Analysis of gene expression in the postmortem brain of neurotypical Black Americans reveals contributions of genetic ancestry

• Published in: Nature neuroscience Vol. 27; no. 6; pp. 1064 - 1074
• Main Authors: Benjamin, Kynon J. M., Chen, Qiang, Eagles, Nicholas J., Huuki-Myers, Louise A., Collado-Torres, Leonardo, Stolz, Joshua M., Pertea, Geo, Shin, Joo Heon, Paquola, Apuã C. M., Hyde, Thomas M., Kleinman, Joel E., Jaffe, Andrew E., Han, Shizhong, Weinberger, Daniel R.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2024; Nature Publishing Group
• Subjects: 631/208/199; 631/378/1689/534; Aged; Alzheimer Disease - ethnology; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Animal Genetics and Genomics; Autopsy; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Black or African American - genetics; Brain; Brain - metabolism; DNA Methylation; Female; Gene expression; Gene Expression - genetics; Genes; Health risks; Heritability; Humans; Immune response; Immune system; Ischemia; Male; Middle Aged; Movement disorders; Neurobiology; Neurodegenerative diseases; Neurological diseases; Neurosciences; Parkinson's disease; Vascular tissue; White People - genetics
• ISSN: 1097-6256; 1546-1726; 1546-1726
• DOI: 10.1038/s41593-024-01636-0

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. Studying gene expression in admixed Black Americans, Benjamin et al. reveal genetic ancestry-linked differences impacting immune and vascular genes and potentially influencing neurological disease risk. These findings highlight the importance of considering ancestry in brain research.