Abstract
Ancestral differences in genomic variation affect the regulation of gene expression; however, most gene expression studies have been limited to European ancestry samples or adjusted to identify ancestry-independent associations. Here, we instead examined the impact of genetic ancestry on gene expression and DNA methylation in the postmortem brain tissue of admixed Black American neurotypical individuals to identify ancestry-dependent and ancestry-independent contributions. Ancestry-associated differentially expressed genes (DEGs), transcripts and gene networks, while notably not implicating neurons, are enriched for genes related to the immune response and vascular tissue and explain up to 26% of heritability for ischemic stroke, 27% of heritability for Parkinson disease and 30% of heritability for Alzheimer’s disease. Ancestry-associated DEGs also show general enrichment for the heritability of diverse immune-related traits but depletion for psychiatric-related traits. We also compared Black and non-Hispanic white Americans, confirming most ancestry-associated DEGs. Our results delineate the extent to which genetic ancestry affects differences in gene expression in the human brain and the implications for brain illness risk.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1064-1074 |
| Number of pages | 11 |
| Journal | Nature neuroscience |
| Volume | 27 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 2024 |
Funding
We thank the Offices of the Chief Medical Examiner of Washington DC, Northern Virginia, Kalamazoo Michigan, Santa Clara County, University of North Dakota and Maryland for the provision of the brain tissues used in this work. We also thank the late L. B. Bigelow and members of the LIBD Neuropathology Section for their work in assembling and curating the clinical and demographic information and organizing the Human Brain Tissue Repository of the LIBD. Finally, we thank the families that have donated this tissue to advance our understanding of psychiatric disorders. We are indebted to many colleagues whose advice and suggestions were critical in this work, including H. Huang, K. Dzirasa, A. Wonkam, Y. Hurd, A. Brown and select leaders of Black In Neuro. The African Ancestry Neuroscience Research Initiative is a collaboration between the LIBD, Morgan State University, Duke University and members of the community led by A. C. Hathaway. We also thank J. Dubose, Y. Raesu and G. E. Thomas for the administrative support they provided. Additionally, we thank K. Ives for her editorial support. The research reported in this work was supported by the LIBD, Brown Capital Management, the Abell Foundation, the State of Maryland and the Chan Zuckerberg Initiative. Additional support was provided by grants from the National Institutes of Health. K.J.M.B. received funding under award no. K99MD01696 from the National Institute on Minority Health and Health Disparities. L.C.-T. and S.H. received funding under award nos. R01MH123183 (L.C.-T.), R01MH121394 (S.H.) and R01MH112751 (S.H.) from the NIMH. This research was supported by the Intramural Research Program of the NIMH (NCT00001260, no. 900142). The funders had no role in research conceptualization, study design, data collection, data analysis, decision to publish or manuscript preparation.
ASJC Scopus subject areas
- General Neuroscience
