Whole-genome sequence-based association analysis of African American individuals with bipolar disorder and schizophrenia

In studies of individuals of primarily European genetic ancestry, common and low-frequency variants and rare coding variants have been found to be associated with the risk of bipolar disorder (BD) and schizophrenia (SZ). However, less is known for individuals of other genetic ancestries or the role of rare non-coding variants in BD and SZ risk. We performed whole-genome sequencing (∼27X) of African American individuals: 1,598 with BD, 3,295 with SZ, and 2,651 unaffected controls (InPSYght study). We increased power by incorporating 14,812 jointly called psychiatrically unscreened ancestry-matched controls from the Trans-Omics for Precision Medicine (TOPMed) Program for a total of 17,463 controls (∼37X). To identify variants and sets of variants associated with BD and/or SZ, we performed single-variant tests, gene-based tests for singleton protein truncating variants, and rare and low-frequency variant annotation-based tests with conservation and universal chromatin states and sliding windows. We found suggestive evidence of the association of BD with single variants on chromosome 18 and of lower BD risk associated with rare and low-frequency variants on chromosome 11 in a region with multiple BD genome-wide association study loci, using a sliding window approach. We also found that chromatin and conservation state tests can be used to detect differential calling of variants in controls sequenced at different centers and to assess the effectiveness of sequencing metric covariate adjustments. Our findings reinforce the need for continued whole-genome sequencing in additional samples of African American individuals and more comprehensive functional annotation of non-coding variants.

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Publication Details

Journal
Human Genetics and Genomics Advances
Published
2025-08-30
DOI
https://doi.org/10.1016/j.xhgg.2025.100499
Primary Topic
Genetic Associations and Epidemiology
Type
article
Field-Weighted Citation Impact
0.00

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article

Whole-genome sequence-based association analysis of African American individuals with bipolar disorder and schizophrenia

Tim B. Bigdeli, Michael Boehnke, Charles Kooperberg, Laura J. Scott et al.
Human Genetics and Genomics Advances
Genetic Associations and Epidemiology
article

Whole-genome sequence-based association analysis of African American individuals with bipolar disorder and schizophrenia

Tim B. Bigdeli, Michael Boehnke, Charles Kooperberg, Laura J. Scott, Karin Ferneyhough Hoth, Kathleen C. Barnes, Giulio Genovese, Jason Ernst, Hyun Min Kang, Ruth J. F. Loos, Anna Neumann, Brian E. Cade, Roel A. Ophoff, Carlos N. Pato, Donna K. Arnett, Janet L. Sobell, Ginger Metcalf, Readman Chiu, Jerome I. Rotter, Adam E. Locke, Zhaohui Qin, Taylor Martins, Robert E. Handsaker, Courtney G. Montgomery, Richard A. Gibbs, Sarah A. Gagliano Taliun, Kevin Liao, Michele T. Pato, Stephen S. Rich, Alexander P. Reiner, Jiongming Wang, Alanna C. Morrison, Jonathon LeFaive, Matthew Flickinger, Sebastian Zöllner, Sinéad B. Chapman, Susan Redline, James A. Knowles, Albert V. Smith, Kent D. Taylor, Goncalo Abecasis, Stacey Gabriel, David Braff, Steve McCarroll, Karine A. Viaud-Martinez, Lifang Hou, Eric Boerwinkle, Myriam Fornage, Runjia Li
article en

Abstract

In studies of individuals of primarily European genetic ancestry, common and low-frequency variants and rare coding variants have been found to be associated with the risk of bipolar disorder (BD) and schizophrenia (SZ). However, less is known for individuals of other genetic ancestries or the role of rare non-coding variants in BD and SZ risk. We performed whole-genome sequencing (∼27X) of African American individuals: 1,598 with BD, 3,295 with SZ, and 2,651 unaffected controls (InPSYght study). We increased power by incorporating 14,812 jointly called psychiatrically unscreened ancestry-matched controls from the Trans-Omics for Precision Medicine (TOPMed) Program for a total of 17,463 controls (∼37X). To identify variants and sets of variants associated with BD and/or SZ, we performed single-variant tests, gene-based tests for singleton protein truncating variants, and rare and low-frequency variant annotation-based tests with conservation and universal chromatin states and sliding windows. We found suggestive evidence of the association of BD with single variants on chromosome 18 and of lower BD risk associated with rare and low-frequency variants on chromosome 11 in a region with multiple BD genome-wide association study loci, using a sliding window approach. We also found that chromatin and conservation state tests can be used to detect differential calling of variants in controls sequenced at different centers and to assess the effectiveness of sequencing metric covariate adjustments. Our findings reinforce the need for continued whole-genome sequencing in additional samples of African American individuals and more comprehensive functional annotation of non-coding variants.

Human Genetics and Genomics AdvancesVol. 7(1)
Rutgers, The State University of New Jersey (US), Broad Institute (US), Northwestern University (US), University of Southern California (US), University of Iowa (US), Brigham and Women's Hospital (US), Emory University (US), University of South Carolina (US), University of California, Los Angeles (US), Illumina (United States) (US), Baylor College of Medicine (US), SUNY Downstate Health Sciences University (US), Regeneron (United States) (US), University of Washington (US), University of Michigan (US), Montreal Heart Institute (CA), UCLA Medical Center (US), Oklahoma Medical Research Foundation (US), Fred Hutch Cancer Center (US), VA San Diego Healthcare System (US), Brown Foundation (US), Genomics England (GB), Statistical Service (CY), Statistical Research (United States) (US), Baylor Genetics (US), Harbor–UCLA Medical Center (US), University of Virginia (US), University of Colorado Anschutz Medical Campus (US), Université de Montréal (CA), The University of Texas Health Science Center at Houston (US), Icahn School of Medicine at Mount Sinai (US)
Fonds de recherche du Québec, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute on Drug Abuse, National Human Genome Research Institute
Openalex Percentile: Top 75%
Genetic Associations and Epidemiology
DOIOpen Access PDFOpenAlex
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