Rare coding variants in ten genes confer substantial risk for schizophrenia
Citation
Singh T, Poterba T, Curtis D, Huda Akil , Ann Arbor, . 'Huda Akil' Akil , Al Eissa M Barchas JD, Bass N, Bigdeli TB, Breen G, Bromet EJ, Buckley PF, Bunney WE, Bybjerg-Grauholm J, Byerley WF, Chapman SB, Chen WJ, Churchhouse C, Craddock N, Cusick CM, DeLisi L, Dodge S, Escamilla MA, Eskelinen S, Fanous AH, Faraone SV, Fiorentino A, Francioli L, Gabriel SB, Gage D, Gagliano Taliun SA, Ganna A, Genovese G, Glahn DC, Grove J, Hall MH, Hämäläinen E, Heyne HO, Holi , Hougaard DM11, Howrigan DP1, Huang H1, Hwu HG27, Kahn RS28, Kang HM29, Karczewski KJ1, Kirov G30, Knowles JA31, Lee FS5, Lehrer DS32, Lescai F11, Malaspina D28, Marder SR28, McCarroll SA13, McIntosh AM33, Medeiros H20, Milani L34, Morley CP21, Morris DW35, Mortensen PB36, Myers RM37, Nordentoft M11, O'Brien NL4, Olivares AM13, Ongur D24, Ouwehand WH38, Palmer DS1, Paunio T39, Quested D40, Rapaport MH41, Rees E30, Rollins B10, Satterstrom FK1, Schatzberg A42, Scolnick E13, Scott LJ29, Sharp SI4, Sklar P28, Smoller JW42, Sobell JL43, Solomonson M44, Stahl EA28, Stevens CR13, Suvisaari J45, Tiao G, Watson SJ, Watts NA, Blackwood DH, Børglum , Cohen B, Corvin , Esko, Freimer , Glatt SJ21, Hultman CM49, McQuillin A4, Palotie A1, Pato CN6, Pato MT6, Pulver AE49, St Clair D50, Tsuang MT51, Vawter MP10, Walters JT30, Werge , Ophoff , Sullivan , Owen , Boehnke , O'Donovan, Neale BM, Daly MJ. Rare coding variants in ten genes confer substantial risk for schizophrenia. Nature. 2022 Apr;604(7906):509-516
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.