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Cited by 314Epigenetics and DNA MethylationGenetic Associations and EpidemiologyGenomics and Chromatin Dynamics

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Population-specificity of human DNA methylation

Open access
Fraser, Hunter B, Lam, Lucia L, Neumann, Sarah M, Kobor, Michael S·2012·Genome Biology
DOI 10.1186/gb-2012-13-2-r8PMC PMC3334571
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Abstract

BACKGROUND: Ethnic differences in human DNA methylation have been shown for a number of CpG sites, but the genome-wide patterns and extent of these differences are largely unknown. In addition, whether the genetic control of polymorphic DNA methylation is population-specific has not been investigated. RESULTS: Here we measure DNA methylation near the transcription start sites of over 14, 000 genes in 180 cell lines derived from one African and one European population. We find population-specific patterns of DNA methylation at over a third of all genes. Furthermore, although the methylation at over a thousand CpG sites is heritable, these heritabilities also differ between populations, suggesting extensive divergence in the genetic control of DNA methylation. In support of this, genetic mapping of DNA methylation reveals that most of the population specificity can be explained by divergence in allele frequencies between populations, and that there is little overlap in genetic associations between populations. These population-specific genetic associations are supported by the patterns of DNA methylation in several hundred brain samples, suggesting that they hold in vivo and across tissues. CONCLUSIONS: These results suggest that DNA methylation is highly divergent between populations, and that this divergence may be due in large part to a combination of differences in allele frequencies and complex epistasis or gene × environment interactions.

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Figure 1 Population-specificity of DNA methylation. (a) Heatmap of the clustered methylation data set. Three representative cases are magnified: a site with a clear population difference; a site showing within- but not between-population variability; and a site with little variability within or between populations. (b) We performed pyrosequencing as an independent means to measure methylation of two CpG sites (IGSF2, chromosome 1, base 117345939; PLSCR2, chromosome 3, base 147696535) in our 180 samples. The agreement validates the accuracy of our microarray data. (c) The methylation of many sites differs between CEU and YRI. We performed the nonparametric Wilcoxon test to identify CpG sites differing in methylation between populations. The P-values are skewed towards small values, as shown by comparing to the expected uniform distribution on either a linear (left) or log (right) scale.
Figure 1 Population-specificity of DNA methylation. (a) Heatmap of the clustered methylation data set. Three representative cases are magnified: a site with a clear population difference; a site showing within- but not between-population variability; and a site with little variability within or between populations. (b) We performed pyrosequencing as an independent means to measure methylation of two CpG sites (IGSF2, chromosome 1, base 117345939; PLSCR2, chromosome 3, base 147696535) in our 180 samples. The agreement validates the accuracy of our microarray data. (c) The methylation of many sites differs between CEU and YRI. We performed the nonparametric Wilcoxon test to identify CpG sites differing in methylation between populations. The P-values are skewed towards small values, as shown by comparing to the expected uniform distribution on either a linear (left) or log (right) scale.CC BY · PubMed Central
Figure 2 Population specificity of DNA methylation heritability. (a) An example of a CpG site (near PLSCR2: chromosome 3, base 147696535) whose methylation is heritable in YRI, but not CEU, as assessed by the similarity of average parental methylation to their offspring methylation (each point represents one family trio). (b) Histograms comparing the observed distribution of per-site heritabilities to a typical randomized distribution (numbers in the text are based on 1, 000 randomizations; Materials and methods). The greater number of sites at high heritabilities in the real data compared to random (arrows) is an estimate of the number of heritable sites we can detect in each population. (c) No similarity between heritabilities in each population (Pearson's r2 = 0.002; each point is a CpG site).
Figure 2 Population specificity of DNA methylation heritability. (a) An example of a CpG site (near PLSCR2: chromosome 3, base 147696535) whose methylation is heritable in YRI, but not CEU, as assessed by the similarity of average parental methylation to their offspring methylation (each point represents one family trio). (b) Histograms comparing the observed distribution of per-site heritabilities to a typical randomized distribution (numbers in the text are based on 1, 000 randomizations; Materials and methods). The greater number of sites at high heritabilities in the real data compared to random (arrows) is an estimate of the number of heritable sites we can detect in each population. (c) No similarity between heritabilities in each population (Pearson's r2 = 0.002; each point is a CpG site).CC BY · PubMed Central
Figure 3 Population specificity of mSNPs. (a) An example of an mSNP (between a CpG site near LDHC (chromosome 11, base 18390591), and rs2643856) that is found in both YRI and CEU. In both cases the T allele is associated with higher methylation. (b) Venn diagram of the overlap among CpG sites associated with an mSNP in YRI and/or CEU. Five CEU sites and eight YRI sites were excluded from the overlap analysis because they overlapped a SNP in the other population. (c) Example of an mSNP (between a CpG site near PLSCR2 (chromosome 3, base 147696535) and rs12489924) that is found in YRI but not CEU. No other SNPs in CEU within 100 kb of the CpG are associated with methylation at the site (r < 0.25 for all), indicating that the difference is unlikely to be due to differing LD between rs12489924 and the causal variant. (d) Scatter plot of all 86 YRI mSNPs, showing the strongest association found for that site in each population. Points are colored according to the significance of the difference in the associations within each population; most mSNP association strengths are significantly (P < 0.005) different between populations. The same plot for CEU mSNPs is shown in Figure S10 in Additional file 1. (e) Overlap of LCL mSNPs with brain mSNPs from two studies of European populations (similar to CEU). Both all CEU mSNPs and CEU-specific mSNPs show similar overlap of 40 to 42%, which is thus a minimum estimate for the extent of mSNPs shared between LCLs and brain. However, YRI-specific mSNPs show only 3.2% overlap, not significantly different from the 1.2% expected from any random set of CpG sites.
Figure 3 Population specificity of mSNPs. (a) An example of an mSNP (between a CpG site near LDHC (chromosome 11, base 18390591), and rs2643856) that is found in both YRI and CEU. In both cases the T allele is associated with higher methylation. (b) Venn diagram of the overlap among CpG sites associated with an mSNP in YRI and/or CEU. Five CEU sites and eight YRI sites were excluded from the overlap analysis because they overlapped a SNP in the other population. (c) Example of an mSNP (between a CpG site near PLSCR2 (chromosome 3, base 147696535) and rs12489924) that is found in YRI but not CEU. No other SNPs in CEU within 100 kb of the CpG are associated with methylation at the site (r < 0.25 for all), indicating that the difference is unlikely to be due to differing LD between rs12489924 and the causal variant. (d) Scatter plot of all 86 YRI mSNPs, showing the strongest association found for that site in each population. Points are colored according to the significance of the difference in the associations within each population; most mSNP association strengths are significantly (P < 0.005) different between populations. The same plot for CEU mSNPs is shown in Figure S10 in Additional file 1. (e) Overlap of LCL mSNPs with brain mSNPs from two studies of European populations (similar to CEU). Both all CEU mSNPs and CEU-specific mSNPs show similar overlap of 40 to 42%, which is thus a minimum estimate for the extent of mSNPs shared between LCLs and brain. However, YRI-specific mSNPs show only 3.2% overlap, not significantly different from the 1.2% expected from any random set of CpG sites.CC BY · PubMed Central

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Metadata

Authors
Fraser, H. B., Lam, L. L., Neumann, S. M., & Kobor, M. S.
Affiliations
  • Stanford University (US)
  • University of British Columbia (CA)
Corresponding author
  • Fraser, Hunter B
  • Kobor, Michael S
ORCID
Venue
Genome Biology
Publisher
Springer Science and Business Media LLC
Published
2012-02-09
Volume
13
Issue
2
Pages
R8-R8
ISSN
  • 1465-6906 (ISSN-L)
  • 1474-760X
DOI
10.1186/gb-2012-13-2-r8
PMC
PMC3334571
OpenAlex
W2170538199
Cited by
313
References
31
Citations by year
2026: 20 · 2025: 21 · 2024: 15 · 2023: 16 · 2022: 18 · 2021: 25 · 2020: 27 · 2019: 21 · 2018: 21 · 2017: 20 · 2016: 31 · 2015: 27 · 2014: 19 · 2013: 24 · 2012: 8
FWCI
10.04
Type
journal article
Language
en
Open access
Licence
Locations
  • Genome biology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • cIRcle (University of British Columbia) (submittedVersion, cc-by)
  • Open Collections
Funders
  • Canadian Institute for Advanced Research
  • National Institutes of Health (5r21hg005750-02)
  • National Institute of Mental Health (R24MH081797)
  • National Human Genome Research Institute (1R21HG005750-01A1, R21 HG005750)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
DNA methylation, ethnic differences, allele frequency divergence, CpG sites, transcription start sites, epistasis, gene-environment interaction
MeSH terms
Cell Line, Gene Frequency, Genetics, Population, Humans, Genetic Variation, Genome, Human, CpG Islands, DNA Methylation, Polymorphism, Single Nucleotide, Transcription Initiation Site, Black People, White People, Genetic Association Studies

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