Biological, clinical and population relevance of 95 loci for blood lipids

Abstract

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

Figure 1. Meta-analysis of plasma lipid concentrations in >100,000 individuals of European descent

The gene name listed in “Locus” column is either a plausible biological candidate gene in the locus or the nearest annotated gene to the lead SNP. Listed in “Lead Trait” column is the lipid trait with best P-value among all four traits. Listed in “Other Traits” are additional lipid traits with P < 5 × 10^-8. Listed in “Alleles/MAF” column are: major allele, minor allele, and minor allele frequency (MAF) within the combined cohorts included in this meta-analysis (alleles designated with respect to the “+” strand; Supplementary Table 2). Numbers in “Effect Size” column are in mg/dL for the lead trait, modeled as an additive effect of the minor allele. P-values are listed for the lead traits. In the “eQTL” column, “Y” indicates that lead SNP has an eQTL with at least one gene within 500 kb with P < 5 × 10^-8 in at least one the three tissues tested (liver, omental fat, subcutaneous fat). In the “CAD” column, “Y” indicates that the lead SNP meets the pre-specified statistical significance threshold of P < 0.001 for association with CAD and being concordant between the direction of lipid effect and the change in CAD risk. In the “Ethnic” column, “+” indicates concordant effect on lead trait of the variant between the primary meta-analysis cohort and the European or non-European group, “−” indicates discordant effect on lead trait, and “?” indicates data not available for the group; in order, the ethnic groups are European, East Asian, South Asian, and African American (Supplementary Table 11).

Figure 2. Effects of altered Galnt2, Ppp1r3b, or Ttc39b expression in mouse liver on plasma lipid levels

a, b, Overexpression and knockdown of Galnt2. Shown are plasma HDL-C levels at baseline, 2 weeks, or 4 weeks after injection of viral vectors. n = 6 mice per group. c, Overexpression of Ppp1r3b. Shown are plasma HDL-C levels at baseline, 2 weeks, or 4 weeks after injection of viral vectors. n = 7 mice per group. d, Knockdown of Ttc39b. Shown are plasma HDL-C levels at baseline, 4 days, or 7 days after injection of viral vectors. n = 6 mice per group. Error bars show standard deviations. Because independent experiments were performed at different times and/or sites, there is variability in baseline HDL-C levels.