Exome chip meta-analysis identifies novel loci and East Asian-specific coding variants that contribute to lipid levels and coronary artery disease

Xiangfeng Lu, Gina M. Peloso, Dajiang J. Liu, Ying Wu, He Zhang, Wei Zhou, Jun Li, Clara Sze Man Tang, Rajkumar Dorajoo, Huaixing Li, Jirong Long, Xiuqing Guo, Ming Xu, Cassandra N. Spracklen, Yang Chen, Xuezhen Liu, Yan Zhang, Chiea Chuen Khor, Jianjun Liu, Liang SunLaiyuan Wang, Yu Tang Gao, Yao Hu, Kuai Yu, Yiqin Wang, Chloe Yu Yan Cheung, Feijie Wang, Jianfeng Huang, Qiao Fan, Qiuyin Cai, Shufeng Chen, Jinxiu Shi, Xueli Yang, Wanting Zhao, Wayne H.H. Sheu, Stacey Shawn Cherny, Meian He, Alan B. Feranil, Linda S. Adair, Penny Gordon-Larsen, Shufa Du, Rohit Varma, Yii Der Ida Chen, Xiao Ou Shu, Karen Siu Ling Lam, Tien Yin Wong, Santhi K. Ganesh, Zengnan Mo, Kristian Hveem, Lars G. Fritsche, Jonas Bille Nielsen, Hung Fat Tse, Yong Huo, Ching Yu Cheng, Y. Eugene Chen, Wei Zheng, E. Shyong Tai, Wei Gao, Xu Lin, Wei Huang, Goncalo Abecasis, Sekar Kathiresan, Karen L. Mohlke, Tangchun Wu, Pak Chung Sham, Dongfeng Gu, Cristen J. Willer

Research output: Contribution to journalArticle

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Abstract

Most genome-wide association studies have been of European individuals, even though most genetic variation in humans is seen only in non-European samples. To search for novel loci associated with blood lipid levels and clarify the mechanism of action at previously identified lipid loci, we used an exome array to examine protein-coding genetic variants in 47,532 East Asian individuals. We identified 255 variants at 41 loci that reached chip-wide significance, including 3 novel loci and 14 East Asian-specific coding variant associations. After a meta-analysis including >300,000 European samples, we identified an additional nine novel loci. Sixteen genes were identified by protein-altering variants in both East Asians and Europeans, and thus are likely to be functional genes. Our data demonstrate that most of the low-frequency or rare coding variants associated with lipids are population specific, and that examining genomic data across diverse ancestries may facilitate the identification of functional genes at associated loci.

Original languageEnglish (US)
Pages (from-to)1722-1730
Number of pages9
JournalNature Genetics
Volume49
Issue number12
DOIs
StatePublished - Dec 1 2017

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Exome
Meta-Analysis
Coronary Artery Disease
Lipids
Genes
Genome-Wide Association Study
Proteins
Population

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Lu, Xiangfeng ; Peloso, Gina M. ; Liu, Dajiang J. ; Wu, Ying ; Zhang, He ; Zhou, Wei ; Li, Jun ; Tang, Clara Sze Man ; Dorajoo, Rajkumar ; Li, Huaixing ; Long, Jirong ; Guo, Xiuqing ; Xu, Ming ; Spracklen, Cassandra N. ; Chen, Yang ; Liu, Xuezhen ; Zhang, Yan ; Khor, Chiea Chuen ; Liu, Jianjun ; Sun, Liang ; Wang, Laiyuan ; Gao, Yu Tang ; Hu, Yao ; Yu, Kuai ; Wang, Yiqin ; Cheung, Chloe Yu Yan ; Wang, Feijie ; Huang, Jianfeng ; Fan, Qiao ; Cai, Qiuyin ; Chen, Shufeng ; Shi, Jinxiu ; Yang, Xueli ; Zhao, Wanting ; Sheu, Wayne H.H. ; Cherny, Stacey Shawn ; He, Meian ; Feranil, Alan B. ; Adair, Linda S. ; Gordon-Larsen, Penny ; Du, Shufa ; Varma, Rohit ; Chen, Yii Der Ida ; Shu, Xiao Ou ; Lam, Karen Siu Ling ; Wong, Tien Yin ; Ganesh, Santhi K. ; Mo, Zengnan ; Hveem, Kristian ; Fritsche, Lars G. ; Nielsen, Jonas Bille ; Tse, Hung Fat ; Huo, Yong ; Cheng, Ching Yu ; Chen, Y. Eugene ; Zheng, Wei ; Tai, E. Shyong ; Gao, Wei ; Lin, Xu ; Huang, Wei ; Abecasis, Goncalo ; Kathiresan, Sekar ; Mohlke, Karen L. ; Wu, Tangchun ; Sham, Pak Chung ; Gu, Dongfeng ; Willer, Cristen J. / Exome chip meta-analysis identifies novel loci and East Asian-specific coding variants that contribute to lipid levels and coronary artery disease. In: Nature Genetics. 2017 ; Vol. 49, No. 12. pp. 1722-1730.
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title = "Exome chip meta-analysis identifies novel loci and East Asian-specific coding variants that contribute to lipid levels and coronary artery disease",
abstract = "Most genome-wide association studies have been of European individuals, even though most genetic variation in humans is seen only in non-European samples. To search for novel loci associated with blood lipid levels and clarify the mechanism of action at previously identified lipid loci, we used an exome array to examine protein-coding genetic variants in 47,532 East Asian individuals. We identified 255 variants at 41 loci that reached chip-wide significance, including 3 novel loci and 14 East Asian-specific coding variant associations. After a meta-analysis including >300,000 European samples, we identified an additional nine novel loci. Sixteen genes were identified by protein-altering variants in both East Asians and Europeans, and thus are likely to be functional genes. Our data demonstrate that most of the low-frequency or rare coding variants associated with lipids are population specific, and that examining genomic data across diverse ancestries may facilitate the identification of functional genes at associated loci.",
author = "Xiangfeng Lu and Peloso, {Gina M.} and Liu, {Dajiang J.} and Ying Wu and He Zhang and Wei Zhou and Jun Li and Tang, {Clara Sze Man} and Rajkumar Dorajoo and Huaixing Li and Jirong Long and Xiuqing Guo and Ming Xu and Spracklen, {Cassandra N.} and Yang Chen and Xuezhen Liu and Yan Zhang and Khor, {Chiea Chuen} and Jianjun Liu and Liang Sun and Laiyuan Wang and Gao, {Yu Tang} and Yao Hu and Kuai Yu and Yiqin Wang and Cheung, {Chloe Yu Yan} and Feijie Wang and Jianfeng Huang and Qiao Fan and Qiuyin Cai and Shufeng Chen and Jinxiu Shi and Xueli Yang and Wanting Zhao and Sheu, {Wayne H.H.} and Cherny, {Stacey Shawn} and Meian He and Feranil, {Alan B.} and Adair, {Linda S.} and Penny Gordon-Larsen and Shufa Du and Rohit Varma and Chen, {Yii Der Ida} and Shu, {Xiao Ou} and Lam, {Karen Siu Ling} and Wong, {Tien Yin} and Ganesh, {Santhi K.} and Zengnan Mo and Kristian Hveem and Fritsche, {Lars G.} and Nielsen, {Jonas Bille} and Tse, {Hung Fat} and Yong Huo and Cheng, {Ching Yu} and Chen, {Y. Eugene} and Wei Zheng and Tai, {E. Shyong} and Wei Gao and Xu Lin and Wei Huang and Goncalo Abecasis and Sekar Kathiresan and Mohlke, {Karen L.} and Tangchun Wu and Sham, {Pak Chung} and Dongfeng Gu and Willer, {Cristen J.}",
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Lu, X, Peloso, GM, Liu, DJ, Wu, Y, Zhang, H, Zhou, W, Li, J, Tang, CSM, Dorajoo, R, Li, H, Long, J, Guo, X, Xu, M, Spracklen, CN, Chen, Y, Liu, X, Zhang, Y, Khor, CC, Liu, J, Sun, L, Wang, L, Gao, YT, Hu, Y, Yu, K, Wang, Y, Cheung, CYY, Wang, F, Huang, J, Fan, Q, Cai, Q, Chen, S, Shi, J, Yang, X, Zhao, W, Sheu, WHH, Cherny, SS, He, M, Feranil, AB, Adair, LS, Gordon-Larsen, P, Du, S, Varma, R, Chen, YDI, Shu, XO, Lam, KSL, Wong, TY, Ganesh, SK, Mo, Z, Hveem, K, Fritsche, LG, Nielsen, JB, Tse, HF, Huo, Y, Cheng, CY, Chen, YE, Zheng, W, Tai, ES, Gao, W, Lin, X, Huang, W, Abecasis, G, Kathiresan, S, Mohlke, KL, Wu, T, Sham, PC, Gu, D & Willer, CJ 2017, 'Exome chip meta-analysis identifies novel loci and East Asian-specific coding variants that contribute to lipid levels and coronary artery disease', Nature Genetics, vol. 49, no. 12, pp. 1722-1730. https://doi.org/10.1038/ng.3978

Exome chip meta-analysis identifies novel loci and East Asian-specific coding variants that contribute to lipid levels and coronary artery disease. / Lu, Xiangfeng; Peloso, Gina M.; Liu, Dajiang J.; Wu, Ying; Zhang, He; Zhou, Wei; Li, Jun; Tang, Clara Sze Man; Dorajoo, Rajkumar; Li, Huaixing; Long, Jirong; Guo, Xiuqing; Xu, Ming; Spracklen, Cassandra N.; Chen, Yang; Liu, Xuezhen; Zhang, Yan; Khor, Chiea Chuen; Liu, Jianjun; Sun, Liang; Wang, Laiyuan; Gao, Yu Tang; Hu, Yao; Yu, Kuai; Wang, Yiqin; Cheung, Chloe Yu Yan; Wang, Feijie; Huang, Jianfeng; Fan, Qiao; Cai, Qiuyin; Chen, Shufeng; Shi, Jinxiu; Yang, Xueli; Zhao, Wanting; Sheu, Wayne H.H.; Cherny, Stacey Shawn; He, Meian; Feranil, Alan B.; Adair, Linda S.; Gordon-Larsen, Penny; Du, Shufa; Varma, Rohit; Chen, Yii Der Ida; Shu, Xiao Ou; Lam, Karen Siu Ling; Wong, Tien Yin; Ganesh, Santhi K.; Mo, Zengnan; Hveem, Kristian; Fritsche, Lars G.; Nielsen, Jonas Bille; Tse, Hung Fat; Huo, Yong; Cheng, Ching Yu; Chen, Y. Eugene; Zheng, Wei; Tai, E. Shyong; Gao, Wei; Lin, Xu; Huang, Wei; Abecasis, Goncalo; Kathiresan, Sekar; Mohlke, Karen L.; Wu, Tangchun; Sham, Pak Chung; Gu, Dongfeng; Willer, Cristen J.

In: Nature Genetics, Vol. 49, No. 12, 01.12.2017, p. 1722-1730.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Exome chip meta-analysis identifies novel loci and East Asian-specific coding variants that contribute to lipid levels and coronary artery disease

AU - Lu, Xiangfeng

AU - Peloso, Gina M.

AU - Liu, Dajiang J.

AU - Wu, Ying

AU - Zhang, He

AU - Zhou, Wei

AU - Li, Jun

AU - Tang, Clara Sze Man

AU - Dorajoo, Rajkumar

AU - Li, Huaixing

AU - Long, Jirong

AU - Guo, Xiuqing

AU - Xu, Ming

AU - Spracklen, Cassandra N.

AU - Chen, Yang

AU - Liu, Xuezhen

AU - Zhang, Yan

AU - Khor, Chiea Chuen

AU - Liu, Jianjun

AU - Sun, Liang

AU - Wang, Laiyuan

AU - Gao, Yu Tang

AU - Hu, Yao

AU - Yu, Kuai

AU - Wang, Yiqin

AU - Cheung, Chloe Yu Yan

AU - Wang, Feijie

AU - Huang, Jianfeng

AU - Fan, Qiao

AU - Cai, Qiuyin

AU - Chen, Shufeng

AU - Shi, Jinxiu

AU - Yang, Xueli

AU - Zhao, Wanting

AU - Sheu, Wayne H.H.

AU - Cherny, Stacey Shawn

AU - He, Meian

AU - Feranil, Alan B.

AU - Adair, Linda S.

AU - Gordon-Larsen, Penny

AU - Du, Shufa

AU - Varma, Rohit

AU - Chen, Yii Der Ida

AU - Shu, Xiao Ou

AU - Lam, Karen Siu Ling

AU - Wong, Tien Yin

AU - Ganesh, Santhi K.

AU - Mo, Zengnan

AU - Hveem, Kristian

AU - Fritsche, Lars G.

AU - Nielsen, Jonas Bille

AU - Tse, Hung Fat

AU - Huo, Yong

AU - Cheng, Ching Yu

AU - Chen, Y. Eugene

AU - Zheng, Wei

AU - Tai, E. Shyong

AU - Gao, Wei

AU - Lin, Xu

AU - Huang, Wei

AU - Abecasis, Goncalo

AU - Kathiresan, Sekar

AU - Mohlke, Karen L.

AU - Wu, Tangchun

AU - Sham, Pak Chung

AU - Gu, Dongfeng

AU - Willer, Cristen J.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Most genome-wide association studies have been of European individuals, even though most genetic variation in humans is seen only in non-European samples. To search for novel loci associated with blood lipid levels and clarify the mechanism of action at previously identified lipid loci, we used an exome array to examine protein-coding genetic variants in 47,532 East Asian individuals. We identified 255 variants at 41 loci that reached chip-wide significance, including 3 novel loci and 14 East Asian-specific coding variant associations. After a meta-analysis including >300,000 European samples, we identified an additional nine novel loci. Sixteen genes were identified by protein-altering variants in both East Asians and Europeans, and thus are likely to be functional genes. Our data demonstrate that most of the low-frequency or rare coding variants associated with lipids are population specific, and that examining genomic data across diverse ancestries may facilitate the identification of functional genes at associated loci.

AB - Most genome-wide association studies have been of European individuals, even though most genetic variation in humans is seen only in non-European samples. To search for novel loci associated with blood lipid levels and clarify the mechanism of action at previously identified lipid loci, we used an exome array to examine protein-coding genetic variants in 47,532 East Asian individuals. We identified 255 variants at 41 loci that reached chip-wide significance, including 3 novel loci and 14 East Asian-specific coding variant associations. After a meta-analysis including >300,000 European samples, we identified an additional nine novel loci. Sixteen genes were identified by protein-altering variants in both East Asians and Europeans, and thus are likely to be functional genes. Our data demonstrate that most of the low-frequency or rare coding variants associated with lipids are population specific, and that examining genomic data across diverse ancestries may facilitate the identification of functional genes at associated loci.

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