RNA modification-related variants in genomic loci associated with body mass index

Genome-wide association studies (GWASs) have identified hundreds of loci for body mass index (BMI), but functional variants in these loci are less known. The purpose of this study was to identify RNA modification-related SNPs (RNAm-SNPs) for BMI in GWAS loci. BMI-associated RNAm-SNPs were identified in a GWAS of approximately 700,000 individuals. Gene expression and circulating protein levels affected by the RNAm-SNPs were identified by QTL analyses. Mendelian randomization (MR) methods were applied to test whether the gene expression and protein levels were associated with BMI.

A total of 78 RNAm-SNPs associated with BMI (P < 5.0 × 10^-8) were identified, including 65 m⁶A-, 10 m¹A-, 3 m⁷G- and 1 A-to-I-related SNPs. Two functional loss, high confidence level m⁶A-SNPs, rs6713978 (P = 6.4 × 10^-60) and rs13410999 (P = 8.2 × 10^-59), in the intron of ADCY3 were the top significant SNPs. These two RNAm-SNPs were associated with ADCY3 gene expression in adipose tissues, whole blood cells, the tibial nerve, the tibial artery and lymphocytes, and the expression levels in these tissues were associated with BMI. Proteins enriched in specific KEGG pathways, such as natural killer cell-mediated cytotoxicity, the Rap1 signaling pathway and the Ras signaling pathway, were affected by the RNAm-SNPs, and circulating levels of some of these proteins (ADH1B, DOCK9, MICB, PRDM1, STOM, TMPRSS11D and TXNDC12) were associated with BMI in MR analyses.

Our study identified RNAm-SNPs in BMI-related genomic loci and suggested that RNA modification may affect BMI by affecting the expression levels of corresponding genes and proteins.