title: Genome-wide meta-analysis of homocysteine and methionine metabolism identifies five one carbon metabolism loci and a novel association of ALDH1L1 with ischemic stroke.
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.
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, United States of America; Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Williams
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America; The Framingham Heart Study, Framingham, Massachusetts, United States of America.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Fang
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Xuan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, United States of America; Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia, United States of America; Department of Biology, East Carolina University, Greenville, North Carolina, United States of America; Center for Health Disparities Research, East Carolina University, Greenville, North Carolina, United States of America.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Keene
authors.affiliation: Jean Mayer USDA Human Nutrition Research Center on Aging and Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Jacques
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Chen
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Galit
authors.initials: G
authors.lastname: Weinstein
authors.affiliation: Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Fang-Chi
authors.initials: FC
authors.lastname: Hsu
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America; Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Alexa
authors.initials: A
authors.lastname: Beiser
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America.
authors.forename: Liewei
authors.initials: L
authors.lastname: Wang
authors.affiliation: National Human Genome Research Institute, Bethesda, Maryland, United States of America.
authors.forename: Ebony
authors.initials: E
authors.lastname: Bookman
authors.affiliation: Center for Inherited Disease Research, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Kimberly F
authors.initials: KF
authors.lastname: Doheny
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Wolf
authors.affiliation: Center for Inherited Disease Research, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Michelle
authors.initials: M
authors.lastname: Zilka
authors.affiliation: Jean Mayer USDA Human Nutrition Research Center on Aging and Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts, United States of America.
authors.forename: Jacob
authors.initials: J
authors.lastname: Selhub
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.
authors.forename: Sarah
authors.initials: S
authors.lastname: Nelson
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Gogarten
authors.affiliation: Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia, United States of America; Department of Neurology University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Bradford B
authors.initials: BB
authors.lastname: Worrall
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Sudha
authors.initials: S
authors.lastname: Seshadri
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, United States of America; Department of Medicine, University of Virginia, Charlottesville, Virginia, United States of America; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Michèle M
authors.initials: MM
authors.lastname: Sale
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D002244:Carbon / Q000378:metabolism; D005492:Folic Acid / Q000378:metabolism; D055106:Genome-Wide Association Study; D005838:Genotype; D006710:Homocysteine / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008715:Methionine / Q000235:genetics / Q000378:metabolism*; D000587:Oxidoreductases Acting on CH-NH Group Donors; D020521:Stroke / Q000235:genetics* / Q000473:pathology; D014805:Vitamin B 12; D000099295:Formyltetrahydrofolate Dehydrogenase
chemical_list: D000444:Aldehyde Dehydrogenase; D002244:Carbon; D005492:Folic Acid; D006710:Homocysteine; D008715:Methionine; D000587:Oxidoreductases Acting on CH-NH Group Donors; D014805:Vitamin B 12; D000099295:Formyltetrahydrofolate Dehydrogenase