Disentangling the Genetics of Sarcopenia: prioritization of NUDT3 and KLF5 as genes for lean mass and HLA-DQB1-AS1 for hand grip strength based on associated SNPs

Abstract

Background: Sarcopenia is a skeletal muscle disease of clinical importance that occurs commonly in old age and in various disease sub-categories. Widening the scope of knowledge of the genetics of muscle mass and strength is important because may allows us to identify new genetic markers or identify patients with an increased risk to develop a specific musculoskeletal diseases or condition such as sarcopenia. It might also allow us to identify drugs that affect muscle in ways unknown before and therefore to reposition drugs to other uses, in accordance to their newly found target. We used bioinformatics tools to identify gene loci responsible for regulating muscle strength and lean muscle mass, which can then be a target for downstream lab experimentation validation. SNPs associated with various disease traits for the muscles and specific loci were chosen according to their muscle phenotype association p-value, as traditionally done in the GWASs. We developed and applied a combination of expression quantitative trait loci study (eQTLs) and GWAS summary information, to prioritize causative SNP and point out the unique genes associated in the tissues of interest (muscle).Results: We found NUDT3 and KLF5 for lean mass and HLA-DQB1-AS1 for hand grip strength as candidate genes to target for these phenotypes. The associated regulatory SNPs are rs464553, rs1028883 and rs3129753 respectively.Conclusion: TWAS approaches of combining GWAS and eQTL summary statistics proved helpful in statistically prioritizing genes and their associated SNPs for the disease phenotype of study, here, Sarcopenia. Potentially regulatory SNPs associated with these genes can be analyzed with respect to TADs and then targeted for knock out in either C2C12 mouse myoblast cells, adipocytes or any other relevant cell, depending on the phenotype it is hypothesized to affect, as a downstream experimental validation plan.