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 Seshadri; Michèle M. Sale

doi:10.1371/journal.pgen.1004214

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

Research output: Contribution to journal › Article › peer-review

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 language	American English
Article number	e1004214
Journal	PLoS Genetics
Volume	10
Issue number	3
DOIs	https://doi.org/10.1371/journal.pgen.1004214
State	Published - Mar 2014
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

All Science Journal Classification (ASJC) codes

Ecology, Evolution, Behavior and Systematics
Molecular Biology
Genetics
Genetics(clinical)
Cancer Research

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10.1371/journal.pgen.1004214

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Williams, S. R., Yang, Q., Chen, F., Liu, X., Keene, K. L., Jacques, P., Chen, W. M., Weinstein, G., Hsu, F. C., Beiser, A., Wang, L., Bookman, E., Doheny, K. F., Wolf, P. A., Zilka, M., Selhub, J., Nelson, S., Gogarten, S. M., Worrall, B. B., ... Sale, M. M. (2014). Genome-Wide Meta-Analysis of Homocysteine and Methionine Metabolism Identifies Five One Carbon Metabolism Loci and a Novel Association of ALDH1L1 with Ischemic Stroke. PLoS Genetics, 10(3), Article e1004214. https://doi.org/10.1371/journal.pgen.1004214

@article{b472cc90a36a430287d8b6f92d197186,

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.",

author = "Williams, \{Stephen R.\} and Qiong Yang and Fang Chen and Xuan Liu and Keene, \{Keith L.\} and Paul Jacques and Chen, \{Wei Min\} and Galit Weinstein and Hsu, \{Fang Chi\} and Alexa Beiser and Liewei Wang and Ebony Bookman and Doheny, \{Kimberly F.\} and Wolf, \{Philip A.\} and Michelle Zilka and Jacob Selhub and Sarah Nelson and Gogarten, \{Stephanie M.\} and Worrall, \{Bradford B.\} and Sudha Seshadri and Sale, \{Mich{\`e}le M.\}",

year = "2014",

month = mar,

doi = "10.1371/journal.pgen.1004214",

language = "American English",

volume = "10",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "3",

}

Williams, SR, Yang, Q, Chen, F, Liu, X, Keene, KL, Jacques, P, Chen, WM, Weinstein, G, Hsu, FC, Beiser, A, Wang, L, Bookman, E, Doheny, KF, Wolf, PA, Zilka, M, Selhub, J, Nelson, S, Gogarten, SM, Worrall, BB, Seshadri, S & Sale, MM 2014, 'Genome-Wide Meta-Analysis of Homocysteine and Methionine Metabolism Identifies Five One Carbon Metabolism Loci and a Novel Association of ALDH1L1 with Ischemic Stroke', PLoS Genetics, vol. 10, no. 3, e1004214. https://doi.org/10.1371/journal.pgen.1004214

TY - JOUR

T1 - Genome-Wide Meta-Analysis of Homocysteine and Methionine Metabolism Identifies Five One Carbon Metabolism Loci and a Novel Association of ALDH1L1 with Ischemic Stroke

AU - Williams, Stephen R.

AU - Yang, Qiong

AU - Chen, Fang

AU - Liu, Xuan

AU - Keene, Keith L.

AU - Jacques, Paul

AU - Chen, Wei Min

AU - Weinstein, Galit

AU - Hsu, Fang Chi

AU - Beiser, Alexa

AU - Wang, Liewei

AU - Bookman, Ebony

AU - Doheny, Kimberly F.

AU - Wolf, Philip A.

AU - Zilka, Michelle

AU - Selhub, Jacob

AU - Nelson, Sarah

AU - Gogarten, Stephanie M.

AU - Worrall, Bradford B.

AU - Seshadri, Sudha

AU - Sale, Michèle M.

PY - 2014/3

Y1 - 2014/3

N2 - 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.

AB - 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.

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U2 - 10.1371/journal.pgen.1004214

DO - 10.1371/journal.pgen.1004214

M3 - Article

C2 - 24651765

SN - 1553-7390

VL - 10

JO - PLoS Genetics

JF - PLoS Genetics

IS - 3

M1 - e1004214

ER -

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

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