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MeQTL mapping in the GENOA study reveals genetic determinants of DNA methylation in African Americans.

ABSTRACT: Identifying genetic variants that are associated with variation in DNA methylation, an analysis commonly referred to as methylation quantitative trait locus (meQTL) mapping, is an important first step towards understanding the genetic architecture underlying epigenetic variation. Most existing meQTL mapping studies have focused on individuals of European ancestry and are underrepresented in other populations, with a particular absence of large studies in populations with African ancestry. We fill this critical knowledge gap by performing a large-scale cis-meQTL mapping study in 961 African Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. We identify a total of 4,565,687 cis-acting meQTLs in 320,965 meCpGs. We find that 45% of meCpGs harbor multiple independent meQTLs, suggesting potential polygenic genetic architecture underlying methylation variation. A large percentage of the cis-meQTLs also colocalize with cis-expression QTLs (eQTLs) in the same population. Importantly, the identified cis-meQTLs explain a substantial proportion (median = 24.6%) of methylation variation. In addition, the cis-meQTL associated CpG sites mediate a substantial proportion (median = 24.9%) of SNP effects underlying gene expression. Overall, our results represent an important step toward revealing the co-regulation of methylation and gene expression, facilitating the functional interpretation of epigenetic and gene regulation underlying common diseases in African Americans.

SUBMITTER: Shang L

PROVIDER: S-EPMC10175543 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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meQTL mapping in the GENOA study reveals genetic determinants of DNA methylation in African Americans.

Shang Lulu L Zhao Wei W Wang Yi Zhe YZ Li Zheng Z Choi Jerome J JJ Kho Minjung M Mosley Thomas H TH Kardia Sharon L R SLR Smith Jennifer A JA Zhou Xiang X

Nature communications 20230511 1

Identifying genetic variants that are associated with variation in DNA methylation, an analysis commonly referred to as methylation quantitative trait locus (meQTL) mapping, is an important first step towards understanding the genetic architecture underlying epigenetic variation. Most existing meQTL mapping studies have focused on individuals of European ancestry and are underrepresented in other populations, with a particular absence of large studies in populations with African ancestry. We fil ...[more]

PMID: 37169753

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Project description:Methylation quantitative trait loci (meQTL) mapping can provide insight into the genetic architecture underlying the epigenome by identifying single-nucleotide polymorphisms (SNPs) associated with differential methylation at methylation sites (CpGs) across the genome. Given that the epigenetic architecture underlying differences in gene expression can vary across racial populations, performing epigenomic studies in African Americans is crucial for understanding the interplay between genetic variation, DNA methylation, and gene expression in this understudied group. By performing cis-meQTL mapping in African American hepatocytes, we identified 410,186 cis-meQTLs associated with methylation at 24,425 CpGs in the liver. Through colocalization analysis, we found that 18,206 of these meQTLs are also colocalized with known liver eQTLs. Additionally, we found that using African American eQTL data results in an increased ability to detect additional colocalized variants that exhibit strong differences in allele frequency between people of European and African ancestry. Furthermore, the presence of smaller linkage disequilibrium blocks in African Americans allows us to identify narrower genomic regions of potentially causal variants compared to when data from Europeans is used. Importantly, these colocalized SNPs are significantly enriched for genetic associations with lipid and inflammatory traits in the GWAS catalog, suggesting that DNA methylation may contribute to the etiologies of these diseases. Furthermore, while it is generally presumed that the genetic regulation of DNA methylation is shared between blood and liver, we found that only 5.4% of African American liver meQTLs colocalize with blood meQTLs. Overall, our results reveal that studying African American populations results in the identification of additional genetic and epigenetic factors that may regulate gene expression in the liver, thereby expanding our understanding of gene regulation in African Americans.

Project description:BackgroundDNA methylation, an epigenetic mechanism modulated by lifestyle and environmental factors, may be an important biomarker of complex diseases including cardiovascular diseases (CVD) and subclinical atherosclerosis.MethodsDNA methylation in peripheral blood samples from 391 African-Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) was assessed at baseline, and atherosclerosis was assessed 5 and 12 years later. Using linear mixed models, we examined the association between previously identified CpGs for coronary artery calcification (CAC) and carotid plaque, both individually and aggregated into methylation risk scores (MRSCAC and MRScarotid), and four measures of atherosclerosis (CAC, abdominal aorta calcification (AAC), ankle-brachial index (ABI), and multi-site atherosclerosis based on gender-specific quartiles of the single-site measures). We also examined the association between four epigenetic age acceleration measures (IEAA, EEAA, PhenoAge acceleration, and GrimAge acceleration) and the four atherosclerosis measures. Finally, we characterized the temporal stability of the epigenetic measures using repeated DNA methylation measured 5 years after baseline (N = 193).ResultsAfter adjusting for CVD risk factors, four CpGs (cg05575921(AHRR), cg09935388 (GFI1), cg21161138 (AHRR), and cg18168448 (LRRC52)) were associated with multi-site atherosclerosis (FDR < 0.1). cg05575921 was also associated with AAC and cg09935388 with ABI. MRSCAC was associated with ABI (Beta = 0.016, P = 0.006), and MRScarotid was associated with both AAC (Beta = 0.605, equivalent to approximately 1.8-fold increase in the Agatston score of AAC, P = 0.004) and multi-site atherosclerosis (Beta = 0.691, P = 0.002). A 5-year increase in GrimAge acceleration (~ 1 SD) was associated with a 1.6-fold (P = 0.012) increase in the Agatston score of AAC and 0.7 units (P = 0.0003) increase in multi-site atherosclerosis, all after adjusting for CVD risk factors. All epigenetic measures were relatively stable over 5 years, with the highest intraclass correlation coefficients observed for MRScarotid and GrimAge acceleration (0.87 and 0.89, respectively).ConclusionsWe found evidence of an association between DNA methylation and atherosclerosis at multiple vascular sites in a sample of African-Americans. Further evaluation of these potential biomarkers is warranted to deepen our understanding of the relationship between epigenetics and atherosclerosis.

Dataset Information

MeQTL mapping in the GENOA study reveals genetic determinants of DNA methylation in African Americans.

Publications

meQTL mapping in the GENOA study reveals genetic determinants of DNA methylation in African Americans.

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