Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels

Abstract

Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P < 5 × 10-8) three novel loci associated with HDL-C near CD163-APOBEC1 (P = 7.4 × 10-9), NCOA2 (P = 1.6 × 10-8), and NID2-PTGDR (P = 4.2 × 10-8), and one novel locus associated with TG near WDR11-FGFR2 (P = 2.7 × 10-10). Conditional analyses identified a second signal near CD163-APOBEC1. We then combined results from the East Asian meta-analysis with association results from up to 187,365 European individuals from the Global Lipids Genetics Consortium in a trans-ancestry meta-analysis. This analysis identified (log10Bayes Factor ≥6.1) eight additional novel lipid loci. Among the twelve total loci identified, the index variants at eight loci have demonstrated at least nominal significance with other metabolic traits in prior studies, and two loci exhibited coincident eQTLs (P < 1 × 10-5) in subcutaneous adipose tissue for BPTF and PDGFC. Taken together, these analyses identified multiple novel lipid loci, providing new potential therapeutic targets.

Figure 1

Regional association plots of the four loci identified from East Asian meta-analysis. (A) WDR11-FGFR2, (B) NID2-PTGDR, (C) CD163-APOBEC1, (D) NCOA2. –log₁₀ (P-values) are plotted against the hg19 genomic coordinates at each locus. The purple circle represents the lead variant, which exhibited the strongest evidence of association at the locus among HapMap-imputed variants. Variants are colored based on 1000 Genomes Project Phase 3 East Asian LD with the lead variant. Results shown in A,B, and D are from Phase 1 of the East Asian meta-analysis, while C is from Phase 2 of the East Asian meta-analysis. Stage 1 indicates the Phase 1 discovery stage results, 1 + 2 indicates the results after the in silico stage, and 1 + 2 + 3 indicates the results after the de novo genotyping stage.

Figure 2

HDL-C locus CD163-APOBEC1 exhibits two signals. (A) The two signals, rs10743940 and rs1419980, identified in Phase 2 of the East Asian meta-analysis, shown with the log₁₀BF on the y-axis. (B) log₁₀BF results from the GLGC European data showing the variant associations at the locus. (C) Trans-ancestry meta-analysis. Variants are colored based on LD with the lead variants, rs10743940 (red) and rs1419980 (blue) based on 1000 Genomes Project Phase 3 East Asian (A) and European (B and C) LD. (D) Fixed effect association results at two lead variants (rs10743940 and rs1419980) in East Asians and Europeans. P_initial is the P value result from the unconditioned analysis. P_conditional is the joint conditional P value for each variant after conditioning on the other variant. (E) Haplotypes of rs10743940 and rs1419980 in the China Health and Nutrition Survey data. Alleles associated with lower HDL-C are shown in purple while alleles associated with higher HDL-C are shown in green. Haplotype association was performed with HDL-C inverse normalized residuals after adjusting for age, age², sex, and BMI from the China Health and Nutrition Survey study using the most frequent haplotype as the reference.