Exome-wide association analysis reveals novel coding sequence variants associated with lipid traits in Chinese

Clara S. Tang; He Zhang; Chloe Y.Y. Cheung; Ming Xu; Jenny C.Y. Ho; Wei Zhou; Stacey S. Cherny; Yan Zhang; Oddgeir Holmen; Ka Wing Au; Haiyi Yu; Lin Xu; Jia Jia; Robert M. Porsch; Lijie Sun; Weixian Xu; Huiping Zheng; Lai Yung Wong; Yiming Mu; Jingtao Dou; Carol H.Y. Fong; Shuyu Wang; Xueyu Hong; Liguang Dong; Yanhua Liao; Jiansong Wang; Levina S.M. Lam; Xi Su; Hua Yan; Min Lee Yang; Jin Chen; Chung Wah Siu; Gaoqiang Xie; Yu Cho Woo; Yangfeng Wu; Kathryn C.B. Tan; Kristian Hveem; Bernard M.Y. Cheung; Sebastian Zöllner; Aimin Xu; Y. Eugene Chen; Chao Qiang Jiang; Youyi Zhang; Tai Hing Lam; Santhi K. Ganesh; Yong Huo; Pak C. Sham; Karen S.L. Lam; Cristen J. Willer; Hung Fat Tse; Wei Gao

doi:10.1038/ncomms10206

Exome-wide association analysis reveals novel coding sequence variants associated with lipid traits in Chinese

Clara S. Tang, He Zhang, Chloe Y.Y. Cheung, Ming Xu, Jenny C.Y. Ho, Wei Zhou, Stacey S. Cherny, Yan Zhang, Oddgeir Holmen, Ka Wing Au, Haiyi Yu, Lin Xu, Jia Jia, Robert M. Porsch, Lijie Sun, Weixian Xu, Huiping Zheng, Lai Yung Wong, Yiming Mu, Jingtao DouCarol H.Y. Fong, Shuyu Wang, Xueyu Hong, Liguang Dong, Yanhua Liao, Jiansong Wang, Levina S.M. Lam, Xi Su, Hua Yan, Min Lee Yang, Jin Chen, Chung Wah Siu, Gaoqiang Xie, Yu Cho Woo, Yangfeng Wu, Kathryn C.B. Tan, Kristian Hveem, Bernard M.Y. Cheung, Sebastian Zöllner, Aimin Xu, Y. Eugene Chen, Chao Qiang Jiang, Youyi Zhang, Tai Hing Lam, Santhi K. Ganesh, Yong Huo, Pak C. Sham, Karen S.L. Lam, Cristen J. Willer^*, Hung Fat Tse, Wei Gao

^*Corresponding author for this work

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

79 Scopus citations

Abstract

Blood lipids are important risk factors for coronary artery disease (CAD). Here we perform an exome-wide association study by genotyping 12,685 Chinese, using a custom Illumina HumanExome BeadChip, to identify additional loci influencing lipid levels. Single-variant association analysis on 65,671 single nucleotide polymorphisms reveals 19 loci associated with lipids at exome-wide significance (P<2.69 × 10^-7), including three Asian-specific coding variants in known genes (CETP p.Asp459Gly, PCSK9 p.Arg93Cys and LDLR p.Arg257Trp). Furthermore, missense variants at two novel loci - PNPLA3 p.Ile148Met and PKD1L3 p.Thr429Ser - also influence levels of triglycerides and low-density lipoprotein cholesterol, respectively. Another novel gene, TEAD2, is found to be associated with high-density lipoprotein cholesterol through gene-based association analysis. Most of these newly identified coding variants show suggestive association (P<0.05) with CAD. These findings demonstrate that exome-wide genotyping on samples of non-European ancestry can identify additional population-specific possible causal variants, shedding light on novel lipid biology and CAD.

Original language	English
Article number	10206
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms10206
State	Published - 22 Dec 2015
Externally published	Yes

Funding

Funders	Funder number
Peking University Health Sciences Center Joint Institute for Clinical and Translational Research
National Heart, Lung, and Blood Institute	R01HL109946
National Heart, Lung, and Blood Institute
Medical School, University of Michigan
Research Grants Council, University Grants Committee	T12-705/11
Research Grants Council, University Grants Committee
General Research Fund of Shanghai Normal University	17128515, ITS/303/ 12, 776412M, 777511M, 776513M
General Research Fund of Shanghai Normal University

UN SDGs

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

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10.1038/ncomms10206

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Tang, C. S., Zhang, H., Cheung, C. Y. Y., Xu, M., Ho, J. C. Y., Zhou, W., Cherny, S. S., Zhang, Y., Holmen, O., Au, K. W., Yu, H., Xu, L., Jia, J., Porsch, R. M., Sun, L., Xu, W., Zheng, H., Wong, L. Y., Mu, Y., ... Gao, W. (2015). Exome-wide association analysis reveals novel coding sequence variants associated with lipid traits in Chinese. Nature Communications, 6, Article 10206. https://doi.org/10.1038/ncomms10206

@article{0f149b8700fb484f891083efc599d923,

title = "Exome-wide association analysis reveals novel coding sequence variants associated with lipid traits in Chinese",

abstract = "Blood lipids are important risk factors for coronary artery disease (CAD). Here we perform an exome-wide association study by genotyping 12,685 Chinese, using a custom Illumina HumanExome BeadChip, to identify additional loci influencing lipid levels. Single-variant association analysis on 65,671 single nucleotide polymorphisms reveals 19 loci associated with lipids at exome-wide significance (P<2.69 × 10-7), including three Asian-specific coding variants in known genes (CETP p.Asp459Gly, PCSK9 p.Arg93Cys and LDLR p.Arg257Trp). Furthermore, missense variants at two novel loci - PNPLA3 p.Ile148Met and PKD1L3 p.Thr429Ser - also influence levels of triglycerides and low-density lipoprotein cholesterol, respectively. Another novel gene, TEAD2, is found to be associated with high-density lipoprotein cholesterol through gene-based association analysis. Most of these newly identified coding variants show suggestive association (P<0.05) with CAD. These findings demonstrate that exome-wide genotyping on samples of non-European ancestry can identify additional population-specific possible causal variants, shedding light on novel lipid biology and CAD.",

author = "Tang, {Clara S.} and He Zhang and Cheung, {Chloe Y.Y.} and Ming Xu and Ho, {Jenny C.Y.} and Wei Zhou and Cherny, {Stacey S.} and Yan Zhang and Oddgeir Holmen and Au, {Ka Wing} and Haiyi Yu and Lin Xu and Jia Jia and Porsch, {Robert M.} and Lijie Sun and Weixian Xu and Huiping Zheng and Wong, {Lai Yung} and Yiming Mu and Jingtao Dou and Fong, {Carol H.Y.} and Shuyu Wang and Xueyu Hong and Liguang Dong and Yanhua Liao and Jiansong Wang and Lam, {Levina S.M.} and Xi Su and Hua Yan and Yang, {Min Lee} and Jin Chen and Siu, {Chung Wah} and Gaoqiang Xie and Woo, {Yu Cho} and Yangfeng Wu and Tan, {Kathryn C.B.} and Kristian Hveem and Cheung, {Bernard M.Y.} and Sebastian Z{\"o}llner and Aimin Xu and Chen, {Y. Eugene} and Jiang, {Chao Qiang} and Youyi Zhang and Lam, {Tai Hing} and Ganesh, {Santhi K.} and Yong Huo and Sham, {Pak C.} and Lam, {Karen S.L.} and Willer, {Cristen J.} and Tse, {Hung Fat} and Wei Gao",

note = "Funding Information: This work was supported by the Hong Kong Research Grant Council: Theme Based Research Scheme (T12-705/11), General Research Fund (777511M, 776412M, 776513M and 17128515) and Innovation and Technology Support Programme (Tier 3) (ITS/303/ 12). We thank Joyce MS Fung, KH Lee and TK Leung for their technical support. The PUUMA-MI project is a collaboration between Peking University Health Science Center and The University of Michigan Medical School. Funding for the project was provided by the University of Michigan Medical School and the Peking University Health Sciences Center Joint Institute for Clinical and Translational Research (Principal Investigators: C.J.W. and W.G.). We thank the volunteer study participants for their contribution to research. We also thank the University of Michigan leadership of the Joint Institute for facilitating this research, particularly David Pinsky, Amy Huang and Joseph Kolars. C.J.W. is additionally supported by HL094535 and HL109946.",

year = "2015",

month = dec,

day = "22",

doi = "10.1038/ncomms10206",

language = "אנגלית",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Tang, CS, Zhang, H, Cheung, CYY, Xu, M, Ho, JCY, Zhou, W, Cherny, SS, Zhang, Y, Holmen, O, Au, KW, Yu, H, Xu, L, Jia, J, Porsch, RM, Sun, L, Xu, W, Zheng, H, Wong, LY, Mu, Y, Dou, J, Fong, CHY, Wang, S, Hong, X, Dong, L, Liao, Y, Wang, J, Lam, LSM, Su, X, Yan, H, Yang, ML, Chen, J, Siu, CW, Xie, G, Woo, YC, Wu, Y, Tan, KCB, Hveem, K, Cheung, BMY, Zöllner, S, Xu, A, Chen, YE, Jiang, CQ, Zhang, Y, Lam, TH, Ganesh, SK, Huo, Y, Sham, PC, Lam, KSL, Willer, CJ, Tse, HF & Gao, W 2015, 'Exome-wide association analysis reveals novel coding sequence variants associated with lipid traits in Chinese', Nature Communications, vol. 6, 10206. https://doi.org/10.1038/ncomms10206

TY - JOUR

T1 - Exome-wide association analysis reveals novel coding sequence variants associated with lipid traits in Chinese

AU - Tang, Clara S.

AU - Zhang, He

AU - Cheung, Chloe Y.Y.

AU - Xu, Ming

AU - Ho, Jenny C.Y.

AU - Zhou, Wei

AU - Cherny, Stacey S.

AU - Zhang, Yan

AU - Holmen, Oddgeir

AU - Au, Ka Wing

AU - Yu, Haiyi

AU - Xu, Lin

AU - Jia, Jia

AU - Porsch, Robert M.

AU - Sun, Lijie

AU - Xu, Weixian

AU - Zheng, Huiping

AU - Wong, Lai Yung

AU - Mu, Yiming

AU - Dou, Jingtao

AU - Fong, Carol H.Y.

AU - Wang, Shuyu

AU - Hong, Xueyu

AU - Dong, Liguang

AU - Liao, Yanhua

AU - Wang, Jiansong

AU - Lam, Levina S.M.

AU - Su, Xi

AU - Yan, Hua

AU - Yang, Min Lee

AU - Chen, Jin

AU - Siu, Chung Wah

AU - Xie, Gaoqiang

AU - Woo, Yu Cho

AU - Wu, Yangfeng

AU - Tan, Kathryn C.B.

AU - Hveem, Kristian

AU - Cheung, Bernard M.Y.

AU - Zöllner, Sebastian

AU - Xu, Aimin

AU - Chen, Y. Eugene

AU - Jiang, Chao Qiang

AU - Zhang, Youyi

AU - Lam, Tai Hing

AU - Ganesh, Santhi K.

AU - Huo, Yong

AU - Sham, Pak C.

AU - Lam, Karen S.L.

AU - Willer, Cristen J.

AU - Tse, Hung Fat

AU - Gao, Wei

N1 - Funding Information: This work was supported by the Hong Kong Research Grant Council: Theme Based Research Scheme (T12-705/11), General Research Fund (777511M, 776412M, 776513M and 17128515) and Innovation and Technology Support Programme (Tier 3) (ITS/303/ 12). We thank Joyce MS Fung, KH Lee and TK Leung for their technical support. The PUUMA-MI project is a collaboration between Peking University Health Science Center and The University of Michigan Medical School. Funding for the project was provided by the University of Michigan Medical School and the Peking University Health Sciences Center Joint Institute for Clinical and Translational Research (Principal Investigators: C.J.W. and W.G.). We thank the volunteer study participants for their contribution to research. We also thank the University of Michigan leadership of the Joint Institute for facilitating this research, particularly David Pinsky, Amy Huang and Joseph Kolars. C.J.W. is additionally supported by HL094535 and HL109946.

PY - 2015/12/22

Y1 - 2015/12/22

N2 - Blood lipids are important risk factors for coronary artery disease (CAD). Here we perform an exome-wide association study by genotyping 12,685 Chinese, using a custom Illumina HumanExome BeadChip, to identify additional loci influencing lipid levels. Single-variant association analysis on 65,671 single nucleotide polymorphisms reveals 19 loci associated with lipids at exome-wide significance (P<2.69 × 10-7), including three Asian-specific coding variants in known genes (CETP p.Asp459Gly, PCSK9 p.Arg93Cys and LDLR p.Arg257Trp). Furthermore, missense variants at two novel loci - PNPLA3 p.Ile148Met and PKD1L3 p.Thr429Ser - also influence levels of triglycerides and low-density lipoprotein cholesterol, respectively. Another novel gene, TEAD2, is found to be associated with high-density lipoprotein cholesterol through gene-based association analysis. Most of these newly identified coding variants show suggestive association (P<0.05) with CAD. These findings demonstrate that exome-wide genotyping on samples of non-European ancestry can identify additional population-specific possible causal variants, shedding light on novel lipid biology and CAD.

AB - Blood lipids are important risk factors for coronary artery disease (CAD). Here we perform an exome-wide association study by genotyping 12,685 Chinese, using a custom Illumina HumanExome BeadChip, to identify additional loci influencing lipid levels. Single-variant association analysis on 65,671 single nucleotide polymorphisms reveals 19 loci associated with lipids at exome-wide significance (P<2.69 × 10-7), including three Asian-specific coding variants in known genes (CETP p.Asp459Gly, PCSK9 p.Arg93Cys and LDLR p.Arg257Trp). Furthermore, missense variants at two novel loci - PNPLA3 p.Ile148Met and PKD1L3 p.Thr429Ser - also influence levels of triglycerides and low-density lipoprotein cholesterol, respectively. Another novel gene, TEAD2, is found to be associated with high-density lipoprotein cholesterol through gene-based association analysis. Most of these newly identified coding variants show suggestive association (P<0.05) with CAD. These findings demonstrate that exome-wide genotyping on samples of non-European ancestry can identify additional population-specific possible causal variants, shedding light on novel lipid biology and CAD.

UR - http://www.scopus.com/inward/record.url?scp=84951334880&partnerID=8YFLogxK

U2 - 10.1038/ncomms10206

DO - 10.1038/ncomms10206

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AN - SCOPUS:84951334880

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 10206

ER -

Exome-wide association analysis reveals novel coding sequence variants associated with lipid traits in Chinese

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