Dataset Information

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.

SUBMITTER: Lu X

PROVIDER: S-EPMC5899829 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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

Lu Xiangfeng X Peloso Gina M GM Liu Dajiang J DJ Wu Ying Y Zhang He H Zhou Wei W Li Jun J Tang Clara Sze-Man CS Dorajoo Rajkumar R Li Huaixing H Long Jirong J Guo Xiuqing X Xu Ming M Spracklen Cassandra N CN Chen Yang Y Liu Xuezhen X Zhang Yan Y Khor Chiea Chuen CC Liu Jianjun J Sun Liang L Wang Laiyuan L Gao Yu-Tang YT Hu Yao Y Yu Kuai K Wang Yiqin Y Cheung Chloe Yu Yan CYY Wang Feijie F Huang Jianfeng J Fan Qiao Q Cai Qiuyin Q Chen Shufeng S Shi Jinxiu J Yang Xueli X Zhao Wanting W Sheu Wayne H-H WH Cherny Stacey Shawn SS He Meian M Feranil Alan B AB Adair Linda S LS Gordon-Larsen Penny P Du Shufa S Varma Rohit R Chen Yii-Der Ida YI Shu Xiao-Ou XO Lam Karen Siu Ling KSL Wong Tien Yin TY Ganesh Santhi K SK Mo Zengnan Z Hveem Kristian K Fritsche Lars G LG Nielsen Jonas Bille JB Tse Hung-Fat HF Huo Yong Y Cheng Ching-Yu CY Chen Y Eugene YE Zheng Wei W Tai E Shyong ES Gao Wei W Lin Xu X Huang Wei W Abecasis Goncalo G Kathiresan Sekar S Mohlke Karen L KL Wu Tangchun T Sham Pak Chung PC Gu Dongfeng D Willer Cristen J CJ

Nature genetics 20171030 12

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 As ...[more]

PMID: 29083407

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Project description:BACKGROUND:Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. OBJECTIVES:This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. METHODS:In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. RESULTS:We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10-4 with a range of other diseases/traits. CONCLUSIONS:We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.

Dataset Information

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

Publications

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

Similar Datasets

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