TY - JOUR
T1 - Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations
AU - Psychiatric Genomics Consortium Phase 3 Targeted Sequencing of Schizophrenia Study Team
AU - Liu, Dongjing
AU - Meyer, Dara
AU - Fennessy, Brian
AU - Feng, Claudia
AU - Cheng, Esther
AU - Johnson, Jessica S.
AU - Park, You Jeong
AU - Rieder, Marysia Kolbe
AU - Ascolillo, Steven
AU - de Pins, Agathe
AU - Dobbyn, Amanda
AU - Lebovitch, Dannielle
AU - Moya, Emily
AU - Nguyen, Tan Hoang
AU - Wilkins, Lillian
AU - Hassan, Arsalan
AU - Aghanwa, Henry S.
AU - Ansari, Moin
AU - Asif, Aftab
AU - Aslam, Rubina
AU - Ayuso, Jose L.
AU - Bigdeli, Tim
AU - Bignotti, Stefano
AU - Bobes, Julio
AU - Bradley, Bekh
AU - Buckley, Peter
AU - Cairns, Murray J.
AU - Catts, Stanley V.
AU - Chaudhry, Abdul Rashid
AU - Cohen, David
AU - Collins, Brett L.
AU - Consoli, Angèle
AU - Costas, Javier
AU - Crespo-Facorro, Benedicto
AU - Daskalakis, Nikolaos P.
AU - Davidson, Michael
AU - Davis, Kenneth L.
AU - Dickerson, Faith
AU - Dogar, Imtiaz A.
AU - Drapeau, Elodie
AU - Fañanás, Lourdes
AU - Fanous, Ayman
AU - Fatima, Warda
AU - Fatjo, Mar
AU - Filippich, Cheryl
AU - Friedman, Joseph
AU - Fullard, John F.
AU - Georgakopoulos, Penelope
AU - Giannitelli, Marianna
AU - Weiser, Mark
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/3
Y1 - 2023/3
N2 - 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 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.
AB - 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 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.
UR - http://www.scopus.com/inward/record.url?scp=85150106663&partnerID=8YFLogxK
U2 - 10.1038/s41588-023-01305-1
DO - 10.1038/s41588-023-01305-1
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C2 - 36914870
AN - SCOPUS:85150106663
SN - 1061-4036
VL - 55
SP - 369
EP - 376
JO - Nature Genetics
JF - Nature Genetics
IS - 3
ER -