Journal Article

Rare coding variants in 10 genes confer substantial risk for schizophrenia

Hougaard, David M., Lescai, Francesco, Marder, Stephen R., Olivares, Ana Maria, Lee, Francis S., Bybjerg-Grauholm, Jonas, Glatt, Stephen J., Morris, Derek W., Smoller, Jordan W., Malaspina, Dolores, Singh, Tarjinder, Paunio, Tiina, Børglum, Anders D., Esko, Tõnu, Barchas, Jack D., Craddock, Nicholas, Buckley, Peter F., Sklar, Pamela, Tsuang, Ming T., Bo Mortensen, Preben, Blackwood, Douglas H., Fiorentino, Alessia, McIntosh, Andrew M., Solomonson, Matthew, Heyne, Henrike O., Pato, Michele T., Ganna, Andrea, Watts, Nicholas A., Watson, Stanley J., Bigdeli, Tim B., Satterstrom, F. Kyle, Eskelinen, Saana, Escamilla, Michael A., Cohen, Bruce M., Palotie, Aarno, Chapman, Sinéad B., Francioli, Laurent, Rapaport, Mark H., Nordentoft, Merete, McCarroll, Steven A., Bass, Nicholas, Hall, Mei-Hua, Gage, Diane, Bromet, Evelyn J., Quested, Digby, Myers, Richard M., Glahn, David C., Sobell, Janet l., Breen, Gerome, Dodge, Sheila, Corvin, Aiden P., Churchhouse, Claire, O’Brien, Niamh L., Schatzberg, Alan, Stevens, Christine R., Huang, Hailiang, Howrigan, Daniel P., Freimer, Nelson B., Bunney, William E., Scott, Laur

2022

Overview

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. 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 × 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 observe an overlap of rare variant risk between schizophrenia, autism spectrum disorders (ASD)1, epilepsy and severe neurodevelopmental disorders (DD/ID)2, though in some shared genes different mutation types are implicated. Most genes described here however are not implicated in neurodevelopment and 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 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 risk genes await discovery using this approach.