Abstract
Muscle weakness is a common consequence of both aging (sarcopenia) and neuromuscular disorders (NMD). Whilst genome-wide association (GWA) studies have identified genetic variants associated with grip strength (GS; measure of muscle strength/weakness) and NMDs, including multiple sclerosis (MS), myasthenia gravis (MG) and amyotrophic lateral sclerosis (ALS), it is not known whether there are common mechanisms between these phenotypes. To examine this, we have integrated GS and NMD associated genetic variants (single nucleotide polymorphisms; SNPs) in a multimorbid analysis that leverages high-throughput chromatin interaction (Hi-C) data and expression quantitative trait loci data to identify target genes (i.e., SNP-mediated gene regulation). Biological pathways enriched by these genes were then identified using next-generation pathway enrichment analysis. Lastly, druggable genes were identified using drug gene interaction (DGI) database. We identified gene regulatory mechanisms associated with GS, MG, MS, and ALS. The SNPs associated with GS regulate a subset of genes that are also regulated by the SNPs of MS, MG, and ALS. Yet, we did not find any genes commonly regulated by all four phenotype associated SNPs. By contrast, we identified significant enrichment in three pathways (mTOR signaling, axon guidance, and alcoholism) that are commonly affected by the gene regulatory mechanisms associated with all four phenotypes. 13% of the genes we identified were known drug targets, and GS shares at least one druggable gene and pathway with each of the NMD phenotypes. We have identified significant biological overlaps between GS and NMD, demonstrating the potential for spatial genetic analysis to identify common mechanisms between potential multimorbid phenotypes. Collectively, our results form the foundation for a shift from a gene to a pathway-based approach to the rationale design of therapeutic interventions and treatments for NMD.
Highlights
Age-associated changes in skeletal muscle structure and composition are influenced by various factors including genetics, physical inactivity, malnutrition, hormonal and environmental changes (Fried et al, 2001; Brook et al, 2016; Morley, 2017)
95% of the spatial eQTL-expression changes of the partner genes (eGenes) regulatory interactions identified across each phenotype occur between proximal rather than distal regions (Figure 1B and Supplementary Table 3)
This is the first report of shared biological mechanisms between genetic variants associated with the generalized age-associated decline of muscle strength and muscle weakness/wasting caused by neuromuscular disorders (i.e., myasthenia gravis (MG), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS))
Summary
Age-associated changes in skeletal muscle structure and composition are influenced by various factors including genetics, physical inactivity, malnutrition, hormonal and environmental changes (Fried et al, 2001; Brook et al, 2016; Morley, 2017). Weakness and wasting of the body due to severe chronic illness (cachexia) is a primary characteristic in a number of chronic neuromuscular diseases (NMD), including myasthenia gravis (MG), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) (Al-Chalabi and Hardiman, 2013; Manca et al, 2016; Vinge et al, 2019). For all of these diseases, the primary disease diagnosis is complicated by reduced physical function, reduced tolerance for therapy, increased burden on the healthcare system, and increased mortality that comes with cachexia (Arthur et al, 2014). Numerous mechanisms have been suggested to be involved in NMD-related muscle weakness, including mitochondrial dysfunction (Nardin and Johns, 2001), reduced numbers of motor units (Kaya et al, 2013), and functional deficits at the neuromuscular junction (NMJ) (van der Pijl et al, 2016)
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