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

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Published in:	Nature genetics Vol. 55; no. 3; pp. 369 - 376
Main 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, 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.
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01-03-2023 Nature Publishing Group
Subjects:	45/23 631/208/205 692/308/2056 692/699/476/1799 Agriculture Alleles Animal Genetics and Genomics Autism Autistic Disorder - genetics Biomedical and Life Sciences Biomedicine Cancer Research Consortia Datasets Gene Function Genes Genetic Predisposition to Disease Genetics Genome-Wide Association Study - methods Genomes Genomics Human Genetics Human populations Humans Letter Medicin och hälsovetenskap Mental disorders Populations Proteins Schizophrenia Schizophrenia - genetics
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Summary:	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. 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/s41588-023-01305-1