Genome-wide enrichment of m6A-associated single-nucleotide polymorphisms in the lipid loci

N6-methyladenosine (m(6)A) plays critical roles in many fundamental biological processes and a variety of diseases. The aim of this study was to investigate the effect of m(6)A-SNPs on lipid levels. We examined the association of m(6)A-SNPs with lipid levels in a genome-wide association studies (GWAS) of 188,578 individuals. Furthermore, we performed expression quantitative trait loci and differential expression analyses to add additional information for the identified m(6)A-SNPs. We found 1,655 m(6)A-SNPs in the GWAS dataset. Among them, 395 (23.9%) were nominally (P < 0.05) associated with lipid levels, and 22 reached the genome-wide significance level (P < 5.0x 10(-8)). Using the fgwas method we found that SNPs, which influence high-density lipoprotein cholesterol (log2 enrichment of 3.35, 95% CI: (0.92, 4.48)) and TG (log enrichment of 3.22, 95% CI: (1.18, 4.44)), were enriched in m(6)A methylation. The high confidence (determined by miCLIP experiment) m(6)A-SNP rs6859 at the 3'-untranslated region of PVRL2 was associated with high-density lipoprotein cholesterol (P=1.21 x 10(-15)), low-density lipoprotein cholesterol (P=1.77 x 10(-106)), total cholesterol (P=4.82 x 10(-82)), and triglycerides (P=8.10 x 10(-5)) levels, coronary artery disease (P=0.01), as well as PVRL2 mRNA expression in artery tibial (P=2.38 x 10(-6)) and whole blood (P=5.59 x 10(-19)). Moreover, PVRL2 was differentially expressed in adipose tissue of familial combined hyperlipidemia (P=9.27 x 10(-4)). The present study found plenty of lipid-associated m(6)A-SNPs and demonstrated that m(6)A-SNPs may play important roles in lipid metabolisms. Further studies were needed to elucidate the mechanisms.