhg.2017.06.004
  • Leveraging Multi-ethnic Evidence for Risk Assessment of Quantitative
           Traits in Minority Populations
    • Authors: Marc A. Coram; Huaying Fang; Sophie I. Candille; Themistocles L. Assimes; Hua Tang
      Pages: 218 - 226
      Abstract: Publication date: 3 August 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 2
      Author(s): Marc A. Coram, Huaying Fang, Sophie I. Candille, Themistocles L. Assimes, Hua Tang
      An essential component of precision medicine is the ability to predict an individual’s risk of disease based on genetic and non-genetic factors. For complex traits and diseases, assessing the risk due to genetic factors is challenging because it requires knowledge of both the identity of variants that influence the trait and their corresponding allelic effects. Although the set of risk variants and their allelic effects may vary between populations, a large proportion of these variants were identified based on studies in populations of European descent. Heterogeneity in genetic architecture underlying complex traits and diseases, while broadly acknowledged, remains poorly characterized. Ignoring such heterogeneity likely reduces predictive accuracy for minority individuals. In this study, we propose an approach, called XP-BLUP, which ameliorates this ethnic disparity by combining trans-ethnic and ethnic-specific information. We build a polygenic model for complex traits that distinguishes candidate trait-relevant variants from the rest of the genome. The set of candidate variants are selected based on studies in any human population, yet the allelic effects are evaluated in a population-specific fashion. Simulation studies and real data analyses demonstrate that XP-BLUP adaptively utilizes trans-ethnic information and can substantially improve predictive accuracy in minority populations. At the same time, our study highlights the importance of the continued expansion of minority cohorts.

      PubDate: 2017-08-05T22:39:11Z
      DOI: 10.1016/j.ajhg.2017.06.015
  • Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on
           Vitamin D Levels and Risk of Multiple Sclerosis
    • Authors: Despoina Manousaki; Tom Dudding; Simon Haworth; Yi-Hsiang Hsu; Ching-Ti Liu; Carolina Medina-Gómez; Trudy Voortman; Nathalie van der Velde; Håkan Melhus; Cassianne Robinson-Cohen; Diana L. Cousminer; Maria Nethander; Liesbeth Vandenput; Raymond Noordam; Vincenzo Forgetta; Celia M.T. Greenwood; Mary L. Biggs; Bruce M. Psaty; Jerome I. Rotter; Babette S. Zemel; Jonathan A. Mitchell; Bruce Taylor; Mattias Lorentzon; Magnus Karlsson; Vincent V.W. Jaddoe; Henning Tiemeier; Natalia Campos-Obando; Oscar H. Franco; Andre G. Utterlinden; Linda Broer; Natasja M. van Schoor; Annelies C. Ham; M. Arfan Ikram; David Karasik; Renée de Mutsert; Frits R. Rosendaal; Martin den Heijer; Thomas J. Wang; Lars Lind; Eric S. Orwoll; Dennis O. Mook-Kanamori; Karl Michaëlsson; Bryan Kestenbaum; Claes Ohlsson; Dan Mellström; Lisette C.P.G.M. de Groot; Struan F.A. Grant; Douglas P. Kiel; M. Carola Zillikens; Fernando Rivadeneira; Stephen Sawcer; Nicholas J. Timpson; J. Brent Richards
      Pages: 227 - 238
      Abstract: Publication date: 3 August 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 2
      Author(s): Despoina Manousaki, Tom Dudding, Simon Haworth, Yi-Hsiang Hsu, Ching-Ti Liu, Carolina Medina-Gómez, Trudy Voortman, Nathalie van der Velde, Håkan Melhus, Cassianne Robinson-Cohen, Diana L. Cousminer, Maria Nethander, Liesbeth Vandenput, Raymond Noordam, Vincenzo Forgetta, Celia M.T. Greenwood, Mary L. Biggs, Bruce M. Psaty, Jerome I. Rotter, Babette S. Zemel, Jonathan A. Mitchell, Bruce Taylor, Mattias Lorentzon, Magnus Karlsson, Vincent V.W. Jaddoe, Henning Tiemeier, Natalia Campos-Obando, Oscar H. Franco, Andre G. Utterlinden, Linda Broer, Natasja M. van Schoor, Annelies C. Ham, M. Arfan Ikram, David Karasik, Renée de Mutsert, Frits R. Rosendaal, Martin den Heijer, Thomas J. Wang, Lars Lind, Eric S. Orwoll, Dennis O. Mook-Kanamori, Karl Michaëlsson, Bryan Kestenbaum, Claes Ohlsson, Dan Mellström, Lisette C.P.G.M. de Groot, Struan F.A. Grant, Douglas P. Kiel, M. Carola Zillikens, Fernando Rivadeneira, Stephen Sawcer, Nicholas J. Timpson, J. Brent Richards
      Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124[A]), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (−0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 × 10−88). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.78–2.78, p = 1.26 × 10−12). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI = 1.19–1.64, p = 2.63 × 10−5) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.

      PubDate: 2017-08-05T22:39:11Z
      DOI: 10.1016/j.ajhg.2017.06.014
  • Biallelic Mutations in MRPS34 Lead to Instability of the Small
           Mitoribosomal Subunit and Leigh Syndrome
    • Authors: Nicole J. Lake; Bryn D. Webb; David A. Stroud; Tara R. Richman; Benedetta Ruzzenente; Alison G. Compton; Hayley S. Mountford; Juliette Pulman; Coralie Zangarelli; Marlene Rio; Nathalie Bodaert; Zahra Assouline; Mingma D. Sherpa; Eric E. Schadt; Sander M. Houten; James Byrnes; Elizabeth M. McCormick; Zarazuela Zolkipli-Cunningham; Katrina Haude; Zhancheng Zhang; Kyle Retterer; Renkui Bai; Sarah E. Calvo; Vamsi K. Mootha; John Christodoulou; Agnes Rötig; Aleksandra Filipovska; Ingrid Cristian; Marni J. Falk; Metodi D. Metodiev; David R. Thorburn
      Pages: 239 - 254
      Abstract: Publication date: 3 August 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 2
      Author(s): Nicole J. Lake, Bryn D. Webb, David A. Stroud, Tara R. Richman, Benedetta Ruzzenente, Alison G. Compton, Hayley S. Mountford, Juliette Pulman, Coralie Zangarelli, Marlene Rio, Nathalie Bodaert, Zahra Assouline, Mingma D. Sherpa, Eric E. Schadt, Sander M. Houten, James Byrnes, Elizabeth M. McCormick, Zarazuela Zolkipli-Cunningham, Katrina Haude, Zhancheng Zhang, Kyle Retterer, Renkui Bai, Sarah E. Calvo, Vamsi K. Mootha, John Christodoulou, Agnes Rötig, Aleksandra Filipovska, Ingrid Cristian, Marni J. Falk, Metodi D. Metodiev, David R. Thorburn
      The synthesis of all 13 mitochondrial DNA (mtDNA)-encoded protein subunits of the human oxidative phosphorylation (OXPHOS) system is carried out by mitochondrial ribosomes (mitoribosomes). Defects in the stability of mitoribosomal proteins or mitoribosome assembly impair mitochondrial protein translation, causing combined OXPHOS enzyme deficiency and clinical disease. Here we report four autosomal-recessive pathogenic mutations in the gene encoding the small mitoribosomal subunit protein, MRPS34, in six subjects from four unrelated families with Leigh syndrome and combined OXPHOS defects. Whole-exome sequencing was used to independently identify all variants. Two splice-site mutations were identified, including homozygous c.321+1G>T in a subject of Italian ancestry and homozygous c.322−10G>A in affected sibling pairs from two unrelated families of Puerto Rican descent. In addition, compound heterozygous MRPS34 mutations were identified in a proband of French ancestry; a missense (c.37G>A [p.Glu13Lys]) and a nonsense (c.94C>T [p.Gln32∗]) variant. We demonstrated that these mutations reduce MRPS34 protein levels and the synthesis of OXPHOS subunits encoded by mtDNA. Examination of the mitoribosome profile and quantitative proteomics showed that the mitochondrial translation defect was caused by destabilization of the small mitoribosomal subunit and impaired monosome assembly. Lentiviral-mediated expression of wild-type MRPS34 rescued the defect in mitochondrial translation observed in skin fibroblasts from affected subjects, confirming the pathogenicity of MRPS34 mutations. Our data establish that MRPS34 is required for normal function of the mitoribosome in humans and furthermore demonstrate the power of quantitative proteomic analysis to identify signatures of defects in specific cellular pathways in fibroblasts from subjects with inherited disease.

      PubDate: 2017-08-05T22:39:11Z
      DOI: 10.1016/j.ajhg.2017.07.005
  • Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13
           by Modulating the Response to DNA Damage
    • Authors: Joshua A. Betts; Mahdi Moradi Marjaneh; Fares Al-Ejeh; Yi Chieh Lim; Wei Shi; Haran Sivakumaran; Romain Tropée; Ann-Marie Patch; Michael B. Clark; Nenad Bartonicek; Adrian P. Wiegmans; Kristine M. Hillman; Susanne Kaufmann; Amanda L. Bain; Brian S. Gloss; Joanna Crawford; Stephen Kazakoff; Shivangi Wani; Shu W. Wen; Bryan Day; Andreas Möller; Nicole Cloonan; John Pearson; Melissa A. Brown; Timothy R. Mercer; Nicola Waddell; Kum Kum Khanna; Eloise Dray; Marcel E. Dinger; Stacey L. Edwards; Juliet D. French
      Pages: 255 - 266
      Abstract: Publication date: 3 August 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 2
      Author(s): Joshua A. Betts, Mahdi Moradi Marjaneh, Fares Al-Ejeh, Yi Chieh Lim, Wei Shi, Haran Sivakumaran, Romain Tropée, Ann-Marie Patch, Michael B. Clark, Nenad Bartonicek, Adrian P. Wiegmans, Kristine M. Hillman, Susanne Kaufmann, Amanda L. Bain, Brian S. Gloss, Joanna Crawford, Stephen Kazakoff, Shivangi Wani, Shu W. Wen, Bryan Day, Andreas Möller, Nicole Cloonan, John Pearson, Melissa A. Brown, Timothy R. Mercer, Nicola Waddell, Kum Kum Khanna, Eloise Dray, Marcel E. Dinger, Stacey L. Edwards, Juliet D. French
      Breast cancer risk is strongly associated with an intergenic region on 11q13. We have previously shown that the strongest risk-associated SNPs fall within a distal enhancer that regulates CCND1. Here, we report that, in addition to regulating CCND1, this enhancer regulates two estrogen-regulated long noncoding RNAs, CUPID1 and CUPID2. We provide evidence that the risk-associated SNPs are associated with reduced chromatin looping between the enhancer and the CUPID1 and CUPID2 bidirectional promoter. We further show that CUPID1 and CUPID2 are predominantly expressed in hormone-receptor-positive breast tumors and play a role in modulating pathway choice for the repair of double-strand breaks. These data reveal a mechanism for the involvement of this region in breast cancer.

      PubDate: 2017-08-05T22:39:11Z
      DOI: 10.1016/j.ajhg.2017.07.007
  • Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with
           Neurodegeneration in Childhood
    • Authors: Simon Edvardson; Claudia M. Nicolae; Pankaj B. Agrawal; Cyril Mignot; Katelyn Payne; Asuri Narayan Prasad; Chitra Prasad; Laurie Sadler; Caroline Nava; Thomas E. Mullen; Amber Begtrup; Berivan Baskin; Zöe Powis; Avraham Shaag; Boris Keren; George-Lucian Moldovan; Orly Elpeleg
      Pages: 267 - 273
      Abstract: Publication date: 3 August 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 2
      Author(s): Simon Edvardson, Claudia M. Nicolae, Pankaj B. Agrawal, Cyril Mignot, Katelyn Payne, Asuri Narayan Prasad, Chitra Prasad, Laurie Sadler, Caroline Nava, Thomas E. Mullen, Amber Begtrup, Berivan Baskin, Zöe Powis, Avraham Shaag, Boris Keren, George-Lucian Moldovan, Orly Elpeleg
      Ribosomal RNA (rRNA) is transcribed from rDNA by RNA polymerase I (Pol I) to produce the 45S precursor of the 28S, 5.8S, and 18S rRNA components of the ribosome. Two transcription factors have been defined for Pol I in mammals, the selectivity factor SL1, and the upstream binding transcription factor (UBF), which interacts with the upstream control element to facilitate the assembly of the transcription initiation complex including SL1 and Pol I. In seven unrelated affected individuals, all suffering from developmental regression starting at 2.5–7 years, we identified a heterozygous variant, c.628G>A in UBTF, encoding p.Glu210Lys in UBF, which occurred de novo in all cases. While the levels of UBF, Ser388 phosphorylated UBF, and other Pol I-related components (POLR1E, TAF1A, and TAF1C) remained unchanged in cells of an affected individual, the variant conferred gain of function to UBF, manifesting by markedly increased UBF binding to the rDNA promoter and to the 5′- external transcribed spacer. This was associated with significantly increased 18S expression, and enlarged nucleoli which were reduced in number per cell. The data link neurodegeneration in childhood with altered rDNA chromatin status and rRNA metabolism.

      PubDate: 2017-08-05T22:39:11Z
      DOI: 10.1016/j.ajhg.2017.07.002
  • Biallelic Mutations in LIPT2 Cause a Mitochondrial Lipoylation Defect
           Associated with Severe Neonatal Encephalopathy
    • Authors: Florence Habarou; Yamina Hamel; Tobias B. Haack; René G. Feichtinger; Elise Lebigot; Iris Marquardt; Kanetee Busiah; Cécile Laroche; Marine Madrange; Coraline Grisel; Clément Pontoizeau; Monika Eisermann; Audrey Boutron; Dominique Chrétien; Bernadette Chadefaux-Vekemans; Robert Barouki; Christine Bole-Feysot; Patrick Nitschke; Nicolas Goudin; Nathalie Boddaert; Ivan Nemazanyy; Agnès Delahodde; Stefan Kölker; Richard J. Rodenburg; G. Christoph Korenke; Thomas Meitinger; Tim M. Strom; Holger Prokisch; Agnes Rotig; Chris Ottolenghi; Johannes A. Mayr; Pascale de Lonlay
      Pages: 283 - 290
      Abstract: Publication date: 3 August 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 2
      Author(s): Florence Habarou, Yamina Hamel, Tobias B. Haack, René G. Feichtinger, Elise Lebigot, Iris Marquardt, Kanetee Busiah, Cécile Laroche, Marine Madrange, Coraline Grisel, Clément Pontoizeau, Monika Eisermann, Audrey Boutron, Dominique Chrétien, Bernadette Chadefaux-Vekemans, Robert Barouki, Christine Bole-Feysot, Patrick Nitschke, Nicolas Goudin, Nathalie Boddaert, Ivan Nemazanyy, Agnès Delahodde, Stefan Kölker, Richard J. Rodenburg, G. Christoph Korenke, Thomas Meitinger, Tim M. Strom, Holger Prokisch, Agnes Rotig, Chris Ottolenghi, Johannes A. Mayr, Pascale de Lonlay
      Lipoate serves as a cofactor for the glycine cleavage system (GCS) and four 2-oxoacid dehydrogenases functioning in energy metabolism (α-oxoglutarate dehydrogenase [α-KGDHc] and pyruvate dehydrogenase [PDHc]), or amino acid metabolism (branched-chain oxoacid dehydrogenase, 2-oxoadipate dehydrogenase). Mitochondrial lipoate synthesis involves three enzymatic steps catalyzed sequentially by lipoyl(octanoyl) transferase 2 (LIPT2), lipoic acid synthetase (LIAS), and lipoyltransferase 1 (LIPT1). Mutations in LIAS have been associated with nonketotic hyperglycinemia-like early-onset convulsions and encephalopathy combined with a defect in mitochondrial energy metabolism. LIPT1 deficiency spares GCS deficiency and has been associated with a biochemical signature of combined 2-oxoacid dehydrogenase deficiency leading to early death or Leigh-like encephalopathy. We report on the identification of biallelic LIPT2 mutations in three affected individuals from two families with severe neonatal encephalopathy. Brain MRI showed major cortical atrophy with white matter abnormalities and cysts. Plasma glycine was mildly increased. Affected individuals’ fibroblasts showed reduced oxygen consumption rates, PDHc, α-KGDHc activities, leucine catabolic flux, and decreased protein lipoylation. A normalization of lipoylation was observed after expression of wild-type LIPT2, arguing for LIPT2 requirement in intramitochondrial lipoate synthesis. Lipoic acid supplementation did not improve clinical condition nor activities of PDHc, α-KGDHc, or leucine metabolism in fibroblasts and was ineffective in yeast deleted for the orthologous LIP2.

      PubDate: 2017-08-05T22:39:11Z
      DOI: 10.1016/j.ajhg.2017.07.001
  • Mutations in TRAPPC12 Manifest in Progressive Childhood Encephalopathy and
           Golgi Dysfunction
    • Authors: Miroslav P. Milev; Megan E. Grout; Djenann Saint-Dic; Yong-Han Hank Cheng; Ian A. Glass; Christopher J. Hale; David S. Hanna; Michael O. Dorschner; Keshika Prematilake; Avraham Shaag; Orly Elpeleg; Michael Sacher; Dan Doherty; Simon Edvardson
      Pages: 291 - 299
      Abstract: Publication date: 3 August 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 2
      Author(s): Miroslav P. Milev, Megan E. Grout, Djenann Saint-Dic, Yong-Han Hank Cheng, Ian A. Glass, Christopher J. Hale, David S. Hanna, Michael O. Dorschner, Keshika Prematilake, Avraham Shaag, Orly Elpeleg, Michael Sacher, Dan Doherty, Simon Edvardson
      Progressive childhood encephalopathy is an etiologically heterogeneous condition characterized by progressive central nervous system dysfunction in association with a broad range of morbidity and mortality. The causes of encephalopathy can be either non-genetic or genetic. Identifying the genetic causes and dissecting the underlying mechanisms are critical to understanding brain development and improving treatments. Here, we report that variants in TRAPPC12 result in progressive childhood encephalopathy. Three individuals from two unrelated families have either a homozygous deleterious variant (c.145delG [p.Glu49Argfs∗14]) or compound-heterozygous variants (c.360dupC [p.Glu121Argfs∗7] and c.1880C>T [p. Ala627Val]). The clinical phenotypes of the three individuals are strikingly similar: severe disability, microcephaly, hearing loss, spasticity, and characteristic brain imaging findings. Fibroblasts derived from all three individuals showed a fragmented Golgi that could be rescued by expression of wild-type TRAPPC12. Protein transport from the endoplasmic reticulum to and through the Golgi was delayed. TRAPPC12 is a member of the TRAPP protein complex, which functions in membrane trafficking. Variants in several other genes encoding members of the TRAPP complex have been associated with overlapping clinical presentations, indicating shared and distinct functions for each complex member. Detailed understanding of the TRAPP-opathies will illuminate the role of membrane protein transport in human disease.

      PubDate: 2017-08-05T22:39:11Z
      DOI: 10.1016/j.ajhg.2017.07.006
  • De Novo Mutations in YWHAG Cause Early-Onset Epilepsy
    • Authors: Ilaria Guella; Marna B. McKenzie; Daniel M. Evans; Sarah E. Buerki; Eric B. Toyota; Margot I. Van Allen; Mohnish Suri; Frances Elmslie; Marleen E.H. Simon; Koen L.I. van Gassen; Delphine Héron; Boris Keren; Caroline Nava; Mary B. Connolly; Michelle Demos; Matthew J. Farrer; Shelin Adam; Cyrus Boelman; Corneliu Bolbocean; Tara Candido; Patrice Eydoux; Gabriella Horvath; Linda Huh; Tanya N. Nelson; Graham Sinclair; Clara van Karnebeek; Suzanne Vercauteren
      Pages: 300 - 310
      Abstract: Publication date: 3 August 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 2
      Author(s): Ilaria Guella, Marna B. McKenzie, Daniel M. Evans, Sarah E. Buerki, Eric B. Toyota, Margot I. Van Allen, Mohnish Suri, Frances Elmslie, Marleen E.H. Simon, Koen L.I. van Gassen, Delphine Héron, Boris Keren, Caroline Nava, Mary B. Connolly, Michelle Demos, Matthew J. Farrer
      Massively parallel sequencing has revealed many de novo mutations in the etiology of developmental and epileptic encephalopathies (EEs), highlighting their genetic heterogeneity. Additional candidate genes have been prioritized in silico by their co-expression in the brain. Here, we evaluate rare coding variability in 20 candidates nominated with the use of a reference gene set of 51 established EE-associated genes. Variants within the 20 candidate genes were extracted from exome-sequencing data of 42 subjects with EE and no previous genetic diagnosis. We identified 7 rare non-synonymous variants in 7 of 20 genes and performed Sanger sequence validation in affected probands and parental samples. De novo variants were found only in SLC1A2 (aka EAAT2 or GLT1) (c.244G>A [p.Gly82Arg]) and YWHAG (aka 14-3-3γ) (c.394C>T [p.Arg132Cys]), highlighting the potential cause of EE in 5% (2/42) of subjects. Seven additional subjects with de novo variants in SLC1A2 (n = 1) and YWHAG (n = 6) were subsequently identified through online tools. We identified a highly significant enrichment of de novo variants in YWHAG, establishing their role in early-onset epilepsy, and we provide additional support for the prior assignment of SLC1A2. Hence, in silico modeling of brain co-expression is an efficient method for nominating EE-associated genes to further elucidate the disorder’s etiology and genotype-phenotype correlations.

      PubDate: 2017-08-05T22:39:11Z
      DOI: 10.1016/j.ajhg.2017.07.004
  • 10 Years of GWAS Discovery: Biology, Function, and Translation
    • Authors: Peter M. Visscher; Naomi R. Wray; Qian Zhang; Pamela Sklar; Mark I. McCarthy; Matthew A. Brown; Jian Yang
      Pages: 5 - 22
      Abstract: Publication date: 6 July 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 1
      Author(s): Peter M. Visscher, Naomi R. Wray, Qian Zhang, Pamela Sklar, Mark I. McCarthy, Matthew A. Brown, Jian Yang
      Application of the experimental design of genome-wide association studies (GWASs) is now 10 years old (young), and here we review the remarkable range of discoveries it has facilitated in population and complex-trait genetics, the biology of diseases, and translation toward new therapeutics. We predict the likely discoveries in the next 10 years, when GWASs will be based on millions of samples with array data imputed to a large fully sequenced reference panel and on hundreds of thousands of samples with whole-genome sequencing data.

      PubDate: 2017-07-10T07:11:06Z
      DOI: 10.1016/j.ajhg.2017.06.005
  • Integrative Genetic and Epigenetic Analysis Uncovers Regulatory Mechanisms
           of Autoimmune Disease
    • Authors: Parisa Shooshtari; Hailiang Huang; Chris Cotsapas
      Pages: 75 - 86
      Abstract: Publication date: 6 July 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 1
      Author(s): Parisa Shooshtari, Hailiang Huang, Chris Cotsapas
      Genome-wide association studies in autoimmune and inflammatory diseases (AID) have uncovered hundreds of loci mediating risk. These associations are preferentially located in non-coding DNA regions and in particular in tissue-specific DNase I hypersensitivity sites (DHSs). While these analyses clearly demonstrate the overall enrichment of disease risk alleles on gene regulatory regions, they are not designed to identify individual regulatory regions mediating risk or the genes under their control, and thus uncover the specific molecular events driving disease risk. To do so we have departed from standard practice by identifying regulatory regions which replicate across samples and connect them to the genes they control through robust re-analysis of public data. We find significant evidence of regulatory potential in 78/301 (26%) risk loci across nine autoimmune and inflammatory diseases, and we find that individual genes are targeted by these effects in 53/78 (68%) of these. Thus, we are able to generate testable mechanistic hypotheses of the molecular changes that drive disease risk.

      PubDate: 2017-07-10T07:11:06Z
      DOI: 10.1016/j.ajhg.2017.06.001
  • A Pentanucleotide ATTTC Repeat Insertion in the Non-coding Region of DAB1,
           Mapping to SCA37, Causes Spinocerebellar Ataxia
    • Authors: Ana I. Seixas; Joana R. Loureiro; Cristina Costa; Andrés Ordóñez-Ugalde; Hugo Marcelino; Cláudia L. Oliveira; José L. Loureiro; Ashutosh Dhingra; Eva Brandão; Vitor T. Cruz; Angela Timóteo; Beatriz Quintáns; Guy A. Rouleau; Patrizia Rizzu; Ángel Carracedo; José Bessa; Peter Heutink; Jorge Sequeiros; Maria J. Sobrido; Paula Coutinho; Isabel Silveira
      Pages: 87 - 103
      Abstract: Publication date: 6 July 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 1
      Author(s): Ana I. Seixas, Joana R. Loureiro, Cristina Costa, Andrés Ordóñez-Ugalde, Hugo Marcelino, Cláudia L. Oliveira, José L. Loureiro, Ashutosh Dhingra, Eva Brandão, Vitor T. Cruz, Angela Timóteo, Beatriz Quintáns, Guy A. Rouleau, Patrizia Rizzu, Ángel Carracedo, José Bessa, Peter Heutink, Jorge Sequeiros, Maria J. Sobrido, Paula Coutinho, Isabel Silveira
      Advances in human genetics in recent years have largely been driven by next-generation sequencing (NGS); however, the discovery of disease-related gene mutations has been biased toward the exome because the large and very repetitive regions that characterize the non-coding genome remain difficult to reach by that technology. For autosomal-dominant spinocerebellar ataxias (SCAs), 28 genes have been identified, but only five SCAs originate from non-coding mutations. Over half of SCA-affected families, however, remain without a genetic diagnosis. We used genome-wide linkage analysis, NGS, and repeat analysis to identify an (ATTTC)n insertion in a polymorphic ATTTT repeat in DAB1 in chromosomal region 1p32.2 as the cause of autosomal-dominant SCA; this region has been previously linked to SCA37. The non-pathogenic and pathogenic alleles have the configurations [(ATTTT)7–400] and [(ATTTT)60–79(ATTTC)31–75(ATTTT)58–90], respectively. (ATTTC)n insertions are present on a distinct haplotype and show an inverse correlation between size and age of onset. In the DAB1-oriented strand, (ATTTC)n is located in 5′ UTR introns of cerebellar-specific transcripts arising mostly during human fetal brain development from the usage of alternative promoters, but it is maintained in the adult cerebellum. Overexpression of the transfected (ATTTC)58 insertion, but not (ATTTT)n, leads to abnormal nuclear RNA accumulation. Zebrafish embryos injected with RNA of the (AUUUC)58 insertion, but not (AUUUU)n, showed lethal developmental malformations. Together, these results establish an unstable repeat insertion in DAB1 as a cause of cerebellar degeneration; on the basis of the genetic and phenotypic evidence, we propose this mutation as the molecular basis for SCA37.

      PubDate: 2017-07-10T07:11:06Z
      DOI: 10.1016/j.ajhg.2017.06.007
  • WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual
           Disability, Seizures, Abnormal Gait, and Distinctive Facial Features
    • Authors: Cara M. Skraban; Constance F. Wells; Preetha Markose; Megan T. Cho; Addie I. Nesbitt; P.Y. Billie Au; Amber Begtrup; John A. Bernat; Lynne M. Bird; Kajia Cao; Arjan P.M. de Brouwer; Elizabeth H. Denenberg; Ganka Douglas; Kristin M. Gibson; Katheryn Grand; Alice Goldenberg; A. Micheil Innes; Jane Juusola; Marlies Kempers; Esther Kinning; David M. Markie; Martina M. Owens; Katelyn Payne; Richard Person; Rolph Pfundt; Amber Stocco; Claire L.S. Turner; Nienke E. Verbeek; Laurence E. Walsh; Taylor C. Warner; Patricia G. Wheeler; Dagmar Wieczorek; Alisha B. Wilkens; Evelien Zonneveld-Huijssoon; Tjitske Kleefstra; Stephen P. Robertson; Avni Santani; Koen L.I. van Gassen; Matthew A. Deardorff
      Pages: 139 - 148
      Abstract: Publication date: 6 July 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 1
      Author(s): Cara M. Skraban, Constance F. Wells, Preetha Markose, Megan T. Cho, Addie I. Nesbitt, P.Y. Billie Au, Amber Begtrup, John A. Bernat, Lynne M. Bird, Kajia Cao, Arjan P.M. de Brouwer, Elizabeth H. Denenberg, Ganka Douglas, Kristin M. Gibson, Katheryn Grand, Alice Goldenberg, A. Micheil Innes, Jane Juusola, Marlies Kempers, Esther Kinning, David M. Markie, Martina M. Owens, Katelyn Payne, Richard Person, Rolph Pfundt, Amber Stocco, Claire L.S. Turner, Nienke E. Verbeek, Laurence E. Walsh, Taylor C. Warner, Patricia G. Wheeler, Dagmar Wieczorek, Alisha B. Wilkens, Evelien Zonneveld-Huijssoon, Tjitske Kleefstra, Stephen P. Robertson, Avni Santani, Koen L.I. van Gassen, Matthew A. Deardorff
      We report 15 individuals with de novo pathogenic variants in WDR26. Eleven of the individuals carry loss-of-function mutations, and four harbor missense substitutions. These 15 individuals comprise ten females and five males, and all have intellectual disability with delayed speech, a history of febrile and/or non-febrile seizures, and a wide-based, spastic, and/or stiff-legged gait. These subjects share a set of common facial features that include a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip. Together, these features comprise a recognizable facial phenotype. We compared these features with those of chromosome 1q41q42 microdeletion syndrome, which typically contains WDR26, and noted that clinical features are consistent between the two subsets, suggesting that haploinsufficiency of WDR26 contributes to the pathology of 1q41q42 microdeletion syndrome. Consistent with this, WDR26 loss-of-function single-nucleotide mutations identified in these subjects lead to nonsense-mediated decay with subsequent reduction of RNA expression and protein levels. We derived a structural model of WDR26 and note that missense variants identified in these individuals localize to highly conserved residues of this WD-40-repeat-containing protein. Given that WDR26 mutations have been identified in ∼1 in 2,000 of subjects in our clinical cohorts and that WDR26 might be poorly annotated in exome variant-interpretation pipelines, we would anticipate that this disorder could be more common than currently appreciated.

      PubDate: 2017-07-10T07:11:06Z
      DOI: 10.1016/j.ajhg.2017.06.002
  • REST Final-Exon-Truncating Mutations Cause Hereditary Gingival
    • Authors: Yavuz Bayram; Janson J. White; Nursel Elcioglu; Megan T. Cho; Neda Zadeh; Asuman Gedikbasi; Sukru Palanduz; Sukru Ozturk; Kivanc Cefle; Ozgur Kasapcopur; Zeynep Coban Akdemir; Davut Pehlivan; Amber Begtrup; Claudia M.B. Carvalho; Ingrid Sophie Paine; Ali Mentes; Kivanc Bektas-Kayhan; Ender Karaca; Shalini N. Jhangiani; Donna M. Muzny; Richard A. Gibbs; James R. Lupski
      Pages: 149 - 156
      Abstract: Publication date: 6 July 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 1
      Author(s): Yavuz Bayram, Janson J. White, Nursel Elcioglu, Megan T. Cho, Neda Zadeh, Asuman Gedikbasi, Sukru Palanduz, Sukru Ozturk, Kivanc Cefle, Ozgur Kasapcopur, Zeynep Coban Akdemir, Davut Pehlivan, Amber Begtrup, Claudia M.B. Carvalho, Ingrid Sophie Paine, Ali Mentes, Kivanc Bektas-Kayhan, Ender Karaca, Shalini N. Jhangiani, Donna M. Muzny, Richard A. Gibbs, James R. Lupski
      Hereditary gingival fibromatosis (HGF) is the most common genetic form of gingival fibromatosis that develops as a slowly progressive, benign, localized or generalized enlargement of keratinized gingiva. HGF is a genetically heterogeneous disorder and can be transmitted either as an autosomal-dominant or autosomal-recessive trait or appear sporadically. To date, four loci (2p22.1, 2p23.3–p22.3, 5q13–q22, and 11p15) have been mapped to autosomes and one gene (SOS1) has been associated with the HGF trait observed to segregate in a dominant inheritance pattern. Here we report 11 individuals with HGF from three unrelated families. Whole-exome sequencing (WES) revealed three different truncating mutations including two frameshifts and one nonsense variant in RE1-silencing transcription factor (REST) in the probands from all families and further genetic and genomic analyses confirmed the WES-identified findings. REST is a transcriptional repressor that is expressed throughout the body; it has different roles in different cellular contexts, such as oncogenic and tumor-suppressor functions and hematopoietic and cardiac differentiation. Here we show the consequences of germline final-exon-truncating mutations in REST for organismal development and the association with the HGF phenotype.

      PubDate: 2017-07-10T07:11:06Z
      DOI: 10.1016/j.ajhg.2017.06.006
  • 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
  • This Month in The Journal
    • Authors: Sarah Ratzel; Sara B. Cullinan
      Pages: 567 - 568
      Abstract: Publication date: 6 July 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 1
      Author(s): Sarah Ratzel, Sara B. Cullinan

      PubDate: 2017-07-10T07:11:06Z
      DOI: 10.1016/j.ajhg.2017.03.007
  • 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: 6 July 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 1
      Author(s): Kathryn B. Garber

      PubDate: 2017-07-10T07:11:06Z
      DOI: 10.1016/j.ajhg.2017.03.006
  • 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
  • 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
  • Continuity and Admixture in the Last Five Millennia of Levantine History
           from Ancient Canaanite and Present-Day Lebanese Genome Sequences
    • Authors: Marc Haber; Claude Doumet-Serhal Christiana Scheib Yali Xue Petr Danecek
      Abstract: Publication date: 3 August 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 2
      Author(s): Marc Haber, Claude Doumet-Serhal, Christiana Scheib, Yali Xue, Petr Danecek, Massimo Mezzavilla, Sonia Youhanna, Rui Martiniano, Javier Prado-Martinez, Michał Szpak, Elizabeth Matisoo-Smith, Holger Schutkowski, Richard Mikulski, Pierre Zalloua, Toomas Kivisild, Chris Tyler-Smith
      The Canaanites inhabited the Levant region during the Bronze Age and established a culture that became influential in the Near East and beyond. However, the Canaanites, unlike most other ancient Near Easterners of this period, left few surviving textual records and thus their origin and relationship to ancient and present-day populations remain unclear. In this study, we sequenced five whole genomes from ∼3,700-year-old individuals from the city of Sidon, a major Canaanite city-state on the Eastern Mediterranean coast. We also sequenced the genomes of 99 individuals from present-day Lebanon to catalog modern Levantine genetic diversity. We find that a Bronze Age Canaanite-related ancestry was widespread in the region, shared among urban populations inhabiting the coast (Sidon) and inland populations (Jordan) who likely lived in farming societies or were pastoral nomads. This Canaanite-related ancestry derived from mixture between local Neolithic populations and eastern migrants genetically related to Chalcolithic Iranians. We estimate, using linkage-disequilibrium decay patterns, that admixture occurred 6,600–3,550 years ago, coinciding with recorded massive population movements in Mesopotamia during the mid-Holocene. We show that present-day Lebanese derive most of their ancestry from a Canaanite-related population, which therefore implies substantial genetic continuity in the Levant since at least the Bronze Age. In addition, we find Eurasian ancestry in the Lebanese not present in Bronze Age or earlier Levantines. We estimate that this Eurasian ancestry arrived in the Levant around 3,750–2,170 years ago during a period of successive conquests by distant populations.

      PubDate: 2017-08-05T22:39:11Z
  • Computational Prediction of Position Effects of Apparently Balanced Human
           Chromosomal Rearrangements
    • Authors: Cinthya J. Zepeda-Mendoza; Jonas Ibn-Salem; Tammy Kammin; David J. Harris; Debra Rita; Karen W. Gripp; Jennifer J. MacKenzie; Andrea Gropman; Brett Graham; Ranad Shaheen; Fowzan S. Alkuraya; Campbell K. Brasington; Edward J. Spence; Diane Masser-Frye; Lynne M. Bird; Erica Spiegel; Rebecca L. Sparkes; Zehra Ordulu; Michael E. Talkowski; Miguel A. Andrade-Navarro; Peter N. Robinson; Cynthia C. Morton
      Abstract: Publication date: Available online 20 July 2017
      Source:The American Journal of Human Genetics
      Author(s): Cinthya J. Zepeda-Mendoza, Jonas Ibn-Salem, Tammy Kammin, David J. Harris, Debra Rita, Karen W. Gripp, Jennifer J. MacKenzie, Andrea Gropman, Brett Graham, Ranad Shaheen, Fowzan S. Alkuraya, Campbell K. Brasington, Edward J. Spence, Diane Masser-Frye, Lynne M. Bird, Erica Spiegel, Rebecca L. Sparkes, Zehra Ordulu, Michael E. Talkowski, Miguel A. Andrade-Navarro, Peter N. Robinson, Cynthia C. Morton
      Interpretation of variants of uncertain significance, especially chromosomal rearrangements in non-coding regions of the human genome, remains one of the biggest challenges in modern molecular diagnosis. To improve our understanding and interpretation of such variants, we used high-resolution three-dimensional chromosomal structural data and transcriptional regulatory information to predict position effects and their association with pathogenic phenotypes in 17 subjects with apparently balanced chromosomal abnormalities. We found that the rearrangements predict disruption of long-range chromatin interactions between several enhancers and genes whose annotated clinical features are strongly associated with the subjects’ phenotypes. We confirm gene-expression changes for a couple of candidate genes to exemplify the utility of our analysis of position effect. These results highlight the important interplay between chromosomal structure and disease and demonstrate the need to utilize chromatin conformational data for the prediction of position effects in the clinical interpretation of non-coding chromosomal rearrangements.

      PubDate: 2017-07-21T07:18:05Z
      DOI: 10.1016/j.ajhg.2017.06.011
  • CRISPR/Cas9-Mediated Scanning for Regulatory Elements Required for HPRT1
           Expression via Thousands of Large, Programmed Genomic Deletions
    • Authors: Molly Gasperini; Gregory M. Findlay; Aaron McKenna; Jennifer H. Milbank; Choli Lee; Melissa D. Zhang; Darren A. Cusanovich; Jay Shendure
      Abstract: Publication date: Available online 14 July 2017
      Source:The American Journal of Human Genetics
      Author(s): Molly Gasperini, Gregory M. Findlay, Aaron McKenna, Jennifer H. Milbank, Choli Lee, Melissa D. Zhang, Darren A. Cusanovich, Jay Shendure
      The extent to which non-coding mutations contribute to Mendelian disease is a major unknown in human genetics. Relatedly, the vast majority of candidate regulatory elements have yet to be functionally validated. Here, we describe a CRISPR-based system that uses pairs of guide RNAs (gRNAs) to program thousands of kilobase-scale deletions that deeply scan across a targeted region in a tiling fashion (“ScanDel”). We applied ScanDel to HPRT1, the housekeeping gene underlying Lesch-Nyhan syndrome, an X-linked recessive disorder. Altogether, we programmed 4,342 overlapping 1 and 2 kb deletions that tiled 206 kb centered on HPRT1 (including 87 kb upstream and 79 kb downstream) with median 27-fold redundancy per base. We functionally assayed programmed deletions in parallel by selecting for loss of HPRT function with 6-thioguanine. As expected, sequencing gRNA pairs before and after selection confirmed that all HPRT1 exons are needed. However, HPRT1 function was robust to deletion of any intergenic or deeply intronic non-coding region, indicating that proximal regulatory sequences are sufficient for HPRT1 expression. Although our screen did identify the disruption of exon-proximal non-coding sequences (e.g., the promoter) as functionally consequential, long-read sequencing revealed that this signal was driven by rare, imprecise deletions that extended into exons. Our results suggest that no singular distal regulatory element is required for HPRT1 expression and that distal mutations are unlikely to contribute substantially to Lesch-Nyhan syndrome burden. Further application of ScanDel could shed light on the role of regulatory mutations in disease at other loci while also facilitating a deeper understanding of endogenous gene regulation.

      PubDate: 2017-07-21T07:18:05Z
      DOI: 10.1016/j.ajhg.2017.06.010
  • Large-Scale Identification of Common Trait and Disease Variants Affecting
           Gene Expression
    • Authors: Mads Engel; Hauberg Wen Zhang Claudia Giambartolomei Oscar David Morris
      Abstract: Publication date: 6 July 2017
      Source:The American Journal of Human Genetics, Volume 101, Issue 1
      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

      PubDate: 2017-07-10T07:11:06Z
  • A Genetic Variant Ameliorates β-Thalassemia Severity by
           Epigenetic-Mediated Elevation of Human Fetal Hemoglobin Expression
    • Authors: Diyu Chen; Yangjin Zuo; Xinhua Zhang; Yuhua Ye; Xiuqin Bao; Haiyan Huang; Wanicha Tepakhan; Lijuan Wang; Junyi Ju; Guangfu Chen; Mincui Zheng; Dun Liu; Shuodan Huang; Lu Zong; Changgang Li; Yajun Chen; Chenguang Zheng; Lihong Shi; Quan Zhao; Qiang Wu; Supan Fucharoen; Cunyou Zhao; Xiangmin Xu
      Abstract: Publication date: Available online 29 June 2017
      Source:The American Journal of Human Genetics
      Author(s): Diyu Chen, Yangjin Zuo, Xinhua Zhang, Yuhua Ye, Xiuqin Bao, Haiyan Huang, Wanicha Tepakhan, Lijuan Wang, Junyi Ju, Guangfu Chen, Mincui Zheng, Dun Liu, Shuodan Huang, Lu Zong, Changgang Li, Yajun Chen, Chenguang Zheng, Lihong Shi, Quan Zhao, Qiang Wu, Supan Fucharoen, Cunyou Zhao, Xiangmin Xu
      A delayed fetal-to-adult hemoglobin (Hb) switch ameliorates the severity of β-thalassemia and sickle cell disease. The molecular mechanism underlying the epigenetic dysregulation of the switch is unclear. To explore the potential cis-variants responsible for the Hb switching, we systematically analyzed an 80-kb region spanning the β-globin cluster using capture-based next-generation sequencing of 1142 Chinese β-thalassemia persons and identified 31 fetal hemoglobin (HbF)-associated haplotypes of the selected 28 tag regulatory single-nucleotide polymorphisms (rSNPs) in seven linkage disequilibrium (LD) blocks. A Ly1 antibody reactive (LYAR)-binding motif disruptive rSNP rs368698783 (G/A) from LD block 5 in the proximal promoter of hemoglobin subunit gamma 1 (HBG1) was found to be a significant predictor for β-thalassemia clinical severity by epigenetic-mediated variant-dependent HbF elevation. We found this rSNP accounted for 41.6% of β-hemoglobinopathy individuals as an ameliorating factor in a total of 2,738 individuals from southern China and Thailand. We uncovered that the minor allele of the rSNP triggers the attenuation of LYAR and two repressive epigenetic regulators DNA methyltransferase 3 alpha (DNMT3A) and protein arginine methyltransferase 5 (PRMT5) from the HBG promoters, mediating allele-biased γ-globin elevation by facilitating demethylation of HBG core promoter CpG sites in erythroid progenitor cells from β-thalassemia persons. The present study demonstrates that this common rSNP in the proximal Aγ-promoter is a major genetic modifier capable of ameliorating the severity of thalassemia major through the epigenetic-mediated regulation of the delayed fetal-to-adult Hb switch and provides potential targets for the treatment of β-hemoglobinopathy.

      PubDate: 2017-07-01T07:05:37Z
      DOI: 10.1016/j.ajhg.2017.05.012
  • Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause
           Intellectual Disability or Epileptic Encephalopathy
    • Authors: Anna Lehman; Samrat Thouta; Grazia M.S. Mancini; Sakkubai Naidu; Marjon van Slegtenhorst; Kirsty McWalter; Richard Person; Jill Mwenifumbo; Ramona Salvarinova; Ilaria Guella; Marna B. McKenzie; Anita Datta; Mary B. Connolly; Somayeh Mojard Kalkhoran; Damon Poburko; Jan M. Friedman; Matthew J. Farrer; Michelle Demos; Sonal Desai; Thomas Claydon; Shelin Adam; Christèle du Souich; Alison M. Elliott; Anna Lehman; Jill Mwenifumbo; Tanya N. Nelson; Clara van Karnebeek; Jan M. Friedman; Shelin Adam; Cyrus Boelman; Corneliu Bolbocean; Sarah E. Buerki; Tara Candido; Patrice Eydoux; Daniel M. Evans; William Gibson; Gabriella Horvath; Linda Huh; Tanya N. Nelson; Graham Sinclair; Tamsin Tarling; Eric B. Toyota; Katelin N. Townsend; Margot I. Van Allen; Clara van Karnebeek; Suzanne Vercauteren
      Abstract: Publication date: Available online 29 June 2017
      Source:The American Journal of Human Genetics
      Author(s): Anna Lehman, Samrat Thouta, Grazia M.S. Mancini, Sakkubai Naidu, Marjon van Slegtenhorst, Kirsty McWalter, Richard Person, Jill Mwenifumbo, Ramona Salvarinova, Ilaria Guella, Marna B. McKenzie, Anita Datta, Mary B. Connolly, Somayeh Mojard Kalkhoran, Damon Poburko, Jan M. Friedman, Matthew J. Farrer, Michelle Demos, Sonal Desai, Thomas Claydon
      KCNQ5 is a highly conserved gene encoding an important channel for neuronal function; it is widely expressed in the brain and generates M-type current. Exome sequencing identified de novo heterozygous missense mutations in four probands with intellectual disability, abnormal neurological findings, and treatment-resistant epilepsy (in two of four). Comprehensive analysis of this potassium channel for the four variants expressed in frog oocytes revealed shifts in the voltage dependence of activation, including altered activation and deactivation kinetics. Specifically, both loss-of-function and gain-of-function KCNQ5 mutations, associated with increased excitability and decreased repolarization reserve, lead to pathophysiology.

      PubDate: 2017-07-01T07:05:37Z
      DOI: 10.1016/j.ajhg.2017.05.016
  • SEQSpark: A Complete Analysis Tool for Large-Scale Rare Variant
           Association Studies using Whole-Genome and Exome Sequence Data
    • Authors: Di Zhang; Linhai Zhao; Biao Li; Zongxiao He; Gao T. Wang; Dajiang J. Liu; Suzanne M. Leal
      Abstract: Publication date: Available online 29 June 2017
      Source:The American Journal of Human Genetics
      Author(s): Di Zhang, Linhai Zhao, Biao Li, Zongxiao He, Gao T. Wang, Dajiang J. Liu, Suzanne M. Leal
      Massively parallel sequencing technologies provide great opportunities for discovering rare susceptibility variants involved in complex disease etiology via large-scale imputation and exome and whole-genome sequence-based association studies. Due to modest effect sizes, large sample sizes of tens to hundreds of thousands of individuals are required for adequately powered studies. Current analytical tools are obsolete when it comes to handling these large datasets. To facilitate the analysis of large-scale sequence-based studies, we developed SEQSpark which implements parallel processing based on Spark to increase the speed and efficiency of performing data quality control, annotation, and association analysis. To demonstrate the versatility and speed of SEQSpark, we analyzed whole-genome sequence data from the UK10K, testing for associations with waist-to-hip ratios. The analysis, which was completed in 1.5 hr, included loading data, annotation, principal component analysis, and single variant and rare variant aggregate association analysis of >9 million variants. For rare variant aggregate analysis, an exome-wide significant association (p < 2.5 × 10−6) was observed with CCDC62 (SKAT-O [p = 6.89 × 10−7], combined multivariate collapsing [p = 1.48 × 10−6], and burden of rare variants [p = 1.48 × 10−6]). SEQSpark was also used to analyze 50,000 simulated exomes and it required 1.75 hr for the analysis of a quantitative trait using several rare variant aggregate association methods. Additionally, the performance of SEQSpark was compared to Variant Association Tools and PLINK/SEQ. SEQSpark was always faster and in some situations computation was reduced to a hundredth of the time. SEQSpark will empower large sequence-based epidemiological studies to quickly elucidate genetic variation involved in the etiology of complex traits.

      PubDate: 2017-07-01T07:05:37Z
      DOI: 10.1016/j.ajhg.2017.05.017
  • Ultra-sensitive Sequencing Identifies High Prevalence of Clonal
           Hematopoiesis-Associated Mutations throughout Adult Life
    • Authors: Rocio Acuna-Hidalgo; Hilal Sengul; Marloes Steehouwer; Maartje van de Vorst; Sita H. Vermeulen; Lambertus A.L.M. Kiemeney; Joris A. Veltman; Christian Gilissen; Alexander Hoischen
      Abstract: Publication date: Available online 29 June 2017
      Source:The American Journal of Human Genetics
      Author(s): Rocio Acuna-Hidalgo, Hilal Sengul, Marloes Steehouwer, Maartje van de Vorst, Sita H. Vermeulen, Lambertus A.L.M. Kiemeney, Joris A. Veltman, Christian Gilissen, Alexander Hoischen
      Clonal hematopoiesis results from somatic mutations in hematopoietic stem cells, which give an advantage to mutant cells, driving their clonal expansion and potentially leading to leukemia. The acquisition of clonal hematopoiesis-driver mutations (CHDMs) occurs with normal aging and these mutations have been detected in more than 10% of individuals ≥65 years. We aimed to examine the prevalence and characteristics of CHDMs throughout adult life. We developed a targeted re-sequencing assay combining high-throughput with ultra-high sensitivity based on single-molecule molecular inversion probes (smMIPs). Using smMIPs, we screened more than 100 loci for CHDMs in more than 2,000 blood DNA samples from population controls between 20 and 69 years of age. Loci screened included 40 regions known to drive clonal hematopoiesis when mutated and 64 novel candidate loci. We identified 224 somatic mutations throughout our cohort, of which 216 were coding mutations in known driver genes (DNMT3A, JAK2, GNAS, TET2, and ASXL1), including 196 point mutations and 20 indels. Our assay’s improved sensitivity allowed us to detect mutations with variant allele frequencies as low as 0.001. CHDMs were identified in more than 20% of individuals 60 to 69 years of age and in 3% of individuals 20 to 29 years of age, approximately double the previously reported prevalence despite screening a limited set of loci. Our findings support the occurrence of clonal hematopoiesis-associated mutations as a widespread mechanism linked with aging, suggesting that mosaicism as a result of clonal evolution of cells harboring somatic mutations is a universal mechanism occurring at all ages in healthy humans.

      PubDate: 2017-07-01T07:05:37Z
      DOI: 10.1016/j.ajhg.2017.05.013
  • A Fast Association Test for Identifying Pathogenic Variants Involved in
           Rare Diseases
    • Authors: Daniel Greene; Sylvia Richardson; Ernest Turro
      Abstract: Publication date: Available online 29 June 2017
      Source:The American Journal of Human Genetics
      Author(s): Daniel Greene, Sylvia Richardson, Ernest Turro
      We present a rapid and powerful inference procedure for identifying loci associated with rare hereditary disorders using Bayesian model comparison. Under a baseline model, disease risk is fixed across all individuals in a study. Under an association model, disease risk depends on a latent bipartition of rare variants into pathogenic and non-pathogenic variants, the number of pathogenic alleles that each individual carries, and the mode of inheritance. A parameter indicating presence of an association and the parameters representing the pathogenicity of each variant and the mode of inheritance can be inferred in a Bayesian framework. Variant-specific prior information derived from allele frequency databases, consequence prediction algorithms, or genomic datasets can be integrated into the inference. Association models can be fitted to different subsets of variants in a locus and compared using a model selection procedure. This procedure can improve inference if only a particular class of variants confers disease risk and can suggest particular disease etiologies related to that class. We show that our method, called BeviMed, is more powerful and informative than existing rare variant association methods in the context of dominant and recessive disorders. The high computational efficiency of our algorithm makes it feasible to test for associations in the large non-coding fraction of the genome. We have applied BeviMed to whole-genome sequencing data from 6,586 individuals with diverse rare diseases. We show that it can identify multiple loci involved in rare diseases, while correctly inferring the modes of inheritance, the likely pathogenic variants, and the variant classes responsible.

      PubDate: 2017-07-01T07:05:37Z
      DOI: 10.1016/j.ajhg.2017.05.015
  • 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
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