Rare coding variants in ten genes confer substantial risk for schizophrenia

作者：Tarjinder Singh, Timothy Poterba, David Curtis, Huda Akil, Mariam Al Eissa, Jack D. Barchas, Nicholas Bass, Tim B. Bigdeli, Gerome D. Breen, Evelyn J. Bromet, P.F. Buckley, William Edward Bunney, Jonas Bybjerg‐Grauholm, William Byerley, Sinéad B. Chapman, Wei J. Chen, Claire L. Churchhouse, Nicholas Craddock, Caroline M. Cusick, Lynn E. DeLisi, Sheila Dodge, Michael Escamilla, Saana Eskelinen, Ayman H. Fanous, Stephen V. Faraone, Alessia Fiorentino, Laurent C. Francioli, Stacey L. Gabriel, Diane Gage, Sarah A. Gagliano Taliun, Andrea Ganna, Giulio Genovese, David C. Glahn, Jakob Grove, Mei‐Hua Hall, Eija Hämäläinen, Henrike Heyne, Matti Mikael Holi, DAVID MICHAEL HOUGAARD, Daniel P. Howrigan, Hailiang Huang, Hai‐Gwo Hwu, René S. Kahn, Hyun Min Kang, Konrad J. Karczewski, George Kirov, James A. Knowles, Francis S. Lee, Douglas S. Lehrer, Francesco Lescai, Dolores Malaspina, Stephen R. Marder, Steven A. McCarroll, Andrew Mark McIntosh, Helena Medeiros, Lili A. Milani, Christopher P. Morley, Derek W. Morris, Preben Bo Mortensen, R Myers, Merete Nordentoft, Niamh Louise O’Brien, Ana Maria Olivares, Döst Öngür, Willem Hendrik Ouwehand, Duncan S. Palmer, Tiina Paunio, Digby J. Quested, Mark Hyman Rapaport, Elliott G Rees, Brandi L. Rollins, F. Kyle Satterstrom, Alan F. Schatzberg, Edward M. Scolnick, Laura J. Scott, Sally Isabel Sharp, Pamela B. Sklar, Jordan W. Smoller, Janet L. Sobell, Matthew Solomonson, Eli A. Stahl, Christine R. Stevens, Jaana Suvisaari, Grace Tiao, Stanley J. Watson, Nicholas A. Watts, Douglas Blackwood, Anders Dupont Børglum, Bruce M. Cohen, Aiden P. Corvin, Tõnu Esko, Nelson B. Freimer, Stephen J. Glatt, Christina M. Hultman, Andrew McQuillin, Aarno V. Palotie, Carlos N. Pato, Michele T. Pato, Ann E. Pulver, David St Clair, Ming T. Tsuang, Marquis P. Vawter, James Walters, Thomas Mears Werge, Roel A. Ophoff, Patrick F. Sullivan, Michael J. Owen, Michael Boehnke, Michael C. O’Donovan, Benjamin M. Neale, Mark J. Daly · 发表于：Nature · 年份：2022 · DOI：10.1038/s41586-022-04556-w · 被引用次数：931 · 研究领域：Genomics and Rare Diseases、Genomic variations and chromosomal abnormalities、Genetic Associations and Epidemiology

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3–50, P < 2.14 × 10−6) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-d-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still c...