https://scholars.lib.ntu.edu.tw/handle/123456789/629552
Title: | Rare coding variants in ten genes confer substantial risk for schizophrenia | Authors: | Singh, Tarjinder Poterba, Timothy Curtis, David Akil, Huda Al Eissa, Mariam Barchas, Jack D Bass, Nicholas Bigdeli, Tim B Breen, Gerome Bromet, Evelyn J Buckley, Peter F Bunney, William E Bybjerg-Grauholm, Jonas Byerley, William F Chapman, Sinéad B WEI J. CHEN Churchhouse, Claire Craddock, Nicholas Cusick, Caroline M DeLisi, Lynn Dodge, Sheila Escamilla, Michael A Eskelinen, Saana Fanous, Ayman H Faraone, Stephen V Fiorentino, Alessia Francioli, Laurent Gabriel, Stacey B Gage, Diane Gagliano Taliun, Sarah A Ganna, Andrea Genovese, Giulio Glahn, David C Grove, Jakob Hall, Mei-Hua Hämäläinen, Eija Heyne, Henrike O Holi, Matti Hougaard, David M Howrigan, Daniel P Huang, Hailiang Hwu, Hai-Gwo Kahn, René S Kang, Hyun Min Karczewski, Konrad J Kirov, George Knowles, James A Lee, Francis S Lehrer, Douglas S Lescai, Francesco Malaspina, Dolores Marder, Stephen R McCarroll, Steven A McIntosh, Andrew M Medeiros, Helena Milani, Lili Morley, Christopher P Morris, Derek W Mortensen, Preben Bo Myers, Richard M Nordentoft, Merete O'Brien, Niamh L Olivares, Ana Maria Ongur, Dost Ouwehand, Willem H Palmer, Duncan S Paunio, Tiina Quested, Digby Rapaport, Mark H Rees, Elliott Rollins, Brandi Satterstrom, F Kyle Schatzberg, Alan Scolnick, Edward Scott, Laura J Sharp, Sally I Sklar, Pamela Smoller, Jordan W Sobell, Janet L Solomonson, Matthew Stahl, Eli A Stevens, Christine R Suvisaari, Jaana Tiao, Grace Watson, Stanley J Watts, Nicholas A Blackwood, Douglas H Børglum, Anders D Cohen, Bruce M Corvin, Aiden P Esko, Tõnu Freimer, Nelson B Glatt, Stephen J Hultman, Christina M McQuillin, Andrew Palotie, Aarno Pato, Carlos N Pato, Michele T Pulver, Ann E St Clair, David Tsuang, Ming T Vawter, Marquis P Walters, James T Werge, Thomas M Ophoff, Roel A Sullivan, Patrick F Owen, Michael J Boehnke, Michael O'Donovan, Michael C Neale, Benjamin M Daly, Mark J |
Keywords: | MUTATIONS; INDIVIDUALS; ASSOCIATION; BURDEN | Issue Date: | Apr-2022 | Publisher: | NATURE PORTFOLIO | Journal Volume: | 604 | Journal Issue: | 7906 | Start page/Pages: | 509 | Source: | Nature | Abstract: | 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 carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/629552 | ISSN: | 0028-0836 | DOI: | 10.1038/s41586-022-04556-w |
Appears in Collections: | 流行病學與預防醫學研究所 |
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