Rare sequence variation and DNA methylation : effects on alcohol and tobacco use phenotypes
[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Alcohol and tobacco use and dependence are known to be influenced by the effects of common variants enriched in non-coding gene regulatory regions, as well as rare protein-coding variation. In contrast, the role of rare non-coding regulatory variation is unknown. Epigenetic factors such as DNA methylation also influence gene expression, and some of these effects are under genomic control. The current study investigated the effects of rare coding and non-coding variation in regions susceptible to DNA methylation, and whether differential levels of methylation mediated their effects in association with alcohol and tobacco use and dependence. Data from whole-genome sequencing and DNA methylation microarrays for participants in the UCSF Family Alcoholism Study (N = 1,852) were used for set-based tests of rare variation, region-based differential methylation, and epigenetic mediation in relation to quantitative measures of alcohol and tobacco use and DSM-IV dependence diagnoses. Rare variants in exonic and intronic regions, as well as CpG islands, were weighted by a measure of deleteriousness and were significantly associated with alcohol and tobacco use phenotypes. Similarly, differential levels of DNA methylation exhibited significant association with lifetime and current measures of use and dependence. However, there was a relative lack of evidence for epigenetic mediation of rare variation, likely due to a lack of power. Findings from the current study suggest that rare regulatory DNA sequence variation and differential levels of DNA methylation influence risk for alcohol and tobacco use, but whether there exists epigenetic mediation of rare variation requires larger sample sizes in future studies.
Access to files is limited to the University of Missouri--Columbia.
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License.