Local ancestry modulates gene expression: shifting our understanding of genetic regulation and disease association within and across populations
Chen, H.-H.; Cai, Y.; Graff, M.; Zhu, W.; Petty, L. E.; Highland, H. M.; Roshani, R.; Polikowsky, H. G.; Lorenz, A. S.; Frankel, E.; Landman, J. M.; Anwar, M. Y.; Franson, E. E.; Haessler, J.; Avery, C. L.; Young, K. L.; Fernandez-Rhodes, L.; Reiner, A. P.; Peters, U.; Gordon-Larsen, P.; Gamazon, E. R.; Pereira, A. C.; Kooperberg, C.; Huff, C. D.; Fisher-Hoch, S. P.; McCormick, J. B.; North, K. E.; Below, J. E.
Show abstract
Genetic variants that influence transcript abundance, called expression quantitative trait loci (eQTL), are fundamental to understanding gene regulation and disease etiology. However, eQTL studies have overlooked the influence of the ancestral origin of a gene on its regulation. We implemented a new statistical framework that maps local ancestry-specific regulatory variation, revealing pervasive ancestry-specific effects on gene expression in Hispanic/Latino and African American populations. Enriched in open chromatin regions, these variants better explain genetic disease risk in these populations. The widespread heterogeneity of local ancestry-based eQTL effects offers mechanistic explanations for inconsistencies in genomic and multi-omic studies across populations. Our findings expand existing models of gene regulation and the importance of applying local genomic context in genetic studies to advance precision medicine and address health disparities.
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