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. 2013 Aug;194(4):987-96.
doi: 10.1534/genetics.113.151381. Epub 2013 Jun 21.

Genome-wide variation of cytosine modifications between European and African populations and the implications for complex traits

Erika L Moen  1 , Xu Zhang, Wenbo Mu, Shannon M Delaney, Claudia Wing, Jennifer McQuade, Jamie Myers, Lucy A Godley, M Eileen Dolan, Wei Zhang
Affiliations

Genome-wide variation of cytosine modifications between European and African populations and the implications for complex traits

Erika L Moen et al. Genetics. 2013 Aug.

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.

Keywords: complex trait; cytosine modification; gene expression; genetic variation; lymphoblastoid cell line.

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Figures

Figure 1
Figure 1
Variation of cytosine modification levels within populations. (A) Genic distribution of cytosine modification levels. The 232,148 CpG sites located in gene regions were binned based on their relative positions in 18,036 genes. The mean β-value across CpG sites was calculated for each gene. The median (dot) and intraquantile range (vertical line) across genes are plotted against the positional bin. (B) Genic distribution of the variability of cytosine modification levels. Coefficients of variation (CV) for the β-values across samples were estimated in each population. The mean CV across CpG sites was calculated for each gene. The median (dot) and intraquantile range (vertical line) across genes are plotted against the positional bin. In A and B, the black and orange dots denote the medians for the CEU and YRI samples, respectively. The blue box denotes the region from TSS to TES. (C) Cytosine co-modification in gene regions. Across the CEU samples, Spearman’s ρ was calculated for all CpG pairs <5 kb apart. The CpG pairs were then grouped by their relative distance and according to whether both cytosines fell in specific gene regions. The median (bar) and intraquantile range (line) of the signed ρ2 across the CpG pairs are plotted against the distance, for 10 kb upstream of TSSs (upstream), 5′-UTRs (UTR5), gene bodies, 3′-UTRs (UTR3), and 10 kb downstream of TESs (downstream).
Figure 2
Figure 2
Distribution of population-specific cytosine modifications. (A) The genic distribution of the CpG sites differentially modified between the CEU and YRI samples. The proportion of differential CpGs was plotted against the positional bin in the gene region. About 87% of the 14,550 CEU > YRI (black) and 65% of the 22,047 YRI > CEU (orange) CpG sites were located within gene regions. (B) The t-scores of differential CpGs are plotted against the chromosomal position (hg19) for gene STK39 (encoding serine threonine kinase 39). The analyzed CpG sites are denoted by dark gray vertical lines. The CEU > YRI (blue) or YRI > CEU (orange) CpG sites are marked by stepwise lines. Exons are denoted by black segments along the horizontal line. The direction of transcription is denoted by a black arrow. (C) The proportions of CpG sites that overlapped with DNase I hypersensitive regions and histone modification peak regions among all analyzed CpG sites (dark gray), the CEU > YRI CpG sites (blue), and the YRI > CEU CpG sites (golden) are shown.
Figure 3
Figure 3
Genetic regulation of population differences in cytosine modifications. (A) The number (blue) and the effect size (golden) of SNP-CpG associations are shown as functions of distance between mQTL and CpG sites. mQTL in strong linkage disequilibrium (r2 > 0.8) were pruned, resulting in 5704 associations for the CEU and 6802 associations for the YRI samples. The ±100-kb regions flanking target CpG sites were binned by 5 kb. The median (golden point) and intraquantile range (golden line) of association r2 are plotted for the CEU (open circle) and YRI (solid square) samples. (B) An example of common mQTL. The G allele of rs2776937 was associated with lower cytosine modification level of cg10312802 located in NRP1 (encoding neuropilin 1) across the CEU (black) and YRI (orange) samples. (C) An example of population-specific mQTL. The G allele of rs28544087 was associated with lower cytosine modification level of cg09307883 in ANAPC2 (encoding anaphase promoting complex subunit 2) in the CEU (black) but not YRI (orange) samples. In B and C, the positions of CpGs and mQTL are denoted by orange crosses and blue triangles, respectively.
Figure 4
Figure 4
SNPs associated with complex traits with known racial disparities are annotated by mQTL. (A) Five SNPs associated with cardiovascular traits such as cholesterol levels and cardiovascular diseases are mQTL for a CpG in the promoter of APOA5 (encoding apolipoprotein A-V). The risk alleles for each trait have a higher frequency in the YRI samples compared with the CEU samples. The risk allele is denoted above each set of bars for each SNP. (B) Cytosine modification levels of the CpG in the APOA5 promoter region are greater in the YRI samples.
Figure 5
Figure 5
Correlation between cytosine modification and gene expression levels. (A) The proportion of CpG sites for which modification levels correlated with gene expression levels is plotted against the positional bin across the gene region. The gray, orange, and black lines denote all significant, positive, and negative correlations, respectively. (B) The expression level of PLA2G4C (encoding phospholipase A2, group IVC) negatively correlates with the cytosine modification level of cg27270541 located in the promoter region, but (C) positively correlates with cg02380983 located in the gene body. The expression level of PLA2G4C is greater in the YRI (orange) relative to the CEU (black) samples. The positions of the CpG sites are denoted by an orange cross. (D) The T allele of m-eQTL rs10779587 is associated with lower expression level of FLVCR1 (encoding feline leukemia virus subgroup C cellular receptor 1) and (E) greater cytosine modification level of cg01313622 located in the proximal regulatory region of FLVCR1, across the CEU (black) and YRI (orange) samples. The positions of CpG sites and m-eQTL are denoted by an orange cross and a blue triangle, respectively.
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