Genome-Wide Variation of Cytosine Modifications Between European and African Populations and the Implications for Complex Traits

Abstract

Elucidating cytosine modification differences between human populations can enhance our understanding of ethnic specificity in complex traits. In this study, cytosine modification levels in 133 HapMap lymphoblastoid cell lines derived from individuals of European or African ancestry were profiled using the Illumina HumanMethylation450 BeadChip. Approximately 13% of the analyzed CpG sites showed differential modification between the two populations at a false discovery rate of 1%. The CpG sites with greater modification levels in European descent were enriched in the proximal regulatory regions, while those greater in African descent were biased toward gene bodies. More than half of the detected population-specific cytosine modifications could be explained primarily by local genetic variation. In addition, a substantial proportion of local modification quantitative trait loci exhibited population-specific effects, suggesting that genetic epistasis and/or genotype · environment interactions could be common. Distinct correlations were observed between gene expression levels and cytosine modifications in proximal regions and gene bodies, suggesting epigenetic regulation of interindividual expression variation. Furthermore, quantitative trait loci associated with population-specific modifications can be colocalized with expression quantitative trait loci and single nucleotide polymorphisms previously identified for complex traits with known racial disparities. Our findings revealed abundant population-specific cytosine modifications and the underlying genetic basis, as well as the relatively independent contribution of genetic and epigenetic variations to population differences in gene expression. DNA methylation is a covalent cytosine modification that occurs at the C-5 position of cytosines at CpG dinucleotides and is dispersed unevenly over the genome (Bird 2002). Interindividual variation in cytosine modifications can be affected by both the stable underlying genetic sequence and dynamic environmental influences (Flanagan et al. 2006;Bock et al. 2008). Cytosine modifications are known to play an important role in the regulation of gene expression, with promoter methylation acting to silence gene expression (Grewal and Moazed 2003). Previous studies of human variation in gene expression have shown that differential gene expression can influence a variety of complex traits, including susceptibilities to common diseases and variation in drug response (Schadt et al. 2005;Emilsson et al. 2008;Cookson et al. 2009).The lymphoblastoid cell lines (LCLs) from the International HapMap Project (HapMap 2003;HapMap 2005) have been used recently for investigating within-and betweenpopulation differences in promoter methylation (Bell et al. 2011;Fraser et al. 2012). Furthermore, previous work from our group and others has demonstrated that common genetic variants and microRNAs contributed to the variation in gene expression between LCLs derived from individuals of We reasoned that an evaluation of the natural variation ...

DNA methylation and healthy human aging

“…Genetic variation has been shown to contribute to longevity, evidenced by the fact that longevity runs in families (Schoenmaker et al ., 2006). Clear relationships also exist between DNA methylation and genetic variability, and recent studies have identified genetic loci whose variation is strongly associated with DNA methylation at nearby sites (Fraser et al ., 2012; Gamazon et al ., 2013; Gutierrez Arcelus et al ., 2013; Moen et al ., 2013). Thus, it is possible that genetic variants associated with longevity may also be correlated with DNA methylation changes.…”

The effect of genotype and in utero environment on interindividual variation in neonate DNA methylomes

“…Methylation levels at ;50% of these population-specific CpGs are explained by divergence in allele frequencies at cis-acting SNPs between populations . Studies of methylation differences using Illumina InfiniumHumanMethylation450 BeadChip array data from 133 lymphoblastoid cell lines from European and African HapMap samples found that 13% of analyzed CpGs showed significant methylation differences between the populations, >50% of which were in methQTLs with local SNPs (Moen et al 2013). CpGs showing differential methylation levels across ethnicities are more likely to be driven by genotype than other CpGs (Heyn et al 2013).…”

Interethnic DNA Methylation Difference and Its Implications in Pharmacoepigenetics

“…These genetic differences among ethnic populations have motivated additional studies to adjust the recommended drug dosage depending on the population [15]. Ethnic differences are also a vital feature of DNA methylation [16][17][18][19]. However, the mechanism through which these differences influence the effect of DNA methylation on the treatment response and the drug ADME remains largely unknown.…”

“…Because methylation patterns are tissue specific [20] and most of the current MeDR genes are related to cancers, we analyzed differential methylation (DM) between African ancestry (AA) and European ancestry (EA) populations in two sources of samples. The first source contained the primary tumor tissues of four cancer types (breast invasive carcinoma [BRCA], colon adenocarcinoma [COAD], head and neck squamous cell carcinoma [HNSC] and uterine corpus endometrial carcinoma [UCEC]) from The Cancer Genome Atlas (TCGA) [21][22][23][24], and the second source contained lymphoblastoid cell lines (LCLs) of general populations from the International HapMap Project [17]. We also investigated the relationship between DNA methylation and gene expression and discussed the influence of DNA methylation on the treatment response and drug ADME.…”