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. 2024 Mar 28;15(1):2713.
doi: 10.1038/s41467-024-47005-0.

Genetic control of DNA methylation is largely shared across European and East Asian populations

Alesha A Hatton  1 , Fei-Fei Cheng  1   2 , Tian Lin  1 , Ren-Juan Shen  3   4 , Jie Chen  4 , Zhili Zheng  1 , Jia Qu  4 , Fan Lyu  4 , Sarah E Harris  5 , Simon R Cox  5 , Zi-Bing Jin  3   4 , Nicholas G Martin  6 , Dongsheng Fan  7 , Grant W Montgomery  1 , Jian Yang  2   8 , Naomi R Wray  1   9 , Riccardo E Marioni  10 , Peter M Visscher  1 , Allan F McRae  11
Affiliations

Genetic control of DNA methylation is largely shared across European and East Asian populations

Alesha A Hatton et al. Nat Commun. .

Abstract

DNA methylation is an ideal trait to study the extent of the shared genetic control across ancestries, effectively providing hundreds of thousands of model molecular traits with large QTL effect sizes. We investigate cis DNAm QTLs in three European (n = 3701) and two East Asian (n = 2099) cohorts to quantify the similarities and differences in the genetic architecture across populations. We observe 80,394 associated mQTLs (62.2% of DNAm probes with significant mQTL) to be significant in both ancestries, while 28,925 mQTLs (22.4%) are identified in only a single ancestry. mQTL effect sizes are highly conserved across populations, with differences in mQTL discovery likely due to differences in allele frequency of associated variants and differing linkage disequilibrium between causal variants and assayed SNPs. This study highlights the overall similarity of genetic control across ancestries and the value of ancestral diversity in increasing the power to detect associations and enhancing fine mapping resolution.

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Conflict of interest statement

R.E.M. is a scientific advisor to the Epigenetic Clock Development Foundation and Optima Partners. The remaining authors declare no completing interests.

Figures

Fig. 1
Fig. 1. Study overview.
Shown are the number of DNAm probes with significant mQTL detected across the five cohorts and following subsequent ancestry-based meta-analysis. The cis-mQTL results were split into two distinct sets to identify those mQTLs stringently replicated in both ancestry and those not replicated across ancestries. A Bonferroni corrected, two-sided p value threshold of p < 10−10 was used to define significance at the cohort level from linear regression and mixed linear regression models, and at the ancestry level using inverse variance-weighted meta-analysis. *BSGS cohort includes related individuals from 177 families. Created with BioRender.com.
Fig. 2
Fig. 2. The correlation (rb) of cis-mQTL SNP effects across cohorts.
Correlations were calculated between the lead SNP from the discovery cohort and the corresponding SNP effect in the replication cohort. Shown are the estimates of rb with corresponding standard errors in parentheses. Cohorts of the same ancestry, boxed in red (EUR cohorts) and purple (EAS cohorts), have a stronger correlation of effect sizes than observed across ancestries.
Fig. 3
Fig. 3. Evidence for shared genetic association at cis-mQTLs identified in both populations.
a The correlation (rb) of cis-mQTL SNP effects between ancestries for 80,394 DNAm probes with significant mQTL identified in both populations. Shown are effect sizes of the lead SNPs from each ancestry and the corresponding SNP effect in other ancestry. Correlations are presented with corresponding standard errors in parentheses. b LD between lead SNPs for DNAm probes with significant mQTL identified in both populations. Shown are the r-squared values between lead SNPs calculated using the 1000 Genomes reference panel for the subset of EUR samples (79,391 SNP pairs; left) and EAS individuals (78,108 SNP pairs; right).
Fig. 4
Fig. 4. Cross-ancestry fine mapping improves resolution between cohorts of EUR and EAS ancestry.
a Box plot of size of 95% credible set presented for 6385 mQTL associations in EUR, EAS and cross-ancestry populations. Single ancestry fine mapping was performed using SuSiE and cross-ancestry using SuSiEx. The cross-ancestry fine mapping resulted in decreased mean credible set size compared to single ancestry fine mapping performed in samples of EUR and EAS ancestry due to leveraged differences in LD structures across ancestries. Median values are shown in each boxplot, the box denotes the interquartile range and whiskers denote the rest of the data distribution. b Fine mapping of DNAm probe cg09192572 demonstrates improved resolution by incorporating cross-ancestry information. Single ancestry fine mapping using SuSiE generated credible sets of 5 SNPs in EUR shown in red (left) and 3 SNPs in EAS shown in purple (right). The cross-ancestry credible set calculated using SuSiEx resulted in a refined set of 1 SNPs shown in blue. p values are from an inverse variance-weighted meta-analysis and are not corrected for multiple testing.
Fig. 5
Fig. 5. Differences in lead SNP allele frequencies for mQTLs which were significant in a single ancestry only.
Allele frequencies for the EUR lead SNPs for EUR-mQTL (a; 21,084 mQTL) and for the EAS lead SNP for EAS-mQTL (b; 7841 mQTL). Allele frequencies were calculated using 1000 Genomes reference data for the subset of EUR samples and EAS samples as presented on the respective axes.
Fig. 6
Fig. 6. Evidence of ancestry-specific pleiotropic associations.
mQTL and GWAS association for Glucocorticoid use (R03BA) in populations of EUR and EAS ancestry. Shown is genomic region surrounding DNAm probe cg19197236 on chromosome 2 identified in mQTL analysis and R03BA GWAS. The presence of an associated genetic signal was observed in EUR with both DNAm (a) and R03BA (c), with the pleiotropic nature of the mQTL confirmed using SMR. Associations were not observed for either DNAm or R03BA in EAS (b, d, respectively). mQTL and GWAS p values were from linear regression analyses. The blue line indicates the significance threshold (p < 10−10) in mQTL analysis, the grey line is the replication threshold (p < 10−6) and the green line indicated the significance threshold (p < 5×10−8) in GWAS. The SNP highlighted in red is the EAS lead SNP used as the exposure outcome in SMR analysis.
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References

    1. Brandes N, Weissbrod O, Linial M. Open problems in human trait genetics. Genome Biol. 2022;23:131. doi: 10.1186/s13059-022-02697-9. - DOI - PMC - PubMed
    1. Peterson RE, et al. Genome-wide association studies in ancestrally diverse populations: opportunities, methods, pitfalls, and recommendations. Cell. 2019;179:589–603. doi: 10.1016/j.cell.2019.08.051. - DOI - PMC - PubMed
    1. Popejoy AB, Fullerton SM. Genomics is failing on diversity. Nature. 2016;538:161–164. doi: 10.1038/538161a. - DOI - PMC - PubMed
    1. Bentley AR, Callier S, Rotimi CN. Diversity and inclusion in genomic research: why the uneven progress? J. Community Genet. 2017;8:255–266. doi: 10.1007/s12687-017-0316-6. - DOI - PMC - PubMed
    1. Galinsky KJ, et al. Estimating cross-population genetic correlations of causal effect sizes. Genet. Epidemiol. 2019;43:180–188. doi: 10.1002/gepi.22173. - DOI - PMC - PubMed