Novel epigenetic determinants of type 2 diabetes in Mexican-American families

Hemant Kulkarni, Mark Z. Kos, Jennifer Neary, Thomas D. Dyer, Jack W. Kent, Harald H H Göring, Shelley A. Cole, Anthony G. Comuzzie, Laura Almasy, Michael C. Mahaney, Joanne E. Curran, John Blangero, Melanie A. Carless

    Research output: Contribution to journalArticle

    54 Scopus citations

    Abstract

    Although DNA methylation is now recognized as an important mediator of complex diseases, the extent to which the genetic basis of such diseases is accounted for by DNA methylation is unknown. In the setting of large, extended families representing a minority, high-risk population of the USA, we aimed to characterize the role of epigenome-wide DNA methylation in type 2 diabetes (T2D). Using Illumina HumanMethylation450 BeadChip arrays, we tested for association of DNA methylation at 446 356 sites with age, sex and phenotypic traits related to T2D in 850 pedigreed Mexican-American individuals. Robust statistical analyses showed that (i) 15% of the methylome is significantly heritable, with a median heritability of 0.14; (ii) DNA methylation at 14% of CpG sites is associated with nearby sequence variants; (iii) 22% and 3% of the autosomal CpG sites are associated with age and sex, respectively; (iv) 53 CpG sites were significantly associated with liability to T2D, fasting blood glucose and insulin resistance; (v) DNA methylation levels at five CpG sites, mapping to three well-characterized genes (TXNIP, ABCG1 and SAMD12) independently explained 7.8% of the heritability of T2D (vi) methylation at these five sites was unlikely to be influenced by neighboring DNA sequence variation. Our study has identified novel epigenetic indicators of T2D risk in Mexican Americans who have increased risk for this disease. These results provide new insights into potential treatment targets of T2D.

    Original languageEnglish (US)
    Article numberddv232
    Pages (from-to)5330-5344
    Number of pages15
    JournalHuman Molecular Genetics
    Volume24
    Issue number18
    DOIs
    StatePublished - Apr 9 2015

    ASJC Scopus subject areas

    • Genetics
    • Genetics(clinical)
    • Molecular Biology

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  • Cite this

    Kulkarni, H., Kos, M. Z., Neary, J., Dyer, T. D., Kent, J. W., Göring, H. H. H., Cole, S. A., Comuzzie, A. G., Almasy, L., Mahaney, M. C., Curran, J. E., Blangero, J., & Carless, M. A. (2015). Novel epigenetic determinants of type 2 diabetes in Mexican-American families. Human Molecular Genetics, 24(18), 5330-5344. [ddv232]. https://doi.org/10.1093/hmg/ddv232