Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations
Dongjing Liu, Dara Meyer, Brian Fennessy, Claudia Feng, Esther Cheng, Jessica Johnson, You Jeong Park, Marysia-Kolbe Rieder, Steven Ascolillo, Agathe de Pins, Amanda Dobbyn, Dannielle Lebovitch, Emily Moya, Tan-Hoang Nguyen, Lillian Wilkins, Arsalan Hassan, Henry S. Aghanwa, Moin Ahmad Ansari, Aftab Asif, Rubina Aslam, José Luis Ayuso, Tim B. Bigdeli, Stefano Bignotti, Julio Bobes, Bekh Bradley, P.F. Buckley, Murray J. Cairns, Stanley V. Catts, Abdul Rashid Chaudhry, David Cohen, Brett Collins, Angèle Consoli, Javier Costas, Benedicto Crespo‐Facorro, Nikolaos P. Daskalakis, Michael Davidson, Kenneth L. Davis, Faith Dickerson, Imtiaz Ahmad Dogar, Elodie Drapeau, Lourdes Fañanás, Ayman H. Fanous, Warda Fatima, Mar Fatjó‐Vilas, Cheryl Filippich, Joseph I. Friedman, John F. Fullard, Penelope Georgakopoulos, Marianna Giannitelli, Ina Giegling, Melissa J. Green, Olivier Guillin, Blanca Gutiérrez, Herlina Y. Handoko, Stella Kim Hansen, Maryam Haroon, Vahram Haroutunian, Frans Henskens, Fahad Hussain, Assen Jablensky, Jamil Junejo, Brian Kelly, Shams-ud-Din Ahmad Khan, Muhammad Nasar Sayeed Khan, Anisuzzaman Khan, Hamid R. Khawaja, Bakht Khizar, Steven P. Kleopoulos, James A. Knowles, Bettina Konte, Agung Kusumawardhani, Naeemullah Leghari, Xudong Liu, Adriana Lori, Carmel M. Loughland, Khalid Mahmood, Saqib Mahmood, Dolores Malaspina, Danish J. Malik, Amy J. M. McNaughton, Patricia T. Michie, Vasiliki Michopolous, Esther Molina, María Dolores Moltó, Asim Munir, Gerard Muntané, Farooq Naeem, Derek J. Nancarrow, Amina Nasar, Tanvir Nasr, Jude U. Ohaeri, Jürg Ott, Christos Pantelis, Sathish Periyasamy, Ana González‐Pinto, Abigail Powers, Belén Ramos, Nusrat Habib Rana, Mark Hyman Rapaport, Abraham Reichenberg
Abstract
Abstract Schizophrenia (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 genes 1 . 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.