Abstract
Genome-wide association studies have identified many susceptible loci to explore the genetic factors of adiposity. However, the specific mechanisms by which these SNPs (single nucleotide polymorphism), particularly in the non-coding region, are involved in the pathogenesis of adiposity remain unclear. Recently, genetic variation is thought to affect N6-methyladenosine (m6A) RNA modification, which is the most common post-transcriptional messenger RNA modification. In this study, we identified a large number of BMI (body mass index)-associated m6A-SNPs from published GWAS summary statistics through a public database and explored their potential mechanisms involved in the pathogenesis of adiposity. In summary, the integrative analysis detected 20,993 BMI-associated m6A-SNPs and 230 m6A-SNPs which reached the genome-wide suggestive threshold (5.0E-05), while 215 of them showed eQTL signals and 167 are the corresponding genes. The leading SNP rs8024 (C/A) was located next to the m6A modification site of 3′UTR of the IPO9 gene, which was predicted to affect the m6A modification site and regulate the expression of the IPO9 gene to participate in the pathogenesis of adiposity. This m6A-SNP/gene expression/adiposity triplets provide a new annotation for the pathogenic mechanism of adiposity risk loci identified by GWAS.
Highlights
Adiposity is considered to be both an independent disease and a clear risk factor that is closely related to the occurrence and death risk of non-communicable chronic diseases such as hypertension, cardiovascular and cerebrovascular disease, diabetes, and specific types of cancer, which has become one of the main sources of the burden of preventability worldwide (Apovian, 2016)
29% of m6A-SNPs are distributed in 3 UTR, 5% of m6A-SNPs are distributed in 5 UTR, and a very small proportion of m6A-SNPs are distributed in the intron region (Supplementary Figure S3)
To further explore the potential functional mechanisms of the 230 m6A-SNPs associated with adiposity, we investigated whether they were related to local gene expression level
Summary
Adiposity is considered to be both an independent disease and a clear risk factor that is closely related to the occurrence and death risk of non-communicable chronic diseases such as hypertension, cardiovascular and cerebrovascular disease, diabetes, and specific types of cancer, which has become one of the main sources of the burden of preventability worldwide (Apovian, 2016). Genome-wide association studies (GWAS) have identified a large number of potential risk loci and susceptible genes for exploring genetic factors of adiposity (Speakman et al, 2018). FTO (fat mass and obesity associated gene) is the first gene associated with adiposity traits identified in the GWAS study (Frayling et al, 2007). Certain genetic variants of FTO gene appeared to be correlated with adiposity in human. Certain genetic variants of FTO gene appeared to be correlated with adiposity in human. Jia et al (2011) revealed that N6-methyladenosine in nuclear RNA is a major substrate of FTO
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