X chromosome-wide analysis identifies DNA methylation sites influenced by cigarette smoking

• Type of Material: Article
• Authors: Yan Sun, Emory University; Daniella Klebaner, Emory University; Yunfeng Huang, Emory University; Qin Hui, Emory University; Jacquelyn Y. Taylor, Yale University; Jack Goldberg, University of Washington; Laura Vaccarino, Emory University
• Language: English
• Date: 2016-02-24
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © Klebaner et al. 2016. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13148-016-0189-2
• Title of Journal or Parent Work: Clinical Epigenetics
• ISSN: 1868-7075
• Volume: 8
• Start Page: 20
• End Page: 20
• Grant/Funding Information: This study was supported by K24 HL077506, R01 HL68630, R01 AG026255, R01 MH056120, R01 HL088726, R01 NR013520, and K24 MH076955 and K12 GM000680 from the NIH; by the Emory University General Clinical Research Center MO1-RR00039; and by Grants 0245115N and 13GRNT17060002 from the American Heart Association.
• Keywords: Epigenetics; Science & Technology; Methylome; DISEASE; LOCI; Heritability; Smoking; Epigenome; Epigenome-wide association study; PROMOTER METHYLATION; HUMAN GENOME; EPIGENOME; Life Sciences & Biomedicine; X chromosome; Oncology; GENE-EXPRESSION; Twin; AFRICAN-AMERICANS; PATTERNS; DNA methylation; ASSOCIATION ANALYSIS; HUMAN SKELETAL-MUSCLE
• Research Categories: Health Sciences, Epidemiology; Biology, Genetics

Abstract

BACKGROUND: Tobacco smoking is a major cause of chronic disease worldwide. Smoking may induce cellular and molecular changes including epigenetic modification, with both short-term and long-term modification patterns that may contribute to phenotypic expression of diseases. Recent epigenome-wide association studies (EWAS) have identified dozens of smoking-related DNA methylation (DNAm) sites. However, the X chromosomal DNAm sites have been largely overlooked due to a lack of an analytical framework for dealing with the sex-dimorphic distribution. To identify novel smoking-related DNAm sites on the X chromosome, we examined the modality of each X chromosomal DNAm site and conducted a sex-specific association study of cigarette smoking. RESULTS: We used a discovery sample of 139 middle-age twins, and three replication samples of 78 twins, 464 and 333 unrelated individuals including 47, 17, 22, and 89 current smokers, respectively. After correction for multiple testing, the top smoking-related DNAm sites in BCOR and TSC22D3 were significantly hypermethylated and hypomethylated, respectively, among current smokers. These smoking-associated sites were replicated with meta-analysis p-values of 9.17 × 10(-12) and 1.61 × 10(-9). For both sites, the smoking effects on methylation levels were larger in males than that in females. CONCLUSIONS: Our findings highlight the importance of investigating X chromosome methylation patterns and their associations with environmental exposures and disease phenotypes and demonstrate a robust statistical methodology for such study. Existing EWAS of human diseases should incorporate the X chromosomal sites to complete a comprehensive epigenome-wide scan.