Journal article
Whole genome sequence-based association analysis of African American individuals with bipolar disorder and schizophrenia
HGG advances, Vol.7(1), 100499
01/2026
DOI: 10.1016/j.xhgg.2025.100499
PMCID: PMC12494821
PMID: 40886051
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 BD association 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 GWAS 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.
Details
- Title: Subtitle
- Whole genome sequence-based association analysis of African American individuals with bipolar disorder and schizophrenia
- Creators
- Runjia Li - University of California, Los AngelesSarah A Gagliano TaliunKevin Liao - University of MichiganMatthew Flickinger - University of MichiganJanet L Sobell - University of Southern CaliforniaGiulio Genovese - Broad InstituteAdam E Locke - RegeneronRebeca Rothwell Chiu - University of MichiganJonathon LeFaive - University of MichiganJiongming Wang - University of MichiganTaylor Martins - Arizona Department of Health ServicesSinéad Chapman - Broad InstituteAnna Neumann - Broad InstituteRobert E Handsaker - Broad InstituteDonna K Arnett - University of South CarolinaKathleen C Barnes - University of Colorado Anschutz Medical CampusEric Boerwinkle - The University of Texas Health Science Center at HoustonDavid Braff - VA San Diego Healthcare SystemBrian E Cade - Brigham and Women's HospitalMyriam Fornage - Brown FoundationRichard A Gibbs - Baylor College of MedicineKarin F Hoth - University of IowaLifang Hou - Northwestern UniversityCharles Kooperberg - Fred Hutch Cancer CenterRuth J F Loos - Icahn School of Medicine at Mount SinaiGinger A Metcalf - Baylor College of MedicineCourtney G Montgomery - Oklahoma Medical Research FoundationAlanna C Morrison - The University of Texas Health Science Center at HoustonZhaohui S Qin - Emory UniversitySusan Redline - Brigham and Women's HospitalAlexander P Reiner - University of WashingtonStephen S Rich - University of VirginiaJerome I Rotter - Harbor–UCLA Medical CenterKent D Taylor - UCLA Medical CenterKarine A Viaud-Martinez - IlluminaTim B Bigdeli - SUNY Downstate Health Sciences UniversityStacey Gabriel - Broad InstituteSebastian Zollner - University of MichiganAlbert V Smith - University of MichiganGoncalo Abecasis - RegeneronSteve McCarroll - Broad InstituteMichele T Pato - Rutgers, The State University of New JerseyCarlos N Pato - Rutgers, The State University of New JerseyMichael Boehnke - University of MichiganJames Knowles - Rutgers, The State University of New JerseyHyun Min Kang - University of MichiganRoel A Ophoff - University of California, Los AngelesJason Ernst - University of California, Los AngelesLaura J Scott - University of MichiganGenomic Psychiatry Cohort investigators
- Resource Type
- Journal article
- Publication Details
- HGG advances, Vol.7(1), 100499
- DOI
- 10.1016/j.xhgg.2025.100499
- PMID
- 40886051
- PMCID
- PMC12494821
- NLM abbreviation
- HGG Adv
- ISSN
- 2666-2477
- eISSN
- 2666-2477
- Publisher
- CELL PRESS
- Grant note
- University of Michigan Precision Health Scholar Award: R01 HG009976, U01MH105653 Fonds de Re-cherche du Quebec-Sante: R01 MH115676, DP1DA044371, U01HG012079
This work was supported by the University of Michigan Precision Health Scholar Award (https://precisionhealth.umich. edu/) (S.A.G.T.) ; R01 HG009976 (M.B.) ; U01MH105653 (M.B., C.N.P., and S.A.M.) ; salary support from the Fonds de Re-cherche du Quebec-Sante: a Junior 1 Award, and currently a Junior 2 Award (S.A.G.T.) ; R01 MH115676 (R.A.O.) ; and DP1DA044371 and U01HG012079 (J.E.) . This work used computational and storage services associated with the Hoff-man2 Cluster, which is operated by the University of Califor-nia, Los Angeles Office of Advanced Research Computing's Research Technology Group. Biosamples and data for the In-PSYght study were obtained from the NIMH Repository & Genomics Resource (U24MH068457) , a centralized national biorepository for genetic studies of psychiatric disorders (https:// www.nimhgenetics.org/) . Contributing studies include the GPC, the Consortium of the Genetics of Schizophrenia, the Bipolar Genome Study, the LiTMUS, and the Systematic Treat-ment Enhancement Program for Bipolar Disorder. We grate-fully acknowledge the participants who provided biological samples and data for these studies. We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. Molecular data for the TOPMed program were supported by the NHLBI. See the supplemental information forTOPMedstudyandTOPMedNeurocognitiveWorkingGroupmembers.Coresupport,includingcentralizedgenomicreadmappingandgenotypecalling,variantqualitymetrics,andfiltering,wasprovidedbytheTOPMedInformaticsResearchCenter(3R01HL-117626-02S1,contractHHSN268201800002I).Coresupport,includingphenotypeharmonization,datamanagement,sample-identityqualitycontrol,andprogramcoordination,wasprovidedbytheTOPMedDataCoordinatingCenter(R01HL-120393andU01HL-120393;contractHHSN268201800001I)
- Language
- English
- Electronic publication date
- 08/30/2025
- Date published
- 01/2026
- Academic Unit
- Psychiatry; Iowa Neuroscience Institute
- Record Identifier
- 9984958289802771
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