Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations

作者：Dongjing Liu, D. Meyer, B. Fennessy, Claudia Feng, Esther Cheng, Jessica S. Johnson, Youngbin Park, M. Rieder, S. Ascolillo, A. de Pins, Amanda Dobbyn, D. Lebovitch, E. Moya, Tan-Hoang Nguyen, Lillian Wilkins, Arsalan Hassan, Henry S. Moin Aftab Rubina Jose L. Tim Stefano Julio Bek Aghanwa Ansari Asif Aslam Ayuso Bigdeli Bignotti B, H. Aghanwa, M. Ansari, A. Asif, Rubina Aslam, J. L. Ayuso, T. Bigdeli, S. Bignotti, J. Bobes, B. Bradley, P. Buckley, Murray J. Cairns, S. Catts, Abdul Rashid Chaudhry, David Cohen, Brett L. Collins, A. Consoli, J. Costas, B. Crespo-Facorro, N. Daskalakis, Michal Davidson, Kenneth L. Davis, F. Dickerson, I. Dogar, Elodie Drapeau, L. Fañanás, A. Fanous, Warda Fatima, M. Fatjó, C. Filippich, J. Friedman, J. Fullard, Penelope Georgakopoulos, M. Giannitelli, I. Giegling, Melissa J. Green, O. Guillin, B. Gutiérrez, H. Handoko, Stella Kim Hansen, Maryam Haroon, V. Haroutunian, F. Henskens, Fahad Hussain, A. Jablensky, Jamil Junejo, Brian J. Kelly, S. Khan, M. N. S. Khan, Anisuzzaman Khan, Hamid R. Khawaja, Bakht Khizar, Steven P. Kleopoulos, J. Knowles, B. Konte, A. Kusumawardhani, N. Leghari, Xudong Liu, A. Lori, C. Loughland, Khalid Mahmood, S. Mahmood, D. Malaspina, D. Malik, Amy J M McNaughton, P. Michie, Vasiliki Michopolous, E. Molina, M. Moltó, A. Munir, G. Muntané, F. Naeem, D. Nancarrow, Amina Nasar, T. Nasr, J. Ohaeri, Jurg Ott, C. Pantelis, S. Periyasamy, Ana G. Pinto, A. Powers, B. Ramos, N. Rana, Mark H. Rapaport, A. Reichenberg, Safa Saker-Delye, U. Schall, P. Schofield, Rodney J. Scott, M. Shanahan, C. Weickert, C. Sjaarda, Heather Smith, J. J. Suárez-Rama, Muhammad Tariq, F. Thibaut, P. Tooney, M. Umar, Elisabet Vilella, M. Weiser, Jin Qin Wu, R. Yolken, K. Burdick, J. Buxbaum, E. Domenici, S. Frangou, A. Hartmann, C. Laurent-Levinson, D. Malhotra, C. Pato, M. Pato, K. Ressler, Panagiotis Roussos, D. Rujescu, C. Arango, A. Bertolino, G. Blasi, L. Bocchio-Chiavetto, D. Campion, V. Carr, J. Fullerton, M. Gennarelli, J. González-Peñas, D. Levinson, B. Mowry, Vishwajit L. Nimgaokar, G. Pergola, A. Rampino, J. Cervilla, M. Rivera, S. Schwab, D. Wildenauer, M. Daly, B. Neale, T. Singh, M. O’Donovan, M. Owen, J. Walters, M. Ayub, A. Malhotra, T. Lencz, Patrick F. Sullivan, P. Sklar, E. Stahl, Laura M. Huckins, A. Charney · 发表于：Nature Genetics · 年份：2023 · DOI：10.1038/s41588-023-01305-1 · 被引用次数：63 · 研究领域：Medicine

Targeted sequencing finds a higher burden of rare protein-truncating variants in constrained genes among schizophrenia cases of diverse ancestries. Meta-analyses with existing datasets show that this excess burden is consistent across five ancestral populations. 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 sha...