Genetic architecture of gene regulation in Indonesian populations identifies QTLs associated with global and local ancestries

Abstract

Lack 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.

Identifying novel regulatory effects for clinically relevant genes through the study of the Greek population

“…DEPTOR, (59)). Overall, our ndings highlight regulatory effects on genes with key roles for human health, and add to a growing literature indicating the relatively high yield that can be provided by modest-sized studies on understudied populations (10,12,19).…”

The whole blood microbiome of Indonesians reveals translocated and pathogenic microbiota

“…In order to provide a more comprehensive understanding of the blood microbiome of remote populations within Indonesia, we analysed unmapped reads from previously-published whole blood transcriptomes, collected from 117 Indonesian individuals living on the islands of Mentawai (MTW) in western Indonesia, and Sumba (SMB) in central Indonesia, as well as the Korowai (KOR), a group living in the Indonesian side of New Guinea Island. The human samples have been extensively described [20, 21]. After extensive quality control, we obtained a mean library size of 8,146 taxonomically informative reads (range: 221 - 403,796), which was further reduced to 8,120 reads after the removal of singletons (range: 196 - 403,771; Supplementary Table 1).…”

“…This was true even for Korowai individuals with low levels of Apicomplexa abundance. Indeed, we have recently [21] identified rs13425622 as an eQTL that strongly impacts expression levels of MARCO in these populations (p = 3.10 × 10 −14 ). All Korowai individuals in our dataset are fixed for the minor G allele, which is associated with lower expression, while the majority of individuals from both Mentawai and Sumba are at least heterozygotes for the major T allele (Figure 4, D).…”

“…Rather, certain individuals, predominantly within the Korowai, were found to drive the correlation between Kitrinoviricota load and sample contributions (Supplementary Figure 14, G). However, we did find that multiple genes involved in response to viruses, such as RSAD2 , were genes which we have previously found to be significantly differentially expressed between comparisons involving Korowai individuals [21]. RSAD2 , or viperin (virus inhibitory protein, endoplasmic reticulum associated, interferon inducible), is a well-characterised gene involved in antiviral activity [62] and its upregulation has been associated with multiple viruses, including Flaviviruses [63–66].…”

Denisovan introgression has shaped the immune system of present-day Papuans

“…Applying our approach to Neanderthal aSNPs segregating within present-day West Eurasians [ 31 ] replicates most of our findings, as well as previously reported signals including a depletion of Neanderthal variants within enhancer-like elements [ 12 ]. Previous studies have shown that, while polygenic risk scores [ 65 ] and eQTLs [ 66 ] have limited cross-population portability, biochemically active functional regulatory elements tend to be under evolutionary constraint within the human lineage [ 67 , 68 ]. Thus, while our approach is contingent on functional data generated in a population that is not of Papuan ancestry, our focus on functional analyses are likely to be more robust to differences across populations in linkage disequilibrium.…”