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Background:  Genome-wide association studies (GWASs) have consistently identified  MAP2K5  as an obesity susceptibility gene. To deepen our understanding of the potential causal genetic variants of this region, a fine-mapping study of  MAP2K5  was conducted.   Methods  and  Results:  SNPs rs7175517 (G &amp;gt; A) and rs4776970 (T &amp;gt; A) were identified as the leading SNPs associated with BMI in both Chinese and the United Kingdom populations. Second, colocalization of GWAS and expression quantitative trait loci (eQTL) analyses and bioinformatic analyses indicated that rs7175517 is the functionally leading variant in the  MAP2K5  gene region. Dual-luciferase assays indicated that the G allele of rs7175517 reduced the mRNA expression of  MAP2K5  in HEK293T cells. The possible mechanism was that the G allele 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 adiposity deposition.   Conclusion:  SNP rs7175517 of the  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 adipogenesis.

Fine Mapping of the MAP2K5 Region Identified rs7175517 as a Causal Variant Related to BMI in China and the United Kingdom Populations