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Genome-wide identification of DNA methylation QTLs in whole blood highlights pathways for cardiovascular disease
Framingham Heart Dis Epidemiol Study, Framingham, MA USA; NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Bethesda, MD USA.
Framingham Heart Dis Epidemiol Study, Framingham, MA USA; NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Bethesda, MD USA.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Framingham Heart Dis Epidemiol Study, Framingham, MA USA; NHLBI, Populat Sci Branch, Div Intramural Res, NIH, , Bethesda, MD USA.
Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Brown Fdn, McGovern Med Sch, Houston, TX USA.
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2019 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 4267Article in journal (Refereed) Published
Abstract [en]

Identifying methylation quantitative trait loci (meQTLs) and integrating them with disease-associated variants from genome-wide association studies (GWAS) may illuminate functional mechanisms underlying genetic variant-disease associations. Here, we perform GWAS of >415 thousand CpG methylation sites in whole blood from 4170 individuals and map 4.7 million cis- and 630 thousand trans-meQTL variants targeting >120 thousand CpGs. Independent replication is performed in 1347 participants from two studies. By linking cis-meQTL variants with GWAS results for cardiovascular disease (CVD) traits, we identify 92 putatively causal CpGs for CVD traits by Mendelian randomization analysis. Further integrating gene expression data reveals evidence of cis CpG-transcript pairs causally linked to CVD. In addition, we identify 22 trans-meQTL hotspots each targeting more than 30 CpGs and find that trans-meQTL hotspots appear to act in cis on expression of nearby transcriptional regulatory genes. Our findings provide a powerful meQTL resource and shed light on DNA methylation involvement in human diseases.

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2019. Vol. 10, article id 4267
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Medical Genetics
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URN: urn:nbn:se:uu:diva-395437DOI: 10.1038/s41467-019-12228-zISI: 000486566400007PubMedID: 31537805OAI: oai:DiVA.org:uu-395437DiVA, id: diva2:1366643
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Swedish Research Council, 2016-00598; 5RC2HL102419; R01NS087541Available from: 2019-10-30 Created: 2019-10-30 Last updated: 2019-10-30Bibliographically approved

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