Differential methylation between ethnic sub-groups reflects the effect of genetic ancestry and environmental exposures

Abstract

In clinical practice and biomedical research populations are often divided categorically into distinct racial/ethnic groups. In reality, these categories, which are based on social rather than biological constructs, comprise diverse groups with highly heterogeneous histories, cultures, traditions, religions, social and environmental exposures and ancestral backgrounds. Their use is thus widely debated and genetic ancestry has been suggested as a complement or alternative to this categorization. However, few studies have examined the relative contributions of racial/ethnic identity, genetic ancestry, and environmental exposures on well-established and fundamental biological processes. We examined the associations between ethnicity, ancestry, and environmental exposures and DNA methylation. We typed over 450,000 CpG sites in primary whole blood of 573 individuals of diverse Hispanic descent who also had high-density genotype data. We found that both self-identified ethnicity and genetically determined ancestry were significantly associated with methylation levels at a large number of CpG sites (916 and 194, respectively). Among loci differentially methylated between ethnic groups, a median of 75.7% (IQR 45.8% to 92%) of the variance in methylation associated with ethnicity could be accounted for by shared genomic ancestry accounts. We also found significant enrichment (p = 4.2 x 10-64) of ethnicity-associated sites amongst loci previously associated with environmental and social exposures, particularly maternal smoking during pregnancy. Our study suggests that although differential methylation between ethnic groups can be partially explained by the shared genetic ancestry, a significant effect of ethnicity is likely due to environmental, social, or cultural factors, which differ between ethnic groups.\n\nOne Sentence SummaryIn order to better understand the role of ethnic self-identification and genetically determined ancestry in biomedical outcomes, we explore their relative contributions to variation in methylation, a fundamental biological process.\n\nSources of FundingThis research was supported in part by the Sandler Family Foundation, the American Asthma Foundation, National Institutes of Health (P60 MD006902, R01 HL117004, R21ES24844, U54MD009523, R01 ES015794, R01 HL088133, M01 RR000083, R01 HL078885, R01 HL104608, U19 AI077439, M01 RR00188, U01 HG009080, and R01 HL135156), ARRA grant RC2 HL101651, and TRDRP 24RT-0025; EGB was supported in part through grants from the Flight Attendant Medical Research Institute (FAMRI), and NIH (K23 HL004464); NZ was supported in part by an NIH career development award from the NHLBI (K25HL121295). JMG was supported in part by NIH Training Grant T32 (T32GM007546) and career development awards from the NHLBI (K23HL111636) and NCATS (KL2TR000143) as well as the Hewett Fellowship; N.T. was supported in part by an institutional training grant from the NIGMS (T32-GM007546) and career development awards from the NHLBI (K12-HL119997 and K23-HL125551), Parker B. Francis Fellowship Program, and the American Thoracic Society; CRG was supported in part by NIH Training Grant T32 (GM007175) and the UCSF Chancellors Research Fellowship and Dissertation Year Fellowship; RK was supported with a career development award from the NHLBI (K23HL093023); HJF was supported in part by the GCRC (RR00188); PCA was supported in part by the Ernest S. Bazley Grant; MAS was supported in part by 1R01HL128439-01. This publication was supported by various institutes within the National Institutes of Health. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.