Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations
Authors: Liu Dongjing , Meyer Dara , Fennessy Brian , Feng Claudia , Cheng Esther , Johnson Jessica S. , Park You Jeong , Rieder Marysia-Kolbe , Ascolillo Steven , de Pins Agathe , Dobbyn Amanda , Lebovitch Dannielle , Moya Emily , Nguyen Tan-Hoang , Wilkins Lillian , Hassan Arsalan ,   Psychiatric Genomics Consortium Phase 3 Targeted Sequencing of Schizophrenia Study Team, Aghanwa Henry S. , Ansari Moin , Asif Aftab , Aslam Rubina , Ayuso Jose L. , Bigdeli Tim , Bignotti Stefano , Bobes Julio , Bradley Bekh , Buckley Peter , Cairns Murray J. , Catts Stanley V. , Chaudhry Abdul Rashid , Cohen David , Collins Brett L. , Consoli Angèle , Costas Javier , Crespo-Facorro Benedicto , Daskalakis Nikolaos P. , Davidson Michael , Davis Kenneth L. , Dickerson Faith , Dogar Imtiaz A. , Drapeau Elodie , Fañanás Lourdes , Fanous Ayman , Fatima Warda , Fatjo Mar , Filippich Cheryl , Friedman Joseph , Fullard John F. , Georgakopoulos Penelope , Giannitelli Marianna , Giegling Ina , Green Melissa J. , Guillin Olivier , Gutierrez Blanca , Handoko Herlina Y. , Hansen Stella Kim , Haroon Maryam , Haroutunian Vahram , Henskens Frans A. , Hussain Fahad , Jablensky Assen V. , Junejo Jamil , Kelly Brian J. , Khan Shams-ud-Din A. , Khan Muhammad N. S. , Khan Anisuzzaman , Khawaja Hamid R. , Khizar Bakht , Kleopoulos Steven P. , Knowles James , Konte Bettina , Kusumawardhani Agung A. A. A. , Leghari Naeemullah , Liu Xudong , Lori Adriana , Loughland Carmel M. , Mahmood Khalid , Mahmood Saqib , Malaspina Dolores , Malik Danish , McNaughton Amy , Michie Patricia T. , Michopolous Vasiliki , Molina Esther , Molto María D. , Munir Asim , Muntané Gerard , Naeem Farooq , Nancarrow Derek J. , Nasar Amina , Nasr Tanvir , Ohaeri Jude U. , Ott Jurg , Pantelis Christos , Periyasamy Sathish , Pinto Ana G. , Powers Abigail , Ramos Belén , Rana Nusrat H. , Rapaport Mark , Reichenberg Abraham , Saker-Delye Safaa , Schall Ulrich , Schofield Peter R. , Scott Rodney J. , Shanahan Megan , Weickert Cynthia Shannon , Sjaarda Calvin , Smith Heather J. , Suárez-Rama Jose Javier , Tariq Muhammad , Thibaut Florence , Tooney Paul A. , Umar Muhammad , Vilella Elisabet , Weiser Mark , Wu Jin Qin , Yolken Robert , Burdick Katherine E. , Buxbaum Joseph D. , Domenici Enrico , Frangou Sophia , Hartmann Annette M. , Laurent-Levinson Claudine , Malhotra Dheeraj , Pato Carlos N. , Pato Michele T. , Ressler Kerry , Roussos Panos , Rujescu Dan , Arango Celso , Bertolino Alessandro , Blasi Giuseppe , Bocchio-Chiavetto Luisella , Campion Dominique , Carr Vaughan , Fullerton Janice M. , Gennarelli Massimo , González-Peñas Javier , Levinson Douglas F. , Mowry Bryan , Nimgaokar Vishwajit L. , Pergola Giulio , Rampino Antonio , Cervilla Jorge A. , Rivera Margarita , Schwab Sibylle G. , Wildenauer Dieter B. , Daly Mark , Neale Benjamin , Singh Tarjinder , O’Donovan Michael C. , Owen Michael J. , Walters James T. , Ayub Muhammad , Malhotra Anil K. , Lencz Todd , Sullivan Patrick F. , Sklar Pamela , Stahl Eli A. , Huckins Laura M. , Charney Alexander W. 
Published: March 2023

AbstractSchizophrenia (SCZ) is a chronic mental illness and among the most debilitating conditions encountered in medical practice. A recent landmark SCZ study of the protein-coding regions of the genome identified a causal role for ten genes and a concentration of rare variant signals in evolutionarily constrained genes1. This recent study—and most other large-scale human genetics studies—was mainly composed of individuals of European (EUR) ancestry, and the generalizability of the findings in non-EUR populations remains unclear. To address this gap, we designed a custom sequencing panel of 161 genes selected based on the current knowledge of SCZ genetics and sequenced a new cohort of 11,580 SCZ cases and 10,555 controls of diverse ancestries. Replicating earlier work, we found that cases carried a significantly higher burden of rare protein-truncating variants (PTVs) among evolutionarily constrained genes (odds ratio = 1.48; P = 5.4 × 10−6). In meta-analyses with existing datasets totaling up to 35,828 cases and 107,877 controls, this excess burden was largely consistent across five ancestral populations. Two genes (SRRM2 and AKAP11) were newly implicated as SCZ risk genes, and one gene (PCLO) was identified as shared by individuals with SCZ and those with autism. Overall, our results lend robust support to the rare allelic spectrum of the genetic architecture of SCZ being conserved across diverse human populations.