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. 2015 Dec 22:6:10206.
doi: 10.1038/ncomms10206.

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

Clara S Tang  1 , He Zhang  2 , Chloe Y Y Cheung  3 , Ming Xu  4 , Jenny C Y Ho  3 , Wei Zhou  2   5 , Stacey S Cherny  1   6   7 , Yan Zhang  8 , Oddgeir Holmen  9   10 , Ka-Wing Au  3 , Haiyi Yu  4 , Lin Xu  11 , Jia Jia  8 , Robert M Porsch  1 , Lijie Sun  4 , Weixian Xu  4 , Huiping Zheng  4 , Lai-Yung Wong  3 , Yiming Mu  12 , Jingtao Dou  12 , Carol H Y Fong  3 , Shuyu Wang  13 , Xueyu Hong  3 , Liguang Dong  14 , Yanhua Liao  14 , Jiansong Wang  14 , Levina S M Lam  6 , Xi Su  15 , Hua Yan  15 , Min-Lee Yang  2 , Jin Chen  2 , Chung-Wah Siu  3   16 , Gaoqiang Xie  17 , Yu-Cho Woo  3 , Yangfeng Wu  18 , Kathryn C B Tan  3   16 , Kristian Hveem  9 , Bernard M Y Cheung  3   16   19 , Sebastian Zöllner  20 , Aimin Xu  3   16   19   21 , Y Eugene Chen  2 , Chao Qiang Jiang  22 , Youyi Zhang  23 , Tai-Hing Lam  11 , Santhi K Ganesh  2   24 , Yong Huo  8 , Pak C Sham  1   6   7 , Karen S L Lam  3   16   19 , Cristen J Willer  2   5   24 , Hung-Fat Tse  3   16   25 , Wei Gao  26
Affiliations

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

Clara S Tang et al. Nat Commun. .

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.

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Figures

Figure 1
Figure 1. Regional plots of two newly discovered exome-wide significant associations.
(a) PKD1L3 rs7185272 with LDL-C and (b) PNPLA3 rs738409 with TG. SNPs are coloured on the basis of their pairwise LD values (r2) with the top SNP (purple), which has the smallest P value in the region. Pairwise LD and the fine-scale recombination rate (light blue line) were estimated based on 1000 Genomes project (March 2012) ASN genotypes. SNPs not present in the reference panel are coloured in grey. Genes are presented by blue lines with arrows indicating the direction of transcription and rectangles as exons in the bottom panel.
Figure 2
Figure 2. Comparison of effect sizes (β) between CAD and LDL-C (square) as well as TG (triangle) for protein-altering variants with independent association.
Five missense variants denoted in Table 3 are illustrated. Points are coloured by the significance of association with CAD. Pearson's correlation coefficient (r) and line of best fit are shown.
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