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

Abstract

Populations are often divided categorically into distinct racial/ethnic groups based on social rather than biological constructs. Genetic ancestry has been suggested as an alternative to this categorization. Herein, we typed over 450,000 CpG sites in whole blood of 573 individuals of diverse Hispanic origin who also had high-density genotype data. We found that both selfidentified ethnicity and genetically determined ancestry were each significantly associated with methylation levels at 916 and 194 CpGs, respectively, and that shared genomic ancestry accounted for a median of 75.7% (IQR 45.8% to 92%) of the variance in methylation associated with ethnicity. There was a significant enrichment (p=4.2Â10 -64 ) of ethnicity-associated sites amongst loci previously associated environmental exposures, particularly maternal smoking during pregnancy. We conclude that differential methylation between ethnic groups is partially explained by the shared genetic ancestry but that environmental factors not captured by ancestry significantly contribute to variation in methylation.

An ancestry‐based approach for detecting interactions

“…The interactions that we detected could be signal from environmental factors interacting with genetic risk factors. Smoking, in particular maternal smoking during pregnancy, has been shown to contribute to methylation status in this dataset (Galanter et al., ). Various other environmental factors have also been shown to differ between racial/ethnic groups and may contribute to these interactions (Nishimura et al., ).…”

“…Gene expression traits have previously been shown to have large-scale differences as a function of genetic ancestry (Price et al, 2008). Other molecular phenotypes, such as low-density lipoprotein (LDL) levels, have also been shown to be associated with genetic ancestry (Fraser, Lam, Neumann, & Kobor, 2012;Galanter et al, 2017;Peralta et al, 2010;Price et al, 2008;Reiner et al, 2007;Spielman et al, 2007). For gene expression in particular, Price et al (2008) showed that the effects of ancestry on expression are widespread and not restricted to a handful of genes.…”

Social and physical environments early in development predict DNA methylation of inflammatory genes in young adulthood

“…Individual genetic differences can contribute to patterns of DNAm and may confound associations with early environmental exposures (45). To determine whether this was a factor in our analysis, we reran our models including the top three principal components of genetic variation, as previously derived for this population (46).…”

“…Recent studies demonstrate that genetic polymorphisms can influence patterns of DNAm as well as moderate patterns of association between environmental exposures, DNAm, and phenotypic outcomes (45,61). In our analyses, we determined that adjusting for principal components of genetic variation did not alter associations between early environmental exposures and DNAm, but this is a relatively limited test of genetic confounding that does not consider the potential role of specific genes in moderating patterns of association.…”

Lung cancer early detection and health disparities: the intersection of epigenetics and ethnicity

“…In particular, the group found that 27 loci known to be associated with maternal smoking showed significantly different degrees of methylation enrichment amongst different ethnic groups (71). Another study, Leng et al, noted that Native American genetic ancestry helps to safeguard exfoliated lung cells, collected from sputum, from DNA methylation alterations.…”