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

N6-methyladenosine (m⁶A) plays critical roles in many fundamental biological processes and a variety of diseases. The aim of this study was to investigate the effect of m⁶A-SNPs on lipid levels. We examined the association of m⁶A-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 m⁶A-SNPs. We found 1,655 m⁶A-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 < 5.0 × 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 m⁶A methylation. The high confidence (determined by miCLIP experiment) m⁶A-SNP rs6859 at the 3'-untranslated region of PVRL2 was associated with high-density lipoprotein cholesterol (P = 1.21 × 10^-15), low-density lipoprotein cholesterol (P = 1.77 × 10^-106), total cholesterol (P = 4.82 × 10^-82), and triglycerides (P = 8.10 × 10^-5) levels, coronary artery disease (P = 0.01), as well as PVRL2 mRNA expression in artery tibial (P = 2.38 × 10^-6) and whole blood (P = 5.59 × 10^-19). Moreover, PVRL2 was differentially expressed in adipose tissue of familial combined hyperlipidemia (P = 9.27 × 10^-4). The present study found plenty of lipid-associated m⁶A-SNPs and demonstrated that m⁶A-SNPs may play important roles in lipid metabolisms. Further studies were needed to elucidate the mechanisms.