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

L. 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 S. Willis; Ethan M. Lange; Leslie A. Lange

doi:10.1038/s10038-017-0384-9

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

L. 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 S. Willis, Ethan M. Lange, Leslie A. Lange

Laboratory Medicine and Pathology

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7 Scopus citations

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 × 10¹¹). 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 language	English (US)
Pages (from-to)	327-337
Number of pages	11
Journal	Journal of Human Genetics
Volume	63
Issue number	3
DOIs	https://doi.org/10.1038/s10038-017-0384-9
State	Published - Mar 1 2018

Bibliographical note

Funding Information:
Acknowledgements Analysis effort for this research was supported by the National Heart, Lung, and Blood Institute (NHLBI) R21 HL126045-02 (EML, LAL), R01 HL129132 (YL, APR), K99HL129045 (NCO), and T32 HL129982 (LMR). The CARDIA Study is conducted and supported by the NHLBI in collaboration with the University of Alabama at Birmingham (HHSN268201300025C and HHSN268201300026C), Northwestern University (HHSN26820 1300027C), University of Minnesota (HHSN268201300028C), Kaiser Foundation Research Institute (HHSN268201300029C), and Johns Hopkins University School of Medicine (HHSN268200900041C). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging. MESA and the MESA SHARe project are conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. The JHS is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN2 68201300048C, HHSN268201300049C, HHSN268201300050C from the NHLBI and the National Institute on Minority Health and Health Disparities. CARe genotyping for the three studies was performed at the Broad Institute of Harvard and MIT (Boston, MA, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. Funding for CARe genotyping was provided by NHLBI Contract N01-HC-65226.

Publisher Copyright:
© 2017 The Japan Society of Human Genetics.

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10.1038/s10038-017-0384-9

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826839

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Raffield, L. M., Ellis, J., Olson, N. C., Duan, Q., Li, J., Durda, P., Pankratz, N., Keating, B. J., Wassel, C. L., Cushman, M., Wilson, J. G., Gross, M. D., Tracy, R. P., Rich, S. S., Reiner, A. P., Li, Y., Willis, M. S., Lange, E. M., & Lange, L. A. (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, 63(3), 327-337. https://doi.org/10.1038/s10038-017-0384-9

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, L. M.; Ellis, Jaclyn; Olson, Nels C. et al.

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

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

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, MS, 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

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title = "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",

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 × 1011). 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.",

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

note = "Funding Information: Acknowledgements Analysis effort for this research was supported by the National Heart, Lung, and Blood Institute (NHLBI) R21 HL126045-02 (EML, LAL), R01 HL129132 (YL, APR), K99HL129045 (NCO), and T32 HL129982 (LMR). The CARDIA Study is conducted and supported by the NHLBI in collaboration with the University of Alabama at Birmingham (HHSN268201300025C and HHSN268201300026C), Northwestern University (HHSN26820 1300027C), University of Minnesota (HHSN268201300028C), Kaiser Foundation Research Institute (HHSN268201300029C), and Johns Hopkins University School of Medicine (HHSN268200900041C). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging. MESA and the MESA SHARe project are conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. The JHS is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN2 68201300048C, HHSN268201300049C, HHSN268201300050C from the NHLBI and the National Institute on Minority Health and Health Disparities. CARe genotyping for the three studies was performed at the Broad Institute of Harvard and MIT (Boston, MA, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. Funding for CARe genotyping was provided by NHLBI Contract N01-HC-65226. Publisher Copyright: {\textcopyright} 2017 The Japan Society of Human Genetics.",

year = "2018",

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day = "1",

doi = "10.1038/s10038-017-0384-9",

language = "English (US)",

volume = "63",

pages = "327--337",

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T1 - 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

AU - Raffield, L. 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 S.

AU - Lange, Ethan M.

AU - Lange, Leslie A.

N1 - Funding Information: Acknowledgements Analysis effort for this research was supported by the National Heart, Lung, and Blood Institute (NHLBI) R21 HL126045-02 (EML, LAL), R01 HL129132 (YL, APR), K99HL129045 (NCO), and T32 HL129982 (LMR). The CARDIA Study is conducted and supported by the NHLBI in collaboration with the University of Alabama at Birmingham (HHSN268201300025C and HHSN268201300026C), Northwestern University (HHSN26820 1300027C), University of Minnesota (HHSN268201300028C), Kaiser Foundation Research Institute (HHSN268201300029C), and Johns Hopkins University School of Medicine (HHSN268200900041C). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging. MESA and the MESA SHARe project are conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. The JHS is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN2 68201300048C, HHSN268201300049C, HHSN268201300050C from the NHLBI and the National Institute on Minority Health and Health Disparities. CARe genotyping for the three studies was performed at the Broad Institute of Harvard and MIT (Boston, MA, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. Funding for CARe genotyping was provided by NHLBI Contract N01-HC-65226. Publisher Copyright: © 2017 The Japan Society of Human Genetics.

PY - 2018/3/1

Y1 - 2018/3/1

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 × 1011). 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.

AB - 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 × 1011). 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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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

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