Fine Mapping the MAP2K5 Region Identified rs7175517 As a Causal Variant Associated With BMI in China And The UK Populations

Background: Genome-wide association studies (GWASs) have consistently identified MAP2K5 as the obesity susceptible gene. To deepen our understanding of the potential causal genetic variants of this region, a fine-mapping study of MAP2K5 was conducted. Results: First, a target single nucleotide polymorphisms (SNPs) sequencing of MAP2K5 was carried out in 2030 Chinese children and followed by a fine mapping with the UK biobank GWAS data in 264,838 adults to identify the leading SNPs within the MAP2K5 gene region. SNP rs7175517 (G>A) and rs4776970(T>A) were identified as the leading SNPs associated with BMI in both Chinese and the UK population. Second, colocalization of GWAS and expression quantitative trait loci (eQTL) analyses and bioinformatic functional annotations indicated that rs7175517 is the leading variants in MAP2K5 gene region functionally. Additionally, dual luciferase assay indicated that the G allele of rs7175517 reduced the mRNA expression of MAP2K5 in HEK293T cells. The possible mechanism was that the G allele of rs7175517 interacted with more RNA repressors from nuclei extracts, which was evidenced by electrophoretic mobility shift assays (EMSAs). Furthermore, the pathway enrichment analyses of the products from DNA pull-down and protein mass spectrometry demonstrated that the G allele of rs7175517 might interact with RNA catabolic or splicing transcription factors, which consequentially increased the adiposity deposition. Conclusions: SNP rs7175517 of MAP2K5 gene was the putative causal variant associated with BMI. More precisely designed in vitro or animal experiments are warranted to further delineate the function of MAP2K5 in the adipogenesis.