Genome-Wide Meta-Analysis of Homocysteine and Methionine Metabolism Identifies Five One Carbon Metabolism Loci and a Novel Association of ALDH1L1 with Ischemic Stroke

Stephen R. Williams, Qiong Yang, Fang Chen, Xuan Liu, Keith L. Keene, Paul Jacques, Wei Min Chen, Galit Weinstein, Fang Chi Hsu, Alexa Beiser, Liewei Wang, Ebony Bookman, Kimberly F. Doheny, Philip A. Wolf, Michelle Zilka, Jacob Selhub, Sarah Nelson, Stephanie M. Gogarten, Bradford B. Worrall, Sudha SeshadriMichèle M. Sale

47 Scopus citations

Abstract

Circulating homocysteine levels (tHcy), a product of the folate one carbon metabolism pathway (FOCM) through the demethylation of methionine, are heritable and are associated with an increased risk of common diseases such as stroke, cardiovascular disease (CVD), cancer and dementia. The FOCM is the sole source of de novo methyl group synthesis, impacting many biological and epigenetic pathways. However, the genetic determinants of elevated tHcy (hyperhomocysteinemia), dysregulation of methionine metabolism and the underlying biological processes remain unclear. We conducted independent genome-wide association studies and a meta-analysis of methionine metabolism, characterized by post-methionine load test tHcy, in 2,710 participants from the Framingham Heart Study (FHS) and 2,100 participants from the Vitamin Intervention for Stroke Prevention (VISP) clinical trial, and then examined the association of the identified loci with incident stroke in FHS. Five genes in the FOCM pathway (GNMT [p = 1.60×10-63], CBS [p = 3.15×10-26], CPS1 [p = 9.10×10-13], ALDH1L1 [p = 7.3×10-13] and PSPH [p = 1.17×10-16]) were strongly associated with the difference between pre- and post-methionine load test tHcy levels (ΔPOST). Of these, one variant in the ALDH1L1 locus, rs2364368, was associated with incident ischemic stroke. Promoter analyses reveal genetic and epigenetic differences that may explain a direct effect on GNMT transcription and a downstream affect on methionine metabolism. Additionally, a genetic-score consisting of the five significant loci explains 13% of the variance of ΔPOST in FHS and 6% of the variance in VISP. Association between variants in FOCM genes with ΔPOST suggest novel mechanisms that lead to differences in methionine metabolism, and possibly the epigenome, impacting disease risk. These data emphasize the importance of a concerted effort to understand regulators of one carbon metabolism as potential therapeutic targets.

Original languageEnglish (US)
Article numbere1004214
JournalPLoS Genetics
Volume10
Issue number3
DOIs
StatePublished - Mar 2014
Externally publishedYes

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