Language
English
Publication Date
8-30-2025
DOI
10.1016/j.xhgg.2025.100499
PMID
40886051
PMCID
PMC12494821
PubMedCentral® Posted Date
8-30-2025
PubMedCentral® Full Text Version
Post-print
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.
Keywords
Whole genome sequencing, bipolar disorder, schizophrenia, burden test, GWAS, African American, non-coding variant, regional burden test, quality control, rare variants
Published Open-Access
yes
Recommended Citation
Li, Runjia; Gagliano Taliun, Sarah A; Liao, Kevin; et al., "Whole-Genome Sequence-Based Association Analysis of African American Individuals With Bipolar Disorder and Schizophrenia" (2025). Faculty and Staff Publications. 4255.
https://digitalcommons.library.tmc.edu/baylor_docs/4255