Abstract
SummaryLack of diversity in human genomics limits our understanding of the genetic underpinnings of complex traits, hinders precision medicine, and contributes to health disparities. To map genetic effects on gene regulation in the underrepresented Indonesian population, we have integrated genotype, gene expression, and CpG methylation data from 115 participants across three island populations that capture the major sources of genomic diversity in the region. In a comparison with European datasets, we identify eQTLs shared between Indonesia and Europe as well as population-specific eQTLs that exhibit differences in allele frequencies and/or overall expression levels between populations. By combining local ancestry and archaic introgression inference with eQTLs and methylQTLs, we identify regulatory loci driven by modern Papuan ancestry as well as introgressed Denisovan and Neanderthal variation. GWAS colocalization connects QTLs detected here to hematological traits, and further comparison with European datasets reflects the poor overall transferability of GWAS statistics across diverse populations. Our findings illustrate how population-specific genetic architecture, local ancestry, and archaic introgression drive variation in gene regulation across genetically distinct and in admixed populations and highlight the need for performing association studies on non-European populations.
Highlights
As we move into the age of precision medicine, the systematic undersampling of global genetic diversity limits our ability to broadly apply biomedical research efforts across diverse ethnicities and population backgrounds.[1,2] the vast majority of human genomics studies to date have been conducted in individuals with European ancestry, who account for a minority of the global population.[3]
We have previously described differences in gene expression and CpG methylation between Indonesian island populations associated with their genome-wide proportions of Papuan ancestry.[8]
Genetic determinants of gene expression and CpG methylation levels in Indonesia To contextualize the genetic diversity in our dataset, we began by clustering the 115 Indonesian samples (Figure 1A) through Principal-component analysis (PCA) of genotype data, along with European and Han Chinese samples from the 1000 Genomes project
Summary
As we move into the age of precision medicine, the systematic undersampling of global genetic diversity limits our ability to broadly apply biomedical research efforts across diverse ethnicities and population backgrounds.[1,2] the vast majority of human genomics studies to date have been conducted in individuals with European ancestry, who account for a minority of the global population.[3]. Its tropical location makes it an epicenter of infectious disease diversity both past and present, making it possible that individuals from the region have adapted to local immune challenges over evolutionary time.[7] We have previously described differences in gene expression and CpG methylation between Indonesian island populations associated with their genome-wide proportions of Papuan ancestry.[8] To investigate the effects of modern and archaic local ancestry on gene regulation in Indonesians, here we integrate genome-wide genotype data with gene expression and DNA methylation measurements from 115 Indonesian individuals Using this rich multimodal dataset, we construct maps of eQTLs and methylQTLs and identify variants contributing to population differences—both within Indonesia and globally—in regulatory architecture
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