Shared regulatory pathways reveal novel genetic correlations between grip strength and neuromuscular disorders

Published on (GMT) by Sreemol Gokuladhas
Muscle weakness and muscle wasting can be a consequence of aging or neuromuscular disorders (NMD). Genome-wide association (GWA) studies have identified genetic variants associated with grip strength (GS, an inverse measure of muscle weakness) and NMD (multiple sclerosis (MS), myasthenia gravis (MG) and amyotrophic lateral sclerosis (ALS)). However, how these variants contribute to the muscle weakness caused by aging and NMD remains obscure. We analyzed these variants using high-throughput chromatin interaction (Hi-C) data and expression quantitative trait loci (eQTL) data to identify genes (i.e. eGenes) that they physically regulate. Pathways that are enriched by colocalized eGenes were then identified using pathway enrichment analysis. We identified gene regulatory mechanisms (eQTL-eGene effects) associated with GS, MG, MS, and ALS. The eQTLs associated with GS regulate a subset of eGenes that are also regulated by the eQTLs of MS, MG, and ALS. Yet, we did not find any eGenes commonly regulated by all four phenotypes associated eQTLs. By contrast, we identified three pathways (mTOR signaling, axon guidance, and alcoholism) that are commonly affected by the gene regulatory mechanisms of all four phenotypes. Collectively, these findings identify significant biological overlaps between GS and NMD, demonstrating the potential for spatial genetic analysis to identify mechanisms underlying muscle wasting due to normal aging and NMD.
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