Muscular dystrophies (MDs) are inherited neuromuscular disorders characterized by progressive muscle degeneration. Although their genetic causes are well known, the contribution of autoimmune diseases to MD risk remains unclear. To address this gap, we performed a bidirectional two-sample Mendelian randomization (2SMR) analysis to investigate the potential causal relationship between genetic liability to 21 autoimmune diseases and MD. Genome-wide significant single-nucleotide polymorphisms (p < 5 × 10−8) were used as instrumental variables. The primary analysis employed inverse-variance weighting, complemented by MR-Egger, weighted median, and weighted mode methods, alongside extensive sensitivity analyses. Our results indicate that five autoimmune conditions demonstrated statistically significant associations with MD. Genetic liability to ankylosing spondylitis (odds ratio [OR] = 0.86, 95% confidence interval [CI]: 0.78–0.95, p = 1.91 × 10−3), multiple sclerosis (OR = 0.55, 0.38–0.79, p = 1.36 × 10−3), ulcerative colitis (OR = 0.57, 0.42–0.77, p = 2.54 × 10−4), and rheumatoid arthritis (RA) (OR = 0.65, 95% CI: 0.51–0.86, p = 7.01 × 10−4) was associated with a lower risk of MD, whereas genetic liability to asthma showed a positive association with MD risk (OR = 2.18, 95% CI: 1.18–4.00, p = 1.17 × 10−3). Per-disease Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses further supported these findings by revealing condition-specific enrichment in immune-related pathways, with the strongest signals observed for RA and asthma through shared HLA class II-driven Th17 and Th1/Th2 differentiation pathways. These findings should be interpreted cautiously given that the MD outcome of genome-wide association study comprised 242 cases and represents a composite phenotype encompassing multiple genetically distinct subtypes. This study provides novel genetic evidence that genetic liability to specific autoimmune diseases is differentially associated with MD risk, highlighting immune-related pathways that may contribute to neuromuscular pathobiology.
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