A genome wide association study identifies common variants associated with lipid levels in the Chinese population

Abstract

Plasma lipid levels are important risk factors for cardiovascular disease and are influenced by genetic and environmental factors. Recent genome wide association studies (GWAS) have identified several lipid-associated loci, but these loci have been identified primarily in European populations. In order to identify genetic markers for lipid levels in a Chinese population and analyze the heterogeneity between Europeans and Asians, especially Chinese, we performed a meta-analysis of two genome wide association studies on four common lipid traits including total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL) and high-density lipoprotein cholesterol (HDL) in a Han Chinese population totaling 3,451 healthy subjects. Replication was performed in an additional 8,830 subjects of Han Chinese ethnicity. We replicated eight loci associated with lipid levels previously reported in a European population. The loci genome wide significantly associated with TC were near DOCK7, HMGCR and ABO; those genome wide significantly associated with TG were near APOA1/C3/A4/A5 and LPL; those genome wide significantly associated with LDL were near HMGCR, ABO and TOMM40; and those genome wide significantly associated with HDL were near LPL, LIPC and CETP. In addition, an additive genotype score of eight SNPs representing the eight loci that were found to be associated with lipid levels was associated with higher TC, TG and LDL levels (P = 5.52 × 10(-16), 1.38 × 10(-6) and 5.59 × 10(-9), respectively). These findings suggest the cumulative effects of multiple genetic loci on plasma lipid levels. Comparisons with previous GWAS of lipids highlight heterogeneity in allele frequency and in effect size for some loci between Chinese and European populations. The results from our GWAS provided comprehensive and convincing evidence of the genetic determinants of plasma lipid levels in a Chinese population.

Figure 1. Manhattan plots of a GWAS meta-analysis of lipid levels in a total of 3,451 subjects in a Chinese population.

The horizontal axis shows the chromosomal positions; the vertical axis shows –log₁₀ P values from the linear regression. The red horizontal line represents the significance level of 5.0×10^-8. The genes that are genome wide significant in the combined analysis are indicated with its gene names in this figure.

Figure 2. Genotype score of top SNPs with TC, TG, LDL, HDL levels.

The genotype score represents the number of risk alleles (the alleles associated with higher TC or TG or LDL or lower HDL) at each of eight SNPs. The eight SNPs were rs11207995 (DOCK7), rs10045497 (HMGCR), rs507666 (ABO), rs328 (LPL), rs651821 (APOA1/C3/A4/A5), rs1160985 (TOMM40), rs2043085 (LIPC) and rs3764261 (CETP). The height of the bars is the mean values of individuals with a specific genotype score. The error bars are Means ± SD of lipid levels in each group.