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

by 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 Seshadri, Michèle M. Sale, the Genomics and Randomized Trials Network , the Framingham Heart Study 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 [...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research