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Publisher: Elsevier   (Total: 3184 journals)

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Showing 1 - 200 of 3184 Journals sorted alphabetically
Academic Pediatrics     Hybrid Journal   (Followers: 37, SJR: 1.655, CiteScore: 2)
Academic Radiology     Hybrid Journal   (Followers: 26, SJR: 1.015, CiteScore: 2)
Accident Analysis & Prevention     Partially Free   (Followers: 100, SJR: 1.462, CiteScore: 3)
Accounting Forum     Hybrid Journal   (Followers: 28, SJR: 0.932, CiteScore: 2)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 40, SJR: 1.771, CiteScore: 3)
Achievements in the Life Sciences     Open Access   (Followers: 6)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 7)
Acta Astronautica     Hybrid Journal   (Followers: 435, SJR: 0.758, CiteScore: 2)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 2)
Acta Biomaterialia     Hybrid Journal   (Followers: 28, SJR: 1.967, CiteScore: 7)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription   (Followers: 3)
Acta de Investigación Psicológica     Open Access   (Followers: 3)
Acta Ecologica Sinica     Open Access   (Followers: 11, SJR: 0.18, CiteScore: 1)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.661, CiteScore: 2)
Acta Materialia     Hybrid Journal   (Followers: 309, SJR: 3.263, CiteScore: 6)
Acta Mathematica Scientia     Full-text available via subscription   (Followers: 5, SJR: 0.504, CiteScore: 1)
Acta Mechanica Solida Sinica     Full-text available via subscription   (Followers: 9, SJR: 0.542, CiteScore: 1)
Acta Oecologica     Hybrid Journal   (Followers: 12, SJR: 0.834, CiteScore: 2)
Acta Otorrinolaringologica (English Edition)     Full-text available via subscription  
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 2, SJR: 0.307, CiteScore: 0)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 1, SJR: 1.793, CiteScore: 6)
Acta Poética     Open Access   (Followers: 4, SJR: 0.101, CiteScore: 0)
Acta Psychologica     Hybrid Journal   (Followers: 25, SJR: 1.331, CiteScore: 2)
Acta Sociológica     Open Access   (Followers: 1)
Acta Tropica     Hybrid Journal   (Followers: 6, SJR: 1.052, CiteScore: 2)
Acta Urológica Portuguesa     Open Access  
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 3, SJR: 0.374, CiteScore: 1)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 2)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 3, SJR: 0.344, CiteScore: 1)
Actas Urológicas Españolas (English Edition)     Full-text available via subscription   (Followers: 1)
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 7, SJR: 0.19, CiteScore: 0)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 3)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 8)
Acute Pain     Full-text available via subscription   (Followers: 15, SJR: 2.671, CiteScore: 5)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.53, CiteScore: 4)
Addictive Behaviors     Hybrid Journal   (Followers: 18, SJR: 1.29, CiteScore: 3)
Addictive Behaviors Reports     Open Access   (Followers: 9, SJR: 0.755, CiteScore: 2)
Additive Manufacturing     Hybrid Journal   (Followers: 11, SJR: 2.611, CiteScore: 8)
Additives for Polymers     Full-text available via subscription   (Followers: 23)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 184, SJR: 4.09, CiteScore: 13)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 12, SJR: 1.167, CiteScore: 4)
Advanced Powder Technology     Hybrid Journal   (Followers: 17, SJR: 0.694, CiteScore: 3)
Advances in Accounting     Hybrid Journal   (Followers: 9, SJR: 0.277, CiteScore: 1)
Advances in Agronomy     Full-text available via subscription   (Followers: 17, SJR: 2.384, CiteScore: 5)
Advances in Anesthesia     Full-text available via subscription   (Followers: 29, SJR: 0.126, CiteScore: 0)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 2)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 11, SJR: 0.992, CiteScore: 1)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 11, SJR: 1.551, CiteScore: 4)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 24, SJR: 2.089, CiteScore: 5)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 15, SJR: 0.572, CiteScore: 2)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.61, CiteScore: 7)
Advances in Botanical Research     Full-text available via subscription   (Followers: 2, SJR: 0.686, CiteScore: 2)
Advances in Cancer Research     Full-text available via subscription   (Followers: 33, SJR: 3.043, CiteScore: 6)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 9, SJR: 1.453, CiteScore: 2)
Advances in Catalysis     Full-text available via subscription   (Followers: 5, SJR: 1.992, CiteScore: 5)
Advances in Cell Aging and Gerontology     Full-text available via subscription   (Followers: 5)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 14)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 29, SJR: 0.156, CiteScore: 1)
Advances in Child Development and Behavior     Full-text available via subscription   (Followers: 10, SJR: 0.713, CiteScore: 1)
Advances in Chronic Kidney Disease     Full-text available via subscription   (Followers: 10, SJR: 1.316, CiteScore: 2)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 26, SJR: 1.562, CiteScore: 3)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 20, SJR: 1.977, CiteScore: 8)
Advances in Computers     Full-text available via subscription   (Followers: 14, SJR: 0.205, CiteScore: 1)
Advances in Dermatology     Full-text available via subscription   (Followers: 15)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 13)
Advances in Digestive Medicine     Open Access   (Followers: 12)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 7)
Advances in Drug Research     Full-text available via subscription   (Followers: 26)
Advances in Ecological Research     Full-text available via subscription   (Followers: 44, SJR: 2.524, CiteScore: 4)
Advances in Engineering Software     Hybrid Journal   (Followers: 29, SJR: 1.159, CiteScore: 4)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 8)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 51, SJR: 5.39, CiteScore: 8)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 1)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 9)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 65, SJR: 0.591, CiteScore: 2)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 17)
Advances in Genetics     Full-text available via subscription   (Followers: 21, SJR: 1.354, CiteScore: 4)
Advances in Genome Biology     Full-text available via subscription   (Followers: 10, SJR: 12.74, CiteScore: 13)
Advances in Geophysics     Full-text available via subscription   (Followers: 7, SJR: 1.193, CiteScore: 3)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 26, SJR: 0.368, CiteScore: 1)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 11, SJR: 0.749, CiteScore: 3)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 24)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 3, SJR: 0.193, CiteScore: 0)
Advances in Immunology     Full-text available via subscription   (Followers: 36, SJR: 4.433, CiteScore: 6)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 10, SJR: 1.163, CiteScore: 2)
Advances in Insect Physiology     Full-text available via subscription   (Followers: 2, SJR: 1.938, CiteScore: 3)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 6, SJR: 0.176, CiteScore: 0)
Advances in Intl. Accounting     Full-text available via subscription   (Followers: 3)
Advances in Life Course Research     Hybrid Journal   (Followers: 9, SJR: 0.682, CiteScore: 2)
Advances in Lipobiology     Full-text available via subscription   (Followers: 1)
Advances in Magnetic and Optical Resonance     Full-text available via subscription   (Followers: 8)
Advances in Marine Biology     Full-text available via subscription   (Followers: 21, SJR: 0.88, CiteScore: 2)
Advances in Mathematics     Full-text available via subscription   (Followers: 12, SJR: 3.027, CiteScore: 2)
Advances in Medical Sciences     Hybrid Journal   (Followers: 8, SJR: 0.694, CiteScore: 2)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 6)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 5, SJR: 1.158, CiteScore: 3)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 24)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 8)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 7, SJR: 0.182, CiteScore: 0)
Advances in Nanoporous Materials     Full-text available via subscription   (Followers: 5)
Advances in Oncobiology     Full-text available via subscription   (Followers: 2)
Advances in Organ Biology     Full-text available via subscription   (Followers: 2)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 18, SJR: 1.875, CiteScore: 4)
Advances in Parallel Computing     Full-text available via subscription   (Followers: 7, SJR: 0.174, CiteScore: 0)
Advances in Parasitology     Full-text available via subscription   (Followers: 5, SJR: 1.579, CiteScore: 4)
Advances in Pediatrics     Full-text available via subscription   (Followers: 27, SJR: 0.461, CiteScore: 1)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 18)
Advances in Pharmacology     Full-text available via subscription   (Followers: 17, SJR: 1.536, CiteScore: 3)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 9, SJR: 0.574, CiteScore: 1)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.109, CiteScore: 1)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 10)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 6)
Advances in Porous Media     Full-text available via subscription   (Followers: 5)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 19)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20, SJR: 0.791, CiteScore: 2)
Advances in Psychology     Full-text available via subscription   (Followers: 66)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 6, SJR: 0.371, CiteScore: 1)
Advances in Radiation Oncology     Open Access   (Followers: 1, SJR: 0.263, CiteScore: 1)
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 3, SJR: 0.101, CiteScore: 0)
Advances in Space Biology and Medicine     Full-text available via subscription   (Followers: 6)
Advances in Space Research     Full-text available via subscription   (Followers: 420, SJR: 0.569, CiteScore: 2)
Advances in Structural Biology     Full-text available via subscription   (Followers: 5)
Advances in Surgery     Full-text available via subscription   (Followers: 13, SJR: 0.555, CiteScore: 2)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 37, SJR: 2.208, CiteScore: 4)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 20)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 15)
Advances in Virus Research     Full-text available via subscription   (Followers: 6, SJR: 2.262, CiteScore: 5)
Advances in Water Resources     Hybrid Journal   (Followers: 53, SJR: 1.551, CiteScore: 3)
Aeolian Research     Hybrid Journal   (Followers: 6, SJR: 1.117, CiteScore: 3)
Aerospace Science and Technology     Hybrid Journal   (Followers: 382, SJR: 0.796, CiteScore: 3)
AEU - Intl. J. of Electronics and Communications     Hybrid Journal   (Followers: 8, SJR: 0.42, CiteScore: 2)
African J. of Emergency Medicine     Open Access   (Followers: 6, SJR: 0.296, CiteScore: 0)
Ageing Research Reviews     Hybrid Journal   (Followers: 12, SJR: 3.671, CiteScore: 9)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 474, SJR: 1.238, CiteScore: 3)
Agri Gene     Hybrid Journal   (Followers: 1, SJR: 0.13, CiteScore: 0)
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 18, SJR: 1.818, CiteScore: 5)
Agricultural Systems     Hybrid Journal   (Followers: 31, SJR: 1.156, CiteScore: 4)
Agricultural Water Management     Hybrid Journal   (Followers: 45, SJR: 1.272, CiteScore: 3)
Agriculture and Agricultural Science Procedia     Open Access   (Followers: 4)
Agriculture and Natural Resources     Open Access   (Followers: 3)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 58, SJR: 1.747, CiteScore: 4)
Ain Shams Engineering J.     Open Access   (Followers: 5, SJR: 0.589, CiteScore: 3)
Air Medical J.     Hybrid Journal   (Followers: 7, SJR: 0.26, CiteScore: 0)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.19, CiteScore: 0)
Alcohol     Hybrid Journal   (Followers: 12, SJR: 1.153, CiteScore: 3)
Alcoholism and Drug Addiction     Open Access   (Followers: 11)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 1)
Alexandria Engineering J.     Open Access   (Followers: 2, SJR: 0.604, CiteScore: 3)
Alexandria J. of Medicine     Open Access   (Followers: 1, SJR: 0.191, CiteScore: 1)
Algal Research     Partially Free   (Followers: 11, SJR: 1.142, CiteScore: 4)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 2)
Allergologia et Immunopathologia     Full-text available via subscription   (Followers: 1, SJR: 0.504, CiteScore: 1)
Allergology Intl.     Open Access   (Followers: 5, SJR: 1.148, CiteScore: 2)
Alpha Omegan     Full-text available via subscription   (SJR: 3.521, CiteScore: 6)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 10, SJR: 0.201, CiteScore: 1)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 54, SJR: 4.66, CiteScore: 10)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 6, SJR: 1.796, CiteScore: 4)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 6, SJR: 1.108, CiteScore: 3)
Ambulatory Pediatrics     Hybrid Journal   (Followers: 5)
American Heart J.     Hybrid Journal   (Followers: 58, SJR: 3.267, CiteScore: 4)
American J. of Cardiology     Hybrid Journal   (Followers: 63, SJR: 1.93, CiteScore: 3)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 46, SJR: 0.604, CiteScore: 1)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 12)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 14, SJR: 1.524, CiteScore: 3)
American J. of Human Genetics     Hybrid Journal   (Followers: 37, SJR: 7.45, CiteScore: 8)
American J. of Infection Control     Hybrid Journal   (Followers: 29, SJR: 1.062, CiteScore: 2)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 36, SJR: 2.973, CiteScore: 4)
American J. of Medicine     Hybrid Journal   (Followers: 50)
American J. of Medicine Supplements     Full-text available via subscription   (Followers: 3, SJR: 1.967, CiteScore: 2)
American J. of Obstetrics and Gynecology     Hybrid Journal   (Followers: 249, SJR: 2.7, CiteScore: 4)
American J. of Ophthalmology     Hybrid Journal   (Followers: 66, SJR: 3.184, CiteScore: 4)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 5, SJR: 0.265, CiteScore: 0)
American J. of Orthodontics and Dentofacial Orthopedics     Full-text available via subscription   (Followers: 6, SJR: 1.289, CiteScore: 1)
American J. of Otolaryngology     Hybrid Journal   (Followers: 25, SJR: 0.59, CiteScore: 1)
American J. of Pathology     Hybrid Journal   (Followers: 32, SJR: 2.139, CiteScore: 4)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 28, SJR: 2.164, CiteScore: 4)
American J. of Surgery     Hybrid Journal   (Followers: 39, SJR: 1.141, CiteScore: 2)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 12, SJR: 0.767, CiteScore: 1)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 7)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.144, CiteScore: 3)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 66, SJR: 0.138, CiteScore: 0)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 24, SJR: 0.411, CiteScore: 1)
Anales de Cirugia Vascular     Full-text available via subscription   (Followers: 1)
Anales de Pediatría     Full-text available via subscription   (Followers: 3, SJR: 0.277, CiteScore: 0)
Anales de Pediatría (English Edition)     Full-text available via subscription  
Anales de Pediatría Continuada     Full-text available via subscription  
Analytic Methods in Accident Research     Hybrid Journal   (Followers: 5, SJR: 4.849, CiteScore: 10)
Analytica Chimica Acta     Hybrid Journal   (Followers: 44, SJR: 1.512, CiteScore: 5)
Analytica Chimica Acta : X     Open Access  
Analytical Biochemistry     Hybrid Journal   (Followers: 210, SJR: 0.633, CiteScore: 2)
Analytical Chemistry Research     Open Access   (Followers: 13, SJR: 0.411, CiteScore: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 14)
Anesthésie & Réanimation     Full-text available via subscription   (Followers: 2)
Anesthesiology Clinics     Full-text available via subscription   (Followers: 25, SJR: 0.683, CiteScore: 2)
Angiología     Full-text available via subscription   (SJR: 0.121, CiteScore: 0)
Angiologia e Cirurgia Vascular     Open Access   (Followers: 1, SJR: 0.111, CiteScore: 0)
Animal Behaviour     Hybrid Journal   (Followers: 218, SJR: 1.58, CiteScore: 3)
Animal Feed Science and Technology     Hybrid Journal   (Followers: 6, SJR: 0.937, CiteScore: 2)
Animal Reproduction Science     Hybrid Journal   (Followers: 7, SJR: 0.704, CiteScore: 2)

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Similar Journals
Journal Cover
American Journal of Human Genetics
Journal Prestige (SJR): 7.45
Citation Impact (citeScore): 8
Number of Followers: 37  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0002-9297 - ISSN (Online) 1537-6605
Published by Elsevier Homepage  [3184 journals]
  • This Month in The Journal
    • Abstract: Publication date: 5 September 2019Source: The American Journal of Human Genetics, Volume 105, Issue 3Author(s): Sarah Ratzel, Sara B. Cullinan
  • De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas,
           Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar
    • Abstract: Publication date: 5 September 2019Source: The American Journal of Human Genetics, Volume 105, Issue 3Author(s): Oguz Kanca, Jonathan C. Andrews, Pei-Tseng Lee, Chirag Patel, Stephen R. Braddock, Anne M. Slavotinek, Julie S. Cohen, Cynthia S. Gubbels, Kimberly A. Aldinger, Judy Williams, Maanasa Indaram, Ali Fatemi, Timothy W. Yu, Pankaj B. Agrawal, Gilbert Vezina, Cas Simons, Joanna Crawford, C. Christopher Lau, Maria T. Acosta, David R. Adams
  • Recessive Spondylocarpotarsal Synostosis Syndrome Due to Compound
           Heterozygosity for Variants in MYH3
    • Abstract: Publication date: 5 September 2019Source: The American Journal of Human Genetics, Volume 105, Issue 3Author(s): Sophia R. Cameron-Christie, Constance F. Wells, Marleen Simon, Marja Wessels, Candy Z.N. Tang, Wenhua Wei, Riku Takei, Coranne Aarts-Tesselaar, Sarah Sandaradura, David O. Sillence, Marie-Pierre Cordier, Hermine E. Veenstra-Knol, Matteo Cassina, Kathrin Ludwig, Eva Trevisson, Melanie Bahlo, David M. Markie, Zandra A. Jenkins, Stephen P. Robertson
  • Mendelian Gene Discovery: Fast and Furious with No End in Sight
    • Abstract: Publication date: 5 September 2019Source: The American Journal of Human Genetics, Volume 105, Issue 3Author(s): Michael J. Bamshad, Deborah A. Nickerson, Jessica X. ChongGene discovery for Mendelian conditions (MCs) offers a direct path to understanding genome function. Approaches based on next-generation sequencing applied at scale have dramatically accelerated gene discovery and transformed genetic medicine. Finding the genetic basis of ∼6,000–13,000 MCs yet to be delineated will require both technical and computational innovation, but will rely to a larger extent on meaningful data sharing.
  • Advancing Research and Privacy: Achievements, Challenges, and Core
    • Abstract: Publication date: 5 September 2019Source: The American Journal of Human Genetics, Volume 105, Issue 3Author(s): The genetics and genomics research community is a leader in leveraging large-scale data to transform science and medicine and in developing related policies and practices to protect the confidentiality of personal genetic information. Many laws also protect the genetic privacy of patients and participants in federally funded research. If the potential benefits of genetics and genomics research are to be advanced in the context of public considerations regarding broader consumer data protections, it is vital to recognize genetic research privacy protections already in place and imperative to avoid inadvertently harming biomedical research. With the growth of privately funded genetics research, ASHG asserts core privacy principles that should be applied to protect the data confidentiality of all research participants, regardless of the funding source.
  • Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid
    • Abstract: Publication date: 5 September 2019Source: The American Journal of Human Genetics, Volume 105, Issue 3Author(s): Cassandra N. Spracklen, Tugce Karaderi, Hanieh Yaghootkar, Claudia Schurmann, Rebecca S. Fine, Zoltan Kutalik, Michael H. Preuss, Yingchang Lu, Laura B.L. Wittemans, Linda S. Adair, Matthew Allison, Najaf Amin, Paul L. Auer, Traci M. Bartz, Matthias Blüher, Michael Boehnke, Judith B. Borja, Jette Bork-Jensen, Linda Broer, Daniel I. Chasman
  • cis Elements that Mediate RNA Polymerase II Pausing Regulate
           Human Gene Expression
    • Abstract: Publication date: Available online 5 September 2019Source: The American Journal of Human GeneticsAuthor(s): Jason A. Watts, Joshua Burdick, Jillian Daigneault, Zhengwei Zhu, Christopher Grunseich, Alan Bruzel, Vivian G. CheungAberrant gene expression underlies many human diseases. RNA polymerase II (Pol II) pausing is a key regulatory step in transcription. Here, we mapped the locations of RNA Pol II in normal human cells and found that RNA Pol II pauses in a consistent manner across individuals and cell types. At more than 1,000 genes including MYO1E and SESN2, RNA Pol II pauses at precise nucleotide locations. Characterization of these sites shows that RNA Pol II pauses at GC-rich regions that are marked by a sequence motif. Sixty-five percent of the pause sites are cytosines. By differential allelic gene expression analysis, we showed in our samples and a population dataset from the Genotype-Tissue Expression (GTEx) consortium that genes with more paused polymerase have lower expression levels. Furthermore, mutagenesis of the pause sites led to a significant increase in promoter activities. Thus, our data uncover that RNA Pol II pauses precisely at sites with distinct sequence features that in turn regulate gene expression.
  • Loss of SMPD4 Causes a Developmental Disorder Characterized by
           Microcephaly and Congenital Arthrogryposis
    • Abstract: Publication date: Available online 5 September 2019Source: The American Journal of Human GeneticsAuthor(s): Pamela Magini, Daphne J. Smits, Laura Vandervore, Rachel Schot, Marta Columbaro, Esmee Kasteleijn, Mees van der Ent, Flavia Palombo, Maarten H. Lequin, Marjolein Dremmen, Marie Claire Y. de Wit, Mariasavina Severino, Maria Teresa Divizia, Pasquale Striano, Natalia Ordonez-Herrera, Amal Alhashem, Ahmed Al Fares, Malak Al Ghamdi, Arndt Rolfs, Peter BauerSphingomyelinases generate ceramide from sphingomyelin as a second messenger in intracellular signaling pathways involved in cell proliferation, differentiation, or apoptosis. Children from 12 unrelated families presented with microcephaly, simplified gyral pattern of the cortex, hypomyelination, cerebellar hypoplasia, congenital arthrogryposis, and early fetal/postnatal demise. Genomic analysis revealed bi-allelic loss-of-function variants in SMPD4, coding for the neutral sphingomyelinase-3 (nSMase-3/SMPD4). Overexpression of human Myc-tagged SMPD4 showed localization both to the outer nuclear envelope and the ER and additionally revealed interactions with several nuclear pore complex proteins by proteomics analysis. Fibroblasts from affected individuals showed ER cisternae abnormalities, suspected for increased autophagy, and were more susceptible to apoptosis under stress conditions, while treatment with siSMPD4 caused delayed cell cycle progression. Our data show that SMPD4 links homeostasis of membrane sphingolipids to cell fate by regulating the cross-talk between the ER and the outer nuclear envelope, while its loss reveals a pathogenic mechanism in microcephaly.
  • Redefining the Etiologic Landscape of Cerebellar Malformations
    • Abstract: Publication date: Available online 29 August 2019Source: The American Journal of Human GeneticsAuthor(s): Kimberly A. Aldinger, Andrew E. Timms, Zachary Thomson, Ghayda M. Mirzaa, James T. Bennett, Alexander B. Rosenberg, Charles M. Roco, Matthew Hirano, Fatima Abidi, Parthiv Haldipur, Chi V. Cheng, Sarah Collins, Kaylee Park, Jordan Zeiger, Lynne M. Overmann, Fowzan S. Alkuraya, Leslie G. Biesecker, Stephen R. Braddock, Sara Cathey, Megan T. ChoCerebellar malformations are diverse congenital anomalies frequently associated with developmental disability. Although genetic and prenatal non-genetic causes have been described, no systematic analysis has been performed. Here, we present a large-exome sequencing study of Dandy-Walker malformation (DWM) and cerebellar hypoplasia (CBLH). We performed exome sequencing in 282 individuals from 100 families with DWM or CBLH, and we established a molecular diagnosis in 36 of 100 families, with a significantly higher yield for CBLH (51%) than for DWM (16%). The 41 variants impact 27 neurodevelopmental-disorder-associated genes, thus demonstrating that CBLH and DWM are often features of monogenic neurodevelopmental disorders. Though only seven monogenic causes (19%) were identified in more than one individual, neuroimaging review of 131 additional individuals confirmed cerebellar abnormalities in 23 of 27 genetic disorders (85%). Prenatal risk factors were frequently found among individuals without a genetic diagnosis (30 of 64 individuals [47%]). Single-cell RNA sequencing of prenatal human cerebellar tissue revealed gene enrichment in neuronal and vascular cell types; this suggests that defective vasculogenesis may disrupt cerebellar development. Further, de novo gain-of-function variants in PDGFRB, a tyrosine kinase receptor essential for vascular progenitor signaling, were associated with CBLH, and this discovery links genetic and non-genetic etiologies. Our results suggest that genetic defects impact specific cerebellar cell types and implicate abnormal vascular development as a mechanism for cerebellar malformations. We also confirmed a major contribution for non-genetic prenatal factors in individuals with cerebellar abnormalities, substantially influencing diagnostic evaluation and counseling regarding recurrence risk and prognosis.
  • Germline 16p11.2 Microdeletion Predisposes to Neuroblastoma
    • Abstract: Publication date: Available online 29 August 2019Source: The American Journal of Human GeneticsAuthor(s): Laura E. Egolf, Zalman Vaksman, Gonzalo Lopez, Jo Lynne Rokita, Apexa Modi, Patricia V. Basta, Hakon Hakonarson, Andrew F. Olshan, Sharon J. DiskinNeuroblastoma is a cancer of the developing sympathetic nervous system. It is diagnosed in 600–700 children per year in the United States and accounts for 12% of pediatric cancer deaths. Despite recent advances in our understanding of this malignancy’s complex genetic architecture, the contribution of rare germline variants remains undefined. Here, we conducted a genome-wide analysis of large (>500 kb), rare (
  • Distinct HLA Associations with Rheumatoid Arthritis Subsets Defined by
           Serological Subphenotype
    • Abstract: Publication date: Available online 29 August 2019Source: The American Journal of Human GeneticsAuthor(s): Chikashi Terao, Boel Brynedal, Zuomei Chen, Xia Jiang, Helga Westerlind, Monika Hansson, Per-Johan Jakobsson, Karin Lundberg, Karl Skriner, Guy Serre, Johan Rönnelid, Linda Mathsson-Alm, Mikael Brink, Solbritt Rantapää Dahlqvist, Leonid Padyukov, Peter K. Gregersen, Anne Barton, Lars Alfredsson, Lars Klareskog, Soumya RaychaudhuriRheumatoid arthritis (RA) is the most common immune-mediated arthritis. Anti-citrullinated peptide antibodies (ACPA) are highly specific to RA and assayed with the commercial CCP2 assay. Genetic drivers of RA within the MHC are different for CCP2-positive and -negative subsets of RA, particularly at HLA-DRB1. However, aspartic acid at amino acid position 9 in HLA-B (Bpos-9) increases risk to both RA subsets. Here we explore how individual serologies associated with RA drive associations within the MHC. To define MHC differences for specific ACPA serologies, we quantified a total of 19 separate ACPAs in RA-affected case subjects from four cohorts (n = 6,805). We found a cluster of tightly co-occurring antibodies (canonical serologies, containing CCP2), along with several independently expressed antibodies (non-canonical serologies). After imputing HLA variants into 6,805 case subjects and 13,467 control subjects, we tested associations between the HLA region and RA subgroups based on the presence of canonical and/or non-canonical serologies. We examined CCP2(+) and CCP2(−) RA-affected case subjects separately. In CCP2(−) RA, we observed that the association between CCP2(−) RA and Bpos-9 was derived from individuals who were positive for non-canonical serologies (omnibus_p = 9.2 × 10−17). Similarly, we observed in CCP2(+) RA that associations between subsets of CCP2(+) RA and Bpos-9 were negatively correlated with the number of positive canonical serologies (p = 0.0096). These findings suggest unique genetic characteristics underlying fine-specific ACPAs, suggesting that RA may be further subdivided beyond simply seropositive and seronegative.
  • Aberrant Function of the C-Terminal Tail of HIST1H1E Accelerates Cellular
           Senescence and Causes Premature Aging
    • Abstract: Publication date: Available online 22 August 2019Source: The American Journal of Human GeneticsAuthor(s): Elisabetta Flex, Simone Martinelli, Anke Van Dijck, Andrea Ciolfi, Serena Cecchetti, Elisa Coluzzi, Luca Pannone, Cristina Andreoli, Francesca Clementina Radio, Simone Pizzi, Giovanna Carpentieri, Alessandro Bruselles, Giuseppina Catanzaro, Lucia Pedace, Evelina Miele, Elena Carcarino, Xiaoyan Ge, Chieko Chijiwa, M.E. Suzanne Lewis, Marije MeuwissenHistones mediate dynamic packaging of nuclear DNA in chromatin, a process that is precisely controlled to guarantee efficient compaction of the genome and proper chromosomal segregation during cell division and to accomplish DNA replication, transcription, and repair. Due to the important structural and regulatory roles played by histones, it is not surprising that histone functional dysregulation or aberrant levels of histones can have severe consequences for multiple cellular processes and ultimately might affect development or contribute to cell transformation. Recently, germline frameshift mutations involving the C-terminal tail of HIST1H1E, which is a widely expressed member of the linker histone family and facilitates higher-order chromatin folding, have been causally linked to an as-yet poorly defined syndrome that includes intellectual disability. We report that these mutations result in stable proteins that reside in the nucleus, bind to chromatin, disrupt proper compaction of DNA, and are associated with a specific methylation pattern. Cells expressing these mutant proteins have a dramatically reduced proliferation rate and competence, hardly enter into the S phase, and undergo accelerated senescence. Remarkably, clinical assessment of a relatively large cohort of subjects sharing these mutations revealed a premature aging phenotype as a previously unrecognized feature of the disorder. Our findings identify a direct link between aberrant chromatin remodeling, cellular senescence, and accelerated aging.
  • Using Transcriptomic Hidden Variables to Infer Context-Specific Genotype
           Effects in the Brain
    • Abstract: Publication date: Available online 22 August 2019Source: The American Journal of Human GeneticsAuthor(s): Bernard Ng, William Casazza, Ellis Patrick, Shinya Tasaki, Gherman Novakovsky, Daniel Felsky, Yiyi Ma, David A. Bennett, Chris Gaiteri, Philip L. De Jager, Sara MostafaviDeciphering the environmental contexts at which genetic effects are most prominent is central for making full use of GWAS results in follow-up experiment design and treatment development. However, measuring a large number of environmental factors at high granularity might not always be feasible. Instead, here we propose extracting cellular embedding of environmental factors from gene expression data by using latent variable (LV) analysis and taking these LVs as environmental proxies in detecting gene-by-environment (GxE) interaction effects on gene expression, i.e., GxE expression quantitative trait loci (eQTLs). Applying this approach to two largest brain eQTL datasets (n = 1,100), we show that LVs and GxE eQTLs in one dataset replicate well in the other dataset. Combining the two samples via meta-analysis, 895 GxE eQTLs are identified. On average, GxE effect explains an additional ∼4% variation in expression of each gene that displays a GxE effect. Ten of these 52 genes are associated with cell-type-specific eQTLs, and the remaining genes are multi-functional. Furthermore, after substituting LVs with expression of transcription factors (TF), we found 91 TF-specific eQTLs, which demonstrates an important use of our brain GxE eQTLs.
  • Pathogenic Abnormal Splicing due to Intronic Deletions that Induce
           Biophysical Space Constraint for Spliceosome Assembly
    • Abstract: Publication date: Available online 22 August 2019Source: The American Journal of Human GeneticsAuthor(s): Samantha J. Bryen, Himanshu Joshi, Frances J. Evesson, Cyrille Girard, Roula Ghaoui, Leigh B. Waddell, Alison C. Testa, Beryl Cummings, Susan Arbuckle, Nicole Graf, Richard Webster, Daniel G. MacArthur, Nigel G. Laing, Mark R. Davis, Reinhard Lührmann, Sandra T. CooperA precise genetic diagnosis is the single most important step for families with genetic disorders to enable personalized and preventative medicine. In addition to genetic variants in coding regions (exons) that can change a protein sequence, abnormal pre-mRNA splicing can be devastating for the encoded protein, inducing a frameshift or in-frame deletion/insertion of multiple residues. Non-coding variants that disrupt splicing are extremely challenging to identify. Stemming from an initial clinical discovery in two index Australian families, we define 25 families with genetic disorders caused by a class of pathogenic non-coding splice variant due to intronic deletions. These pathogenic intronic deletions spare all consensus splice motifs, though they critically shorten the minimal distance between the 5′ splice-site (5′SS) and branchpoint. The mechanistic basis for abnormal splicing is due to biophysical constraint precluding U1/U2 spliceosome assembly, which stalls in A-complexes (that bridge the 5′SS and branchpoint). Substitution of deleted nucleotides with non-specific sequences restores spliceosome assembly and normal splicing, arguing against loss of an intronic element as the primary causal basis. Incremental lengthening of 5′SS-branchpoint length in our index EMD case subject defines 45–47 nt as the critical elongation enabling (inefficient) spliceosome assembly for EMD intron 5. The 5′SS-branchpoint space constraint mechanism, not currently factored by genomic informatics pipelines, is relevant to diagnosis and precision medicine across the breadth of Mendelian disorders and cancer genomics.
  • Heterozygous FOXN1 Variants Cause Low TRECs and Severe T Cell Lymphopenia,
           Revealing a Crucial Role of FOXN1 in Supporting Early Thymopoiesis
    • Abstract: Publication date: Available online 22 August 2019Source: The American Journal of Human GeneticsAuthor(s): Marita Bosticardo, Yasuhiro Yamazaki, Jennifer Cowan, Giuliana Giardino, Cristina Corsino, Giulia Scalia, Rosaria Prencipe, Melanie Ruffner, David A. Hill, Inga Sakovich, Irma Yemialyanava, Jonathan S. Tam, Nurcicek Padem, Melissa E. Elder, John W. Sleasman, Elena Perez, Hana Niebur, Christine M. Seroogy, Svetlana Sharapova, Jennifer GebbiaFOXN1 is the master regulatory gene of thymic epithelium development. FOXN1 deficiency leads to thymic aplasia, alopecia, and nail dystrophy, accounting for the nude/severe combined immunodeficiency (nu/SCID) phenotype in humans and mice. We identified several newborns with low levels of T cell receptor excision circles (TRECs) and T cell lymphopenia at birth, who carried heterozygous loss-of-function FOXN1 variants. Longitudinal analysis showed persistent T cell lymphopenia during infancy, often associated with nail dystrophy. Adult individuals with heterozygous FOXN1 variants had in most cases normal CD4+ but lower than normal CD8+ cell counts. We hypothesized a FOXN1 gene dosage effect on the function of thymic epithelial cells (TECs) and thymopoiesis and postulated that these effects would be more prominent early in life. To test this hypothesis, we analyzed TEC subset frequency and phenotype, early thymic progenitor (ETP) cell count, and expression of FOXN1 target genes (Ccl25, Cxcl12, Dll4, Scf, Psmb11, Prss16, and Cd83) in Foxn1nu/+ (nu/+) mice and age-matched wild-type (+/+) littermate controls. Both the frequency and the absolute count of ETP were significantly reduced in nu/+ mice up to 3 weeks of age. Analysis of the TEC compartment showed reduced expression of FOXN1 target genes and delayed maturation of the medullary TEC compartment in nu/+ mice. These observations establish a FOXN1 gene dosage effect on thymic function and identify FOXN1 haploinsufficiency as an important genetic determinant of T cell lymphopenia at birth.
  • Harmonizing Clinical Sequencing and Interpretation for the eMERGE III
    • Abstract: Publication date: Available online 22 August 2019Source: The American Journal of Human GeneticsAuthor(s): The eMERGE ConsortiumThe advancement of precision medicine requires new methods to coordinate and deliver genetic data from heterogeneous sources to physicians and patients. The eMERGE III Network enrolled>25,000 participants from biobank and prospective cohorts of predominantly healthy individuals for clinical genetic testing to determine clinically actionable findings. The network developed protocols linking together the 11 participant collection sites and 2 clinical genetic testing laboratories. DNA capture panels targeting 109 genes were used for testing of DNA and sample collection, data generation, interpretation, reporting, delivery, and storage were each harmonized. A compliant and secure network enabled ongoing review and reconciliation of clinical interpretations, while maintaining communication and data sharing between clinicians and investigators. A total of 202 individuals had positive diagnostic findings relevant to the indication for testing and 1,294 had additional/secondary findings of medical significance deemed to be returnable, establishing data return rates for other testing endeavors. This study accomplished integration of structured genomic results into multiple electronic health record (EHR) systems, setting the stage for clinical decision support to enable genomic medicine. Further, the established processes enable different sequencing sites to harmonize technical and interpretive aspects of sequencing tests, a critical achievement toward global standardization of genomic testing. The eMERGE protocols and tools are available for widespread dissemination.
  • Rates of Actionable Genetic Findings in Individuals with Colorectal Cancer
           or Polyps Ascertained from a Community Medical Setting
    • Abstract: Publication date: Available online 15 August 2019Source: The American Journal of Human GeneticsAuthor(s): Adam S. Gordon, Elisabeth A. Rosenthal, David S. Carrell, Laura M. Amendola, Michael O. Dorschner, Aaron Scrol, Ian B. Stanaway, Shannon DeVange, James D. Ralston, Hana Zouk, Heidi L. Rehm, Eric Larson, David R. Crosslin, Kathy A. Leppig, Gail P. JarvikAs clinical testing for Mendelian causes of colorectal cancer (CRC) is largely driven by recognition of family history and early age of onset, the rates of such findings among individuals with prevalent CRC not recognized to have these features is largely unknown. We evaluated actionable genomic findings in community-based participants ascertained by three phenotypes: (1) CRC, (2) one or more adenomatous colon polyps, and (3) control participants over age 59 years without CRC or colon polyps. These participants underwent sequencing for a panel of genes that included colorectal cancer/polyp (CRC/P)-associated and actionable incidental findings genes. Those with CRC had a 3.8% rate of positive results (pathogenic or likely pathogenic) for a CRC-associated gene variant, despite generally being older at CRC onset (mean 72 years). Those ascertained for polyps had a 0.8% positive rate and those with no CRC/P had a positive rate of 0.2%. Though incidental finding rates unrelated to colon cancer were similar for all groups, our positive rate for cardiovascular findings exceeds disease prevalence, suggesting that variant interpretation challenges or low penetrance in these genes. The rate of HFE c.845G>A (p.Cys282Tyr) homozygotes in the CRC group reinforces a previously reported, but relatively unexplored, association between hemochromatosis and CRC. These results in a general clinical population suggest that current testing strategies could be improved in order to better detect Mendelian CRC-associated conditions. These data also underscore the need for additional functional and familial evidence to clarify the pathogenicity and penetrance of variants deemed pathogenic or likely pathogenic, particularly among the actionable genes associated with cardiovascular disease.
  • Rare De Novo Missense Variants in RNA Helicase DDX6 Cause Intellectual
           Disability and Dysmorphic Features and Lead to P-Body Defects and RNA
    • Abstract: Publication date: Available online 15 August 2019Source: The American Journal of Human GeneticsAuthor(s): Chris Balak, Marianne Benard, Elise Schaefer, Sumaiya Iqbal, Keri Ramsey, Michèle Ernoult-Lange, Francesca Mattioli, Lorida Llaci, Véronique Geoffroy, Maité Courel, Marcus Naymik, Kristine K. Bachman, Rolph Pfundt, Patrick Rump, Johanna ter Beest, Ingrid M. Wentzensen, Kristin G. Monaghan, Kirsty McWalter, Ryan Richholt, Antony Le BéchecThe human RNA helicase DDX6 is an essential component of membrane-less organelles called processing bodies (PBs). PBs are involved in mRNA metabolic processes including translational repression via coordinated storage of mRNAs. Previous studies in human cell lines have implicated altered DDX6 in molecular and cellular dysfunction, but clinical consequences and pathogenesis in humans have yet to be described. Here, we report the identification of five rare de novo missense variants in DDX6 in probands presenting with intellectual disability, developmental delay, and similar dysmorphic features including telecanthus, epicanthus, arched eyebrows, and low-set ears. All five missense variants (p.His372Arg, p.Arg373Gln, p.Cys390Arg, p.Thr391Ile, and p.Thr391Pro) are located in two conserved motifs of the RecA-2 domain of DDX6 involved in RNA binding, helicase activity, and protein-partner binding. We use functional studies to demonstrate that the first variants identified (p.Arg373Gln and p.Cys390Arg) cause significant defects in PB assembly in primary fibroblast and model human cell lines. These variants’ interactions with several protein partners were also disrupted in immunoprecipitation assays. Further investigation via complementation assays included the additional variants p.Thr391Ile and p.Thr391Pro, both of which, similarly to p.Arg373Gln and p.Cys390Arg, demonstrated significant defects in P-body assembly. Complementing these molecular findings, modeling of the variants on solved protein structures showed distinct spatial clustering near known protein binding regions. Collectively, our clinical and molecular data describe a neurodevelopmental syndrome associated with pathogenic missense variants in DDX6. Additionally, we suggest DDX6 join the DExD/H-box genes DDX3X and DHX30 in an emerging class of neurodevelopmental disorders involving RNA helicases.
  • Bi-allelic GOT2 Mutations Cause a Treatable Malate-Aspartate
           Shuttle-Related Encephalopathy
    • Abstract: Publication date: Available online 15 August 2019Source: The American Journal of Human GeneticsAuthor(s): Clara D.M. van Karnebeek, Rúben J. Ramos, Xiao-Yan Wen, Maja Tarailo-Graovac, Joseph G. Gleeson, Cristina Skrypnyk, Koroboshka Brand-Arzamendi, Farhad Karbassi, Mahmoud Y. Issa, Robin van der Lee, Britt I. Drögemöller, Janet Koster, Justine Rousseau, Philippe M. Campeau, Youdong Wang, Feng Cao, Meng Li, Jos Ruiter, Jolita Ciapaite, Leo A.J. KluijtmansEarly-infantile encephalopathies with epilepsy are devastating conditions mandating an accurate diagnosis to guide proper management. Whole-exome sequencing was used to investigate the disease etiology in four children from independent families with intellectual disability and epilepsy, revealing bi-allelic GOT2 mutations. In-depth metabolic studies in individual 1 showed low plasma serine, hypercitrullinemia, hyperlactatemia, and hyperammonemia. The epilepsy was serine and pyridoxine responsive. Functional consequences of observed mutations were tested by measuring enzyme activity and by cell and animal models. Zebrafish and mouse models were used to validate brain developmental and functional defects and to test therapeutic strategies. GOT2 encodes the mitochondrial glutamate oxaloacetate transaminase. GOT2 enzyme activity was deficient in fibroblasts with bi-allelic mutations. GOT2, a member of the malate-aspartate shuttle, plays an essential role in the intracellular NAD(H) redox balance. De novo serine biosynthesis was impaired in fibroblasts with GOT2 mutations and GOT2-knockout HEK293 cells. Correcting the highly oxidized cytosolic NAD-redox state by pyruvate supplementation restored serine biosynthesis in GOT2-deficient cells. Knockdown of got2a in zebrafish resulted in a brain developmental defect associated with seizure-like electroencephalography spikes, which could be rescued by supplying pyridoxine in embryo water. Both pyridoxine and serine synergistically rescued embryonic developmental defects in zebrafish got2a morphants. The two treated individuals reacted favorably to their treatment. Our data provide a mechanistic basis for the biochemical abnormalities in GOT2 deficiency that may also hold for other MAS defects.
  • Extreme Polygenicity of Complex Traits Is Explained by Negative Selection
    • Abstract: Publication date: Available online 8 August 2019Source: The American Journal of Human GeneticsAuthor(s): Luke J. O'Connor, Armin P. Schoech, Farhad Hormozdiari, Steven Gazal, Nick Patterson, Alkes L. PriceComplex traits and common diseases are extremely polygenic, their heritability spread across thousands of loci. One possible explanation is that thousands of genes and loci have similarly important biological effects when mutated. However, we hypothesize that for most complex traits, relatively few genes and loci are critical, and negative selection—purging large-effect mutations in these regions—leaves behind common-variant associations in thousands of less critical regions instead. We refer to this phenomenon as flattening. To quantify its effects, we introduce a mathematical definition of polygenicity, the effective number of independently associated SNPs (Me), which describes how evenly the heritability of a trait is spread across the genome. We developed a method, stratified LD fourth moments regression (S-LD4M), to estimate Me, validating that it produces robust estimates in simulations. Analyzing 33 complex traits (average N = 361k), we determined that heritability is spread ∼4× more evenly among common SNPs than among low-frequency SNPs. This difference, together with evolutionary modeling of new mutations, suggests that complex traits would be orders of magnitude less polygenic if not for the influence of negative selection. We also determined that heritability is spread more evenly within functionally important regions in proportion to their heritability enrichment; functionally important regions do not harbor common SNPs with greatly increased causal effect sizes, due to selective constraint. Our results suggest that for most complex traits, the genes and loci with the most critical biological effects often differ from those with the strongest common-variant associations.
  • Identifying Putative Susceptibility Genes and Evaluating Their
           Associations with Somatic Mutations in Human Cancers
    • Abstract: Publication date: Available online 8 August 2019Source: The American Journal of Human GeneticsAuthor(s): Zhishan Chen, Wanqing Wen, Alicia Beeghly-Fadiel, Xiao-ou Shu, Virginia Díez-Obrero, Jirong Long, Jiandong Bao, Jing Wang, Qi Liu, Qiuyin Cai, Victor Moreno, Wei Zheng, Xingyi GuoGenome-wide association studies (GWASs) have identified hundreds of genetic risk variants for human cancers. However, target genes for the majority of risk loci remain largely unexplored. It is also unclear whether GWAS risk-loci-associated genes contribute to mutational signatures and tumor mutational burden (TMB) in cancer tissues. We systematically conducted cis-expression quantitative trait loci (cis-eQTL) analyses for 294 GWAS-identified variants for six major types of cancer—colorectal, lung, ovary, prostate, pancreas, and melanoma—by using transcriptome data from the Genotype-Tissue Expression (GTEx) Project, the Cancer Genome Atlas (TCGA), and other public data sources. By using integrative analysis strategies, we identified 270 candidate target genes, including 99 with previously unreported associations, for six cancer types. By analyzing functional genomic data, our results indicate that 180 genes (66.7% of 270) had evidence of cis-regulation by putative functional variants via proximal promoter or distal enhancer-promoter interactions. Together with our previously reported associations for breast cancer risk, our results show that 24 genes are shared by at least two cancer types, including four genes for both breast and ovarian cancer. By integrating mutation data from TCGA, we found that expression levels of 33 and 66 putative susceptibility genes were associated with specific mutational signatures and TMB of cancer-driver genes, respectively, at a Bonferroni-corrected p < 0.05. Together, these findings provide further insight into our understanding of how genetic risk variants might contribute to carcinogenesis through the regulation of susceptibility genes that are related to the biogenesis of somatic mutations.
  • De Novo Missense Variants in FBXW11 Cause Diverse Developmental Phenotypes
           Including Brain, Eye, and Digit Anomalies
    • Abstract: Publication date: Available online 8 August 2019Source: The American Journal of Human GeneticsAuthor(s): Richard J. Holt, Rodrigo M. Young, Berta Crespo, Fabiola Ceroni, Cynthia J. Curry, Emanuele Bellacchio, Dorine A. Bax, Andrea Ciolfi, Marleen Simon, Christina R. Fagerberg, Ellen van Binsbergen, Alessandro De Luca, Luigi Memo, William B. Dobyns, Alaa Afif Mohammed, Samuel J.H. Clokie, Celia Zazo Seco, Yong-Hui Jiang, Kristina P. Sørensen, Helle AndersenThe identification of genetic variants implicated in human developmental disorders has been revolutionized by second-generation sequencing combined with international pooling of cases. Here, we describe seven individuals who have diverse yet overlapping developmental anomalies, and who all have de novo missense FBXW11 variants identified by whole exome or whole genome sequencing and not reported in the gnomAD database. Their phenotypes include striking neurodevelopmental, digital, jaw, and eye anomalies, and in one individual, features resembling Noonan syndrome, a condition caused by dysregulated RAS signaling. FBXW11 encodes an F-box protein, part of the Skp1-cullin-F-box (SCF) ubiquitin ligase complex, involved in ubiquitination and proteasomal degradation and thus fundamental to many protein regulatory processes. FBXW11 targets include β-catenin and GLI transcription factors, key mediators of Wnt and Hh signaling, respectively, critical to digital, neurological, and eye development. Structural analyses indicate affected residues cluster at the surface of the loops of the substrate-binding domain of FBXW11, and the variants are predicted to destabilize the protein and/or its interactions. In situ hybridization studies on human and zebrafish embryonic tissues demonstrate FBXW11 is expressed in the developing eye, brain, mandibular processes, and limb buds or pectoral fins. Knockdown of the zebrafish FBXW11 orthologs fbxw11a and fbxw11b resulted in embryos with smaller, misshapen, and underdeveloped eyes and abnormal jaw and pectoral fin development. Our findings support the role of FBXW11 in multiple developmental processes, including those involving the brain, eye, digits, and jaw.
  • Genes for Good: Engaging the Public in Genetics Research via Social Media
    • Abstract: Publication date: 1 August 2019Source: The American Journal of Human Genetics, Volume 105, Issue 2Author(s): Katharine Brieger, Gregory J.M. Zajac, Anita Pandit, Johanna R. Foerster, Kevin W. Li, Aubrey C. Annis, Ellen M. Schmidt, Chris P. Clark, Karly McMorrow, Wei Zhou, Jingjing Yang, Alan M. Kwong, Andrew P. Boughton, Jinxi Wu, Chris Scheller, Tanvi Parikh, Alejandro de la Vega, David M. Brazel, Maia Frieser, Gianna Rea-Sandin
  • Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia
           Differentiates Roles of Early Neurodevelopmental and Adult Synaptic
    • Abstract: Publication date: 1 August 2019Source: The American Journal of Human Genetics, Volume 105, Issue 2Author(s): Max Lam, W. David Hill, Joey W. Trampush, Jin Yu, Emma Knowles, Gail Davies, Eli Stahl, Laura Huckins, David C. Liewald, Srdjan Djurovic, Ingrid Melle, Kjetil Sundet, Andrea Christoforou, Ivar Reinvang, Pamela DeRosse, Astri J. Lundervold, Vidar M. Steen, Thomas Espeseth, Katri Räikkönen, Elisabeth WidenSusceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected (“concordant”) direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive (“discordant”) relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10−8. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms—early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways—that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness.
  • DNA Damage and Associated DNA Repair Defects in Disease and Premature
    • Abstract: Publication date: 1 August 2019Source: The American Journal of Human Genetics, Volume 105, Issue 2Author(s): Vinod Tiwari, David M. WilsonGenetic information is constantly being attacked by intrinsic and extrinsic damaging agents, such as reactive oxygen species, atmospheric radiation, environmental chemicals, and chemotherapeutics. If DNA modifications persist, they can adversely affect the polymerization of DNA or RNA, leading to replication fork collapse or transcription arrest, or can serve as mutagenic templates during nucleic acid synthesis reactions. To combat the deleterious consequences of DNA damage, organisms have developed complex repair networks that remove chemical modifications or aberrant base arrangements and restore the genome to its original state. Not surprisingly, inherited or sporadic defects in DNA repair mechanisms can give rise to cellular outcomes that underlie disease and aging, such as transformation, apoptosis, and senescence. In the review here, we discuss several genetic disorders linked to DNA repair defects, attempting to draw correlations between the nature of the accumulating DNA damage and the pathological endpoints, namely cancer, neurological disease, and premature aging.
  • Using the Data We Have: Improving Diversity in Genomic Research
    • Abstract: Publication date: 1 August 2019Source: The American Journal of Human Genetics, Volume 105, Issue 2Author(s): Teri A. ManolioThe shortage of genomic research data in persons of non-European ancestry is impeding our ability to use genomics in the clinical care of non-European individuals. Improved efforts to utilize data on non-European populations will increase the quality of genomic research and the inferences drawn from it for people of all backgrounds.
  • This Month in The Journal
    • Abstract: Publication date: 1 August 2019Source: The American Journal of Human Genetics, Volume 105, Issue 2Author(s): Sarah Ratzel, Sara B. Cullinan
  • Bi-allelic TARS Mutations Are Associated with Brittle Hair
    • Abstract: Publication date: 1 August 2019Source: The American Journal of Human Genetics, Volume 105, Issue 2Author(s): Arjan F. Theil, Elena Botta, Anja Raams, Desiree E.C. Smith, Marisa I. Mendes, Giuseppina Caligiuri, Sarah Giachetti, Silvia Bione, Roberta Carriero, Giordano Liberi, Luca Zardoni, Sigrid M.A. Swagemakers, Gajja S. Salomons, Alain Sarasin, Alan Lehmann, Peter J. van der Spek, Tomoo Ogi, Jan H.J. Hoeijmakers, Wim Vermeulen, Donata OrioliBrittle and “tiger-tail” hair is the diagnostic hallmark of trichothiodystrophy (TTD), a rare recessive disease associated with a wide spectrum of clinical features including ichthyosis, intellectual disability, decreased fertility, and short stature. As a result of premature abrogation of terminal differentiation, the hair is brittle and fragile and contains reduced cysteine content. Hypersensitivity to UV light is found in about half of individuals with TTD; all of these individuals harbor bi-allelic mutations in components of the basal transcription factor TFIIH, and these mutations lead to impaired nucleotide excision repair and basal transcription. Different genes have been found to be associated with non-photosensitive TTD (NPS-TTD); these include MPLKIP (also called TTDN1), GTF2E2 (also called TFIIEβ), and RNF113A. However, a relatively large group of these individuals with NPS-TTD have remained genetically uncharacterized. Here we present the identification of an NPS-TTD-associated gene, threonyl-tRNA synthetase (TARS), found by next-generation sequencing of a group of uncharacterized individuals with NPS-TTD. One individual has compound heterozygous TARS variants, c.826A>G (p.Lys276Glu) and c.1912C>T (p.Arg638∗), whereas a second individual is homozygous for the TARS variant: c.680T>C (p.Leu227Pro). We showed that these variants have a profound effect on TARS protein stability and enzymatic function. Our results expand the spectrum of genes involved in TTD to include genes implicated in amino acid charging of tRNA, which is required for the last step in gene expression, namely protein translation. We previously proposed that some of the TTD-specific features derive from subtle transcription defects as a consequence of unstable transcription factors. We now extend the definition of TTD from a transcription syndrome to a “gene-expression” syndrome.
  • Phenome-wide Burden of Copy-Number Variation in the UK Biobank
    • Abstract: Publication date: Available online 25 July 2019Source: The American Journal of Human GeneticsAuthor(s): Matthew Aguirre, Manuel A. Rivas, James PriestCopy-number variations (CNVs) represent a significant proportion of the genetic differences between individuals and many CNVs associate causally with syndromic disease and clinical outcomes. Here, we characterize the landscape of copy-number variation and their phenome-wide effects in a sample of 472,228 array-genotyped individuals from the UK Biobank. In addition to population-level selection effects against genic loci conferring high mortality, we describe genetic burden from potentially pathogenic and previously uncharacterized CNV loci across more than 3,000 quantitative and dichotomous traits, with separate analyses for common and rare classes of variation. Specifically, we highlight the effects of CNVs at two well-known syndromic loci 16p11.2 and 22q11.2, previously uncharacterized variation at 9p23, and several genic associations in the context of acute coronary artery disease and high body mass index. Our data constitute a deeply contextualized portrait of population-wide burden of copy-number variation, as well as a series of dosage-mediated genic associations across the medical phenome.
  • Haploinsufficiency of the Notch Ligand DLL1 Causes Variable
           Neurodevelopmental Disorders
    • Abstract: Publication date: Available online 25 July 2019Source: The American Journal of Human GeneticsAuthor(s): Björn Fischer-Zirnsak, Lara Segebrecht, Max Schubach, Perrine Charles, Emily Alderman, Kathleen Brown, Maxime Cadieux-Dion, Tracy Cartwright, Yanmin Chen, Carrie Costin, Sarah Fehr, Keely M. Fitzgerald, Emily Fleming, Kimberly Foss, Thoa Ha, Gabriele Hildebrand, Denise Horn, Shuxi Liu, Elysa J. Marco, Marie McDonaldNotch signaling is an established developmental pathway for brain morphogenesis. Given that Delta-like 1 (DLL1) is a ligand for the Notch receptor and that a few individuals with developmental delay, intellectual disability, and brain malformations have microdeletions encompassing DLL1, we hypothesized that insufficiency of DLL1 causes a human neurodevelopmental disorder. We performed exome sequencing in individuals with neurodevelopmental disorders. The cohort was identified using known Matchmaker Exchange nodes such as GeneMatcher. This method identified 15 individuals from 12 unrelated families with heterozygous pathogenic DLL1 variants (nonsense, missense, splice site, and one whole gene deletion). The most common features in our cohort were intellectual disability, autism spectrum disorder, seizures, variable brain malformations, muscular hypotonia, and scoliosis. We did not identify an obvious genotype-phenotype correlation. Analysis of one splice site variant showed an in-frame insertion of 12 bp. In conclusion, heterozygous DLL1 pathogenic variants cause a variable neurodevelopmental phenotype and multi-systemic features. The clinical and molecular data support haploinsufficiency as a mechanism for the pathogenesis of this DLL1-related disorder and affirm the importance of DLL1 in human brain development.
  • Mutations in PIGU Impair the Function of the GPI Transamidase Complex,
           Causing Severe Intellectual Disability, Epilepsy, and Brain Anomalies
    • Abstract: Publication date: Available online 25 July 2019Source: The American Journal of Human GeneticsAuthor(s): Alexej Knaus, Fanny Kortüm, Tjitske Kleefstra, Asbjørg Stray-Pedersen, Dejan Đukić, Yoshiko Murakami, Thorsten Gerstner, Hans van Bokhoven, Zafar Iqbal, Denise Horn, Taroh Kinoshita, Maja Hempel, Peter M. KrawitzThe glycosylphosphatidylinositol (GPI) anchor links over 150 proteins to the cell surface and is present on every cell type. Many of these proteins play crucial roles in neuronal development and function. Mutations in 18 of the 29 genes implicated in the biosynthesis of the GPI anchor have been identified as the cause of GPI biosynthesis deficiencies (GPIBDs) in humans. GPIBDs are associated with intellectual disability and seizures as their cardinal features. An essential component of the GPI transamidase complex is PIGU, along with PIGK, PIGS, PIGT, and GPAA1, all of which link GPI-anchored proteins (GPI-APs) onto the GPI anchor in the endoplasmic reticulum (ER). Here, we report two homozygous missense mutations (c.209T>A [p.Ile70Lys] and c.1149C>A [p.Asn383Lys]) in five individuals from three unrelated families. All individuals presented with global developmental delay, severe-to-profound intellectual disability, muscular hypotonia, seizures, brain anomalies, scoliosis, and mild facial dysmorphism. Using multicolor flow cytometry, we determined a characteristic profile for GPI transamidase deficiency. On granulocytes this profile consisted of reduced cell-surface expression of fluorescein-labeled proaerolysin (FLAER), CD16, and CD24, but not of CD55 and CD59; additionally, B cells showed an increased expression of free GPI anchors determined by T5 antibody. Moreover, computer-assisted facial analysis of different GPIBDs revealed a characteristic facial gestalt shared among individuals with mutations in PIGU and GPAA1. Our findings improve our understanding of the role of the GPI transamidase complex in the development of nervous and skeletal systems and expand the clinical spectrum of disorders belonging to the group of inherited GPI-anchor deficiencies.
  • De Novo Heterozygous POLR2A Variants Cause a Neurodevelopmental Syndrome
           with Profound Infantile-Onset Hypotonia
    • Abstract: Publication date: Available online 25 July 2019Source: The American Journal of Human GeneticsAuthor(s): Hanneke A. Haijes, Maria J.E. Koster, Holger Rehmann, Dong Li, Hakon Hakonarson, Gerarda Cappuccio, Miroslava Hancarova, Daphne Lehalle, Willie Reardon, G. Bradley Schaefer, Anna Lehman, Ingrid M.B.H. van de Laar, Coranne D. Tesselaar, Clesson Turner, Alice Goldenberg, Sophie Patrier, Julien Thevenon, Michele Pinelli, Nicola Brunetti-Pierri, Darina PrchalováThe RNA polymerase II complex (pol II) is responsible for transcription of all ∼21,000 human protein-encoding genes. Here, we describe sixteen individuals harboring de novo heterozygous variants in POLR2A, encoding RPB1, the largest subunit of pol II. An iterative approach combining structural evaluation and mass spectrometry analyses, the use of S. cerevisiae as a model system, and the assessment of cell viability in HeLa cells allowed us to classify eleven variants as probably disease-causing and four variants as possibly disease-causing. The significance of one variant remains unresolved. By quantification of phenotypic severity, we could distinguish mild and severe phenotypic consequences of the disease-causing variants. Missense variants expected to exert only mild structural effects led to a malfunctioning pol II enzyme, thereby inducing a dominant-negative effect on gene transcription. Intriguingly, individuals carrying these variants presented with a severe phenotype dominated by profound infantile-onset hypotonia and developmental delay. Conversely, individuals carrying variants expected to result in complete loss of function, thus reduced levels of functional pol II from the normal allele, exhibited the mildest phenotypes. We conclude that subtle variants that are central in functionally important domains of POLR2A cause a neurodevelopmental syndrome characterized by profound infantile-onset hypotonia and developmental delay through a dominant-negative effect on pol-II-mediated transcription of DNA.
  • Family Clustering of Autoimmune Vitiligo Results Principally from
           Polygenic Inheritance of Common Risk Alleles
    • Abstract: Publication date: Available online 18 July 2019Source: The American Journal of Human GeneticsAuthor(s): Genevieve H.L. Roberts, Subrata Paul, Daniel Yorgov, Stephanie A. Santorico, Richard A. SpritzVitiligo is an autoimmune disease that results in patches of depigmented skin and hair. Previous genome-wide association studies (GWASs) of vitiligo have identified 50 susceptibility loci. Variants at the associated loci are generally common and have individually small effects on risk. Most vitiligo cases are “simplex,” where there is no family history of vitiligo, though occasional family clustering of vitiligo occurs, and some “multiplex” families report numerous close affected relatives. Here, we investigate whether simplex and multiplex vitiligo comprise different disease subtypes with different underlying genetic etiologies. We developed and compared the performance of several different vitiligo polygenic risk scores derived from GWAS data. By using the best-performing risk score, we find increased polygenic burden of risk alleles identified by GWAS in multiplex vitiligo cases relative to simplex cases. We additionally find evidence of polygenic transmission of common, low-effect-size risk alleles within multiplex-vitiligo-affected families. Our findings strongly suggest that family clustering of vitiligo involves a high burden of the same common, low-effect-size variants that are relevant in simplex cases. We furthermore find that a variant within the major histocompatibility complex (MHC) class II region contributes disproportionately more to risk in multiplex vitiligo cases than in simplex cases, supporting a special role for adaptive immune triggering in the etiology of multiplex cases. We suggest that genetic risk scores can be a useful tool in analyzing the genetic architecture of clinical disease subtypes and identifying subjects with unusual etiologies for further investigation.
  • De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas,
           Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar
    • Abstract: Publication date: Available online 18 July 2019Source: The American Journal of Human GeneticsAuthor(s): Oguz Kanca, Jonathan C. Andrews, Pei-Tseng Lee, Chirag Patel, Stephen R. Braddock, Anne M. Slavotinek, Julie S. Cohen, Cynthia S. Gubbels, Kimberly A. Aldinger, Judy Williams, Maanasa Indaram, Ali Fatemi, Timothy W. Yu, Pankaj B. Agrawal, Gilbert Vezina, Cas Simons, Joanna Crawford, C. Christopher Lau, Maria T. Acosta, David R. AdamsWD40 repeat-containing proteins form a large family of proteins present in all eukaryotes. Here, we identified five pediatric probands with de novo variants in WDR37, which encodes a member of the WD40 repeat protein family. Two probands shared one variant and the others have variants in nearby amino acids outside the WD40 repeats. The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia. The WDR37 protein is highly conserved in vertebrate and invertebrate model organisms and is currently not associated with a human disease. We generated a null allele of the single Drosophila ortholog to gain functional insights and replaced the coding region of the fly gene CG12333/wdr37 with GAL4. These flies are homozygous viable but display severe bang sensitivity, a phenotype associated with seizures in flies. Additionally, the mutant flies fall when climbing the walls of the vials, suggesting a defect in grip strength, and repeat the cycle of climbing and falling. Similar to wall clinging defect, mutant males often lose grip of the female abdomen during copulation. These phenotypes are rescued by using the GAL4 in the CG12333/wdr37 locus to drive the UAS-human reference WDR37 cDNA. The two variants found in three human subjects failed to rescue these phenotypes, suggesting that these alleles severely affect the function of this protein. Taken together, our data suggest that variants in WDR37 underlie a novel syndromic neurological disorder.
  • Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing
           Study of 17,606 Individuals
    • Abstract: Publication date: Available online 18 July 2019Source: The American Journal of Human GeneticsAuthor(s): Epi25 CollaborativeSequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.
  • De Novo Missense Variants in WDR37 Cause a Severe
           Multisystemic Syndrome
    • Abstract: Publication date: Available online 18 July 2019Source: The American Journal of Human GeneticsAuthor(s): Linda M. Reis, Elena A. Sorokina, Samuel Thompson, Sanaa Muheisen, Milen Velinov, Carlos Zamora, Arthur S. Aylsworth, Elena V. SeminaWhile genetic causes are known for many syndromes involving developmental anomalies, a large number of individuals with overlapping phenotypes remain undiagnosed. Using exome-sequencing analysis and review of matchmaker databases, we have discovered four de novo missense variants predicted to affect the N-terminal region of WDR37—p.Ser119Phe, p.Thr125Ile, p.Ser129Cys, and p.Thr130Ile—in unrelated individuals with a previously unrecognized syndrome. Features of WDR37 syndrome include the following: ocular anomalies such as corneal opacity/Peters anomaly, coloboma, and microcornea; dysmorphic facial features; significant neurological impairment with structural brain defects and seizures; poor feeding; poor post-natal growth; variable skeletal, cardiac, and genitourinary defects; and death in infancy in one individual. WDR37 encodes a protein of unknown function with seven predicted WD40 domains and no previously reported human pathogenic variants. Immunocytochemistry and western blot studies showed that wild-type WDR37 is localized predominantly in the cytoplasm and mutant proteins demonstrate similar protein levels and localization. CRISPR-Cas9-mediated genome editing generated zebrafish mutants with novel missense and frameshift alleles: p.Ser129Phe, p.Ser129Cys (which replicates one of the human variants), p.Ser129Tyr, p.Lys127Cysfs, and p.Gln95Argfs. Zebrafish carrying heterozygous missense variants demonstrated poor growth and larval lethality, while heterozygotes with frameshift alleles survived to adulthood, suggesting a potential dominant-negative mechanism for the missense variants. RNA-seq analysis of zebrafish embryos carrying a missense variant detected significant upregulation of cholesterol biosynthesis pathways. This study identifies variants in WDR37 associated with human disease and provides insight into its essential role in vertebrate development and possible molecular functions.
  • De Novo Variants Disturbing the Transactivation Capacity of POU3F3 Cause a
           Characteristic Neurodevelopmental Disorder
    • Abstract: Publication date: Available online 11 July 2019Source: The American Journal of Human GeneticsAuthor(s): Lot Snijders Blok, Tjitske Kleefstra, Hanka Venselaar, Saskia Maas, Hester Y. Kroes, Augusta M.A. Lachmeijer, Koen L.I. van Gassen, Helen V. Firth, Susan Tomkins, Simon Bodek, The DDD Study, Katrin Õunap, Monica H. Wojcik, Christopher Cunniff, Katherine Bergstrom, Zoë Powis, Sha Tang, Deepali N. Shinde, Catherine Au, Alejandro D. Iglesias, Kosuke IzumiPOU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder.
  • Comparing Within- and Between-Family Polygenic Score Prediction
    • Abstract: Publication date: Available online 11 July 2019Source: The American Journal of Human GeneticsAuthor(s): Saskia Selzam, Stuart J. Ritchie, Jean-Baptiste Pingault, Chandra A. Reynolds, Paul F. O’Reilly, Robert PlominPolygenic scores are a popular tool for prediction of complex traits. However, prediction estimates in samples of unrelated participants can include effects of population stratification, assortative mating, and environmentally mediated parental genetic effects, a form of genotype-environment correlation (rGE). Comparing genome-wide polygenic score (GPS) predictions in unrelated individuals with predictions between siblings in a within-family design is a powerful approach to identify these different sources of prediction. Here, we compared within- to between-family GPS predictions of eight outcomes (anthropometric, cognitive, personality, and health) for eight corresponding GPSs. The outcomes were assessed in up to 2,366 dizygotic (DZ) twin pairs from the Twins Early Development Study from age 12 to age 21. To account for family clustering, we used mixed-effects modeling, simultaneously estimating within- and between-family effects for target- and cross-trait GPS prediction of the outcomes. There were three main findings: (1) DZ twin GPS differences predicted DZ differences in height, BMI, intelligence, educational achievement, and ADHD symptoms; (2) target and cross-trait analyses indicated that GPS prediction estimates for cognitive traits (intelligence and educational achievement) were on average 60% greater between families than within families, but this was not the case for non-cognitive traits; and (3) much of this within- and between-family difference for cognitive traits disappeared after controlling for family socio-economic status (SES), suggesting that SES is a major source of between-family prediction through rGE mechanisms. These results provide insights into the patterns by which rGE contributes to GPS prediction, while ruling out confounding due to population stratification and assortative mating.
  • Mutations in ANAPC1, Encoding a Scaffold Subunit of the Anaphase-Promoting
           Complex, Cause Rothmund-Thomson Syndrome Type 1
    • Abstract: Publication date: Available online 11 July 2019Source: The American Journal of Human GeneticsAuthor(s): Norbert F. Ajeawung, Thi Tuyet Mai Nguyen, Linchao Lu, Thomas J. Kucharski, Justine Rousseau, Sirinart Molidperee, Joshua Atienza, Isabel Gamache, Weidong Jin, Sharon E. Plon, Brendan H. Lee, Jose G. Teodoro, Lisa L. Wang, Philippe M. CampeauRothmund-Thomson syndrome (RTS) is an autosomal-recessive disorder characterized by poikiloderma, sparse hair, short stature, and skeletal anomalies. Type 2 RTS, which is defined by the presence of bi-allelic mutations in RECQL4, is characterized by increased cancer susceptibility and skeletal anomalies, whereas the genetic basis of RTS type 1, which is associated with juvenile cataracts, is unknown. We studied ten individuals, from seven families, who had RTS type 1 and identified a deep intronic splicing mutation of the ANAPC1 gene, a component of the anaphase-promoting complex/cyclosome (APC/C), in all affected individuals, either in the homozygous state or in trans with another mutation. Fibroblast studies showed that the intronic mutation causes the activation of a 95 bp pseudoexon, leading to mRNAs with premature termination codons and nonsense-mediated decay, decreased ANAPC1 protein levels, and prolongation of interphase. Interestingly, mice that were heterozygous for a knockout mutation have an increased incidence of cataracts. Our results demonstrate that deficiency in the APC/C is a cause of RTS type 1 and suggest a possible link between the APC/C and RECQL4 helicase because both proteins are involved in DNA repair and replication.
  • Inference of Population Structure from Time-Series Genotype Data
    • Abstract: Publication date: Available online 27 June 2019Source: The American Journal of Human GeneticsAuthor(s): Tyler A. Joseph, Itsik Pe’erSequencing ancient DNA can offer direct probing of population history. Yet, such data are commonly analyzed with standard tools that assume DNA samples are all contemporary. We present DyStruct, a model and inference algorithm for inferring shared ancestry from temporally sampled genotype data. DyStruct explicitly incorporates temporal dynamics by modeling individuals as mixtures of unobserved populations whose allele frequencies drift over time. We develop an efficient inference algorithm for our model using stochastic variational inference. On simulated data, we show that DyStruct outperforms the current state of the art when individuals are sampled over time. Using a dataset of 296 modern and 80 ancient samples, we demonstrate DyStruct is able to capture a well-supported admixture event of steppe ancestry into modern Europe. We further apply DyStruct to a genome-wide dataset of 2,067 modern and 262 ancient samples used to study the origin of farming in the Near East. We show that DyStruct provides new insight into population history when compared with alternate approaches, within feasible run time.
  • Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an
           Axonal Neuropathy and Metabolic Abnormality in Severe Cases
    • Abstract: Publication date: Available online 27 June 2019Source: The American Journal of Human GeneticsAuthor(s): Yoshiko Murakami, Thi Tuyet Mai Nguyen, Nissan Baratang, Praveen K. Raju, Alexej Knaus, Sian Ellard, Gabriela Jones, Baiba Lace, Justine Rousseau, Norbert Fonya Ajeawung, Atsushi Kamei, Gaku Minase, Manami Akasaka, Nami Araya, Eriko Koshimizu, Jenneke van den Ende, Florian Erger, Janine Altmüller, Zita Krumina, Jurgis StrautmanisProteins anchored to the cell surface via glycosylphosphatidylinositol (GPI) play various key roles in the human body, particularly in development and neurogenesis. As such, many developmental disorders are caused by mutations in genes involved in the GPI biosynthesis and remodeling pathway. We describe ten unrelated families with bi-allelic mutations in PIGB, a gene that encodes phosphatidylinositol glycan class B, which transfers the third mannose to the GPI. Ten different PIGB variants were found in these individuals. Flow cytometric analysis of blood cells and fibroblasts from the affected individuals showed decreased cell surface presence of GPI-anchored proteins. Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy. Eight children passed away before four years old. Two of them had a clinical diagnosis of DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures), a condition that includes sensorineural deafness, shortened terminal phalanges with small finger and toenails, intellectual disability, and seizures; this condition overlaps with the severe phenotypes associated with inherited GPI deficiency. Most individuals tested showed elevated alkaline phosphatase, which is a characteristic of the inherited GPI deficiency but not DOORS syndrome. It is notable that two severely affected individuals showed 2-oxoglutaric aciduria, which can be seen in DOORS syndrome, suggesting that severe cases of inherited GPI deficiency and DOORS syndrome might share some molecular pathway disruptions.
  • Paralog Studies Augment Gene Discovery: DDX and DHX
    • Abstract: Publication date: Available online 27 June 2019Source: The American Journal of Human GeneticsAuthor(s): Ingrid Paine, Jennifer E. Posey, Christopher M. Grochowski, Shalini N. Jhangiani, Sarah Rosenheck, Robert Kleyner, Taylor Marmorale, Margaret Yoon, Kai Wang, Reid Robison, Gerarda Cappuccio, Michele Pinelli, Adriano Magli, Zeynep Coban Akdemir, Joannie Hui, Wai Lan Yeung, Bibiana K.Y. Wong, Lucia Ortega, Mir Reza Bekheirnia, Tatjana BierhalsMembers of a paralogous gene family in which variation in one gene is known to cause disease are eight times more likely to also be associated with human disease. Recent studies have elucidated DHX30 and DDX3X as genes for which pathogenic variant alleles are involved in neurodevelopmental disorders. We hypothesized that variants in paralogous genes encoding members of the DExD/H-box RNA helicase superfamily might also underlie developmental delay and/or intellectual disability (DD and/or ID) disease phenotypes. Here we describe 15 unrelated individuals who have DD and/or ID, central nervous system (CNS) dysfunction, vertebral anomalies, and dysmorphic features and were found to have probably damaging variants in DExD/H-box RNA helicase genes. In addition, these individuals exhibit a variety of other tissue and organ system involvement including ocular, outer ear, hearing, cardiac, and kidney tissues. Five individuals with homozygous (one), compound-heterozygous (two), or de novo (two) missense variants in DHX37 were identified by exome sequencing. We identified ten total individuals with missense variants in three other DDX/DHX paralogs: DHX16 (four individuals), DDX54 (three individuals), and DHX34 (three individuals). Most identified variants are rare, predicted to be damaging, and occur at conserved amino acid residues. Taken together, these 15 individuals implicate the DExD/H-box helicases in both dominantly and recessively inherited neurodevelopmental phenotypes and highlight the potential for more than one disease mechanism underlying these disorders.
  • TIGAR: An Improved Bayesian Tool for Transcriptomic Data Imputation
           Enhances Gene Mapping of Complex Traits
    • Abstract: Publication date: Available online 20 June 2019Source: The American Journal of Human GeneticsAuthor(s): Sini Nagpal, Xiaoran Meng, Michael P. Epstein, Lam C. Tsoi, Matthew Patrick, Greg Gibson, Philip L. De Jager, David A. Bennett, Aliza P. Wingo, Thomas S. Wingo, Jingjing YangThe transcriptome-wide association studies (TWASs) that test for association between the study trait and the imputed gene expression levels from cis-acting expression quantitative trait loci (cis-eQTL) genotypes have successfully enhanced the discovery of genetic risk loci for complex traits. By using the gene expression imputation models fitted from reference datasets that have both genetic and transcriptomic data, TWASs facilitate gene-based tests with GWAS data while accounting for the reference transcriptomic data. The existing TWAS tools like PrediXcan and FUSION use parametric imputation models that have limitations for modeling the complex genetic architecture of transcriptomic data. Therefore, to improve on this, we employ a nonparametric Bayesian method that was originally proposed for genetic prediction of complex traits, which assumes a data-driven nonparametric prior for cis-eQTL effect sizes. The nonparametric Bayesian method is flexible and general because it includes both of the parametric imputation models used by PrediXcan and FUSION as special cases. Our simulation studies showed that the nonparametric Bayesian model improved both imputation R2 for transcriptomic data and the TWAS power over PrediXcan when ≥1% cis-SNPs co-regulate gene expression and gene expression heritability ≤0.2. In real applications, the nonparametric Bayesian method fitted transcriptomic imputation models for 57.8% more genes over PrediXcan, thus improving the power of follow-up TWASs. We implement both parametric PrediXcan and nonparametric Bayesian methods in a convenient software tool “TIGAR” (Transcriptome-Integrated Genetic Association Resource), which imputes transcriptomic data and performs subsequent TWASs using individual-level or summary-level GWAS data.
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