Genome-wide association study of homocysteine in African Americans from the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Coronary Artery Risk in Young Adults study

Laura M. Raffield, Jaclyn Ellis, Nels C. Olson, Qing Duan, Jin Li, Peter Durda, Nathan Pankratz, Brendan J. Keating, Christina L. Wassel, Mary Cushman, James G. Wilson, Myron D. Gross, Russell P. Tracy, Stephen S. Rich, Alex P. Reiner, Yun Li, Monte Willis, Ethan M. Lange, Leslie A. Lange

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Homocysteine (Hcy) is a heritable biomarker for CVD, peripheral artery disease, stroke, and dementia. Little is known about genetic associations with Hcy in individuals of African ancestry. We performed a genome-wide association study for Hcy in 4927 AAs from the Jackson Heart Study (JHS), the Multi-Ethnic Study of Atherosclerosis (MESA), and the Coronary Artery Risk in Young Adults (CARDIA) study. Analyses were stratified by sex and results were meta-analyzed within and across sex. In the sex-combined meta-analysis, we observed genome-wide significant evidence (p < 5.0 × 10 -8 ) for the NOX4 locus (lead variant rs2289125, β =-0.15, p = 5.3 × 10 11 ). While the NOX4 locus was previously reported as associated with Hcy in European-American populations, rs2289125 remained genome-wide significant when conditioned on the previously reported lead variants. Previously reported genome-wide significant associations at NOX4, MTR, CBS, and MMACHC were also nominally (p < 0.050) replicated in AAs. Associations at the CPS1 locus, previously reported in females only, also was replicated specifically in females in this analysis, supporting sex-specific effects for this locus. These results suggest that there may be a combination of cross-population and population-specific genetic effects, as well as differences in genetic effects between males and females, in the regulation of Hcy levels.

Original languageEnglish (US)
Pages (from-to)327-337
Number of pages11
JournalJournal of Human Genetics
Volume63
Issue number3
DOIs
StatePublished - Mar 1 2018
Externally publishedYes

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Genome-Wide Association Study
Homocysteine
African Americans
Young Adult
Atherosclerosis
Coronary Vessels
Genome
Peripheral Arterial Disease
Population Genetics
Population
Dementia
Meta-Analysis
Biomarkers
Stroke

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Genome-wide association study of homocysteine in African Americans from the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Coronary Artery Risk in Young Adults study. / Raffield, Laura M.; Ellis, Jaclyn; Olson, Nels C.; Duan, Qing; Li, Jin; Durda, Peter; Pankratz, Nathan; Keating, Brendan J.; Wassel, Christina L.; Cushman, Mary; Wilson, James G.; Gross, Myron D.; Tracy, Russell P.; Rich, Stephen S.; Reiner, Alex P.; Li, Yun; Willis, Monte; Lange, Ethan M.; Lange, Leslie A.

In: Journal of Human Genetics, Vol. 63, No. 3, 01.03.2018, p. 327-337.

Research output: Contribution to journalArticle

Raffield, LM, Ellis, J, Olson, NC, Duan, Q, Li, J, Durda, P, Pankratz, N, Keating, BJ, Wassel, CL, Cushman, M, Wilson, JG, Gross, MD, Tracy, RP, Rich, SS, Reiner, AP, Li, Y, Willis, M, Lange, EM & Lange, LA 2018, 'Genome-wide association study of homocysteine in African Americans from the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Coronary Artery Risk in Young Adults study', Journal of Human Genetics, vol. 63, no. 3, pp. 327-337. https://doi.org/10.1038/s10038-017-0384-9
Raffield, Laura M. ; Ellis, Jaclyn ; Olson, Nels C. ; Duan, Qing ; Li, Jin ; Durda, Peter ; Pankratz, Nathan ; Keating, Brendan J. ; Wassel, Christina L. ; Cushman, Mary ; Wilson, James G. ; Gross, Myron D. ; Tracy, Russell P. ; Rich, Stephen S. ; Reiner, Alex P. ; Li, Yun ; Willis, Monte ; Lange, Ethan M. ; Lange, Leslie A. / Genome-wide association study of homocysteine in African Americans from the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Coronary Artery Risk in Young Adults study. In: Journal of Human Genetics. 2018 ; Vol. 63, No. 3. pp. 327-337.
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abstract = "Homocysteine (Hcy) is a heritable biomarker for CVD, peripheral artery disease, stroke, and dementia. Little is known about genetic associations with Hcy in individuals of African ancestry. We performed a genome-wide association study for Hcy in 4927 AAs from the Jackson Heart Study (JHS), the Multi-Ethnic Study of Atherosclerosis (MESA), and the Coronary Artery Risk in Young Adults (CARDIA) study. Analyses were stratified by sex and results were meta-analyzed within and across sex. In the sex-combined meta-analysis, we observed genome-wide significant evidence (p < 5.0 × 10 -8 ) for the NOX4 locus (lead variant rs2289125, β =-0.15, p = 5.3 × 10 11 ). While the NOX4 locus was previously reported as associated with Hcy in European-American populations, rs2289125 remained genome-wide significant when conditioned on the previously reported lead variants. Previously reported genome-wide significant associations at NOX4, MTR, CBS, and MMACHC were also nominally (p < 0.050) replicated in AAs. Associations at the CPS1 locus, previously reported in females only, also was replicated specifically in females in this analysis, supporting sex-specific effects for this locus. These results suggest that there may be a combination of cross-population and population-specific genetic effects, as well as differences in genetic effects between males and females, in the regulation of Hcy levels.",
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AU - Raffield, Laura M.

AU - Ellis, Jaclyn

AU - Olson, Nels C.

AU - Duan, Qing

AU - Li, Jin

AU - Durda, Peter

AU - Pankratz, Nathan

AU - Keating, Brendan J.

AU - Wassel, Christina L.

AU - Cushman, Mary

AU - Wilson, James G.

AU - Gross, Myron D.

AU - Tracy, Russell P.

AU - Rich, Stephen S.

AU - Reiner, Alex P.

AU - Li, Yun

AU - Willis, Monte

AU - Lange, Ethan M.

AU - Lange, Leslie A.

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N2 - Homocysteine (Hcy) is a heritable biomarker for CVD, peripheral artery disease, stroke, and dementia. Little is known about genetic associations with Hcy in individuals of African ancestry. We performed a genome-wide association study for Hcy in 4927 AAs from the Jackson Heart Study (JHS), the Multi-Ethnic Study of Atherosclerosis (MESA), and the Coronary Artery Risk in Young Adults (CARDIA) study. Analyses were stratified by sex and results were meta-analyzed within and across sex. In the sex-combined meta-analysis, we observed genome-wide significant evidence (p < 5.0 × 10 -8 ) for the NOX4 locus (lead variant rs2289125, β =-0.15, p = 5.3 × 10 11 ). While the NOX4 locus was previously reported as associated with Hcy in European-American populations, rs2289125 remained genome-wide significant when conditioned on the previously reported lead variants. Previously reported genome-wide significant associations at NOX4, MTR, CBS, and MMACHC were also nominally (p < 0.050) replicated in AAs. Associations at the CPS1 locus, previously reported in females only, also was replicated specifically in females in this analysis, supporting sex-specific effects for this locus. These results suggest that there may be a combination of cross-population and population-specific genetic effects, as well as differences in genetic effects between males and females, in the regulation of Hcy levels.

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