Dataset Information

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.

SUBMITTER: Tang CS

PROVIDER: S-EPMC4703860 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Tang Clara S CS Zhang He H Cheung Chloe Y Y CY Xu Ming M Ho Jenny C Y JC Zhou Wei W Cherny Stacey S SS Zhang Yan Y Holmen Oddgeir O Au Ka-Wing KW Yu Haiyi H Xu Lin L Jia Jia J Porsch Robert M RM Sun Lijie L Xu Weixian W Zheng Huiping H Wong Lai-Yung LY Mu Yiming Y Dou Jingtao J Fong Carol H Y CH Wang Shuyu S Hong Xueyu X Dong Liguang L Liao Yanhua Y Wang Jiansong J Lam Levina S M LS Su Xi X Yan Hua H Yang Min-Lee ML Chen Jin J Siu Chung-Wah CW Xie Gaoqiang G Woo Yu-Cho YC Wu Yangfeng Y Tan Kathryn C B KC Hveem Kristian K Cheung Bernard M Y BM Zöllner Sebastian S Xu Aimin A Eugene Chen Y Y Jiang Chao Qiang CQ Zhang Youyi Y Lam Tai-Hing TH Ganesh Santhi K SK Huo Yong Y Sham Pak C PC Lam Karen S L KS Willer Cristen J CJ Tse Hung-Fat HF Gao Wei W

Nature communications 20151222

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, PCSK ...[more]

PMID: 26690388

Similar Datasets

Project description:Metabolite quantitative traits carry great promise for epidemiological studies, and their genetic background has been addressed using Genome-Wide Association Studies (GWAS). Thus far, the role of less common variants has not been exhaustively studied. Here, we set out a GWAS for metabolite quantitative traits in serum, followed by exome sequence analysis to zoom in on putative causal variants in the associated genes. 1H Nuclear Magnetic Resonance (1H-NMR) spectroscopy experiments yielded successful quantification of 42 unique metabolites in 2,482 individuals from The Erasmus Rucphen Family (ERF) study. Heritability of metabolites were estimated by SOLAR. GWAS was performed by linear mixed models, using HapMap imputations. Based on physical vicinity and pathway analyses, candidate genes were screened for coding region variation using exome sequence data. Heritability estimates for metabolites ranged between 10% and 52%. GWAS replicated three known loci in the metabolome wide significance: CPS1 with glycine (P-value = 1.27×10-32), PRODH with proline (P-value = 1.11×10-19), SLC16A9 with carnitine level (P-value = 4.81×10-14) and uncovered a novel association between DMGDH and dimethyl-glycine (P-value = 1.65×10-19) level. In addition, we found three novel, suggestively significant loci: TNP1 with pyruvate (P-value = 1.26×10-8), KCNJ16 with 3-hydroxybutyrate (P-value = 1.65×10-8) and 2p12 locus with valine (P-value = 3.49×10-8). Exome sequence analysis identified potentially causal coding and regulatory variants located in the genes CPS1, KCNJ2 and PRODH, and revealed allelic heterogeneity for CPS1 and PRODH. Combined GWAS and exome analyses of metabolites detected by high-resolution 1H-NMR is a robust approach to uncover metabolite quantitative trait loci (mQTL), and the likely causative variants in these loci. It is anticipated that insight in the genetics of intermediate phenotypes will provide additional insight into the genetics of complex traits.

Project description:Genome-wide association studies (GWASs) have identified loci contributing to total serum bilirubin level. However, no exome-wide approaches have been performed to address this question. Using exome-wide approach, we assessed the influence of protein-coding variants on unconjugated, conjugated, and total serum bilirubin levels in a well-characterized cohort of 773 ambulatory elderly subjects from Italy. Coding variants were replicated in 227 elderly subjects from the same area. We identified 4 missense rare (minor allele frequency, MAF?<?0.5%) and low-frequency (MAF, 0.5%-5%) coding variants located in the first exon of the UGT1A1 gene, which encodes for the substrate-binding domain (rs4148323 [MAF?=?0.06%; p.Gly71Arg], rs144398951 [MAF?=?0.06%; p.Ile215Val], rs35003977 [MAF?=?0.78%; p.Val225Gly], and rs57307513 [MAF?=?0.06%; p.Ser250Pro]). These variants were in strong linkage disequilibrium with 3 intronic UGT1A1 variants (rs887829, rs4148325, rs6742078), which were significantly associated with total bilirubin level (P?=?2.34?×?10(-34), P?=?7.02?×?10(-34), and P?=?8.27?×?10(-34)), as well as unconjugated, and conjugated bilirubin levels. We also identified UGT1A6 variants in association with total (rs6759892, p.Ser7Ala, P?=?1.98?×?10(-26); rs2070959, p.Thr181Ala, P?=?2.87?×?10(-27); and rs1105879, p.Arg184Ser, P?=?3.27?×?10(-29)), unconjugated, and conjugated bilirubin levels. All UGT1A1 intronic variants (rs887829, rs6742078, and rs4148325) and UGT1A6 coding variants (rs6759892, rs2070959, and rs1105879) were significantly associated with gallstone-related cholecystectomy risk. The UGT1A6 variant rs2070959 (p.Thr181Ala) was associated with the highest risk of gallstone-related cholecystectomy (OR, 4.58; 95% CI, 1.58-13.28; P?=?3.21?×?10(-3)). Using an exome-wide approach we identified coding variants on UGT1A1 and UGT1A6 genes in association with serum bilirubin level and hyperbilirubinemia risk in elderly subjects. UGT1A1 intronic single-nucleotide polymorphisms (SNPs) (rs6742078, rs887829, rs4148324) serve as proxy markers for the low-frequency and rare UGT1A1 variants, thereby providing mechanistic explanation to the relationship between UGT1A1 intronic SNPs and the UGT1A1 enzyme activity. UGT1A1 and UGT1A6 variants might be potentially associated with gallstone-related cholecystectomy risk.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets