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

The Pharmacogenomics Journal volume 19, pages 347–357 (2019)Cite this article

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Abstract

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.

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Acknowledgements

The study was supported by Natural Science Foundation of China (81773508), the Key Research Project (Social Development Plan) of Jiangsu Province (BE2016667), the Startup Fund from Soochow University (Q413900313, Q413900412), Project funded by China Postdoctoral Science Foundation (2013M530269 and 2014M551649, 2014T70547), and a Project of the Priority Academic Program Development of Jiangsu Higher Education Institutions.

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  1. Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, 199 Renai Road, Suzhou, Jiangsu, 215123, P. R. China

    Xingbo Mo, Shufeng Lei, Yonghong Zhang & Huan Zhang

  2. Center for Genetic Epidemiology and Genomics, School of Public Health, Soochow University, 199 Renai Road, Suzhou, Jiangsu, 215123, P. R. China

    Xingbo Mo & Shufeng Lei

  3. Department of Epidemiology, School of Public Health, Soochow University, 199 Renai Road, Suzhou, Jiangsu, 215123, P. R. China

    Xingbo Mo, Shufeng Lei, Yonghong Zhang & Huan Zhang

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Correspondence to Huan Zhang.

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Mo, X., Lei, S., Zhang, Y. et al. Genome-wide enrichment of m6A-associated single-nucleotide polymorphisms in the lipid loci. Pharmacogenomics J 19, 347–357 (2019). https://doi.org/10.1038/s41397-018-0055-z

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