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Exome sequencing identifies rare coding variants in 10 genes which confer substantial risk for schizophrenia

By Tarjinder Singh, Timothy Poterba, David Curtis, Huda Akil, Mariam Al Eissa, Jack D Barchas, Nicholas J Bass, Tim B. Bigdeli, Gerome Breen, Evelyn J Bromet, Peter F Buckley, William E Bunney, Jonas Bybjerg-Grauholm, William F Byerley, Sinead B Chapman, Wei J. Chen, Claire Churchhouse, Nicholas Craddock, Charles Curtis, Caroline M Cusick, Lynn DeLisi, Sheila Dodge, Michael A Escamilla, Saana Eskelinen, Ayman H. Fanous, Stephen V Faraone, Alessia Fiorentino, Laurent Francioli, Stacey B Gabriel, Diane Gage, Sarah A Gagliano Taliun, Andrea Ganna, Giulio Genovese, David C Glahn, Jakob Grove, Mei-Hua Hall, Eija Hamalainen, Henrike O. Heyne, Matti Holi, David M Hougaard, Daniel P Howrigan, Hailiang Huang, Hai-Gwo Hwu, Rene S Kahn, Hyun Min Kang, Konrad Karczewski, George Kirov, James A Knowles, Francis S Lee, Douglas S Lehrer, Francesco Lescai, Dolores Malaspina, Stephen R Marder, Steven A McCarroll, Helena Medeiros, Lili Milani, Christopher P Morley, Derek W. Morris, Preben Bo Mortensen, Richard M Myers, Merete Nordentoft, Niamh L O'Brien, Ana Maria Olivares, Dost Ongur, Willem Hendrik Ouwehand, Duncan S Palmer, T. Paunio, Digby Quested, Mark H Rapaport, Elliott Rees, Brandi Rollins, F. Kyle Satterstrom, Alan Schatzberg, Edward Scolnick, Laura Scott, Sally I Sharp, Pamela Sklar, Jordan W Smoller, Janet l Sobell, Matthew Solomonson, Christine R Stevens, J. Suvisaari, Grace Tiao, Stanley J. Watson, Nicholas A Watts, Douglas H Blackwood, Anders Borglum, Bruce M. Cohen, Aiden P Corvin, Tonu Esko, Nelson B Freimer, Stephen J Glatt, Christina M Hultman, Andrew McQuillin, Aarno Palotie, Carlos N. Pato, Michele T Pato, Ann E Pulver, David St Clair, Ming T Tsuang, Marquis P Vawter, James T R Walters, Thomas Werge, Roel A Ophoff, Patrick F Sullivan, Michael J Owen, Michael Boehnke, Michael O'Donovan, Benjamin M Neale, M. Daly

Posted 18 Sep 2020
medRxiv DOI: 10.1101/2020.09.18.20192815

By meta-analyzing the whole-exomes of 24,248 cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in ten genes as conferring substantial risk for schizophrenia (odds ratios 3 - 50, P < 2.14 x 10^-6), and 32 genes at a FDR < 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 NMDA receptor subunit GRIN2A and AMPA receptor subunit GRIA3 provide support for the dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We find significant evidence for an overlap of rare variant risk between schizophrenia, autism spectrum disorders (ASD), and severe neurodevelopmental disorders (DD/ID), supporting a neurodevelopmental etiology for schizophrenia. We show that protein-truncating variants in GRIN2A, TRIO, and CACNA1G confer risk for schizophrenia whereas specific missense mutations in these genes confer risk for DD/ID. Nevertheless, few of the strongly associated schizophrenia genes appear to confer risk for DD/ID. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk, suggesting that common and rare genetic risk factors at least partially converge on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, implying that more schizophrenia risk genes await discovery using this approach.

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