Genetic evidence for the most common risk factors for chronic axonal polyneuropathy in the general population

Background and purpose: Chronic axonal polyneuropathy is a common disease, but the etiology remains only partially understood. Previous etiologic studies have identified clinical risk factors, but genetic evidence supporting causality between these factors and polyneuropathy are largely lacking. In this study, we investigate whether there is a genetic association of clinically established important risk factors (diabetes, body mass index [BMI], vitamin B12 levels, and alcohol intake) with chronic axonal polyneuropathy. Methods: This study was performed within the population-based Rotterdam Study and included 1565 participants (median age = 73.6 years, interquartile range = 64.6–78.8, 53.5% female), of whom 215 participants (13.7%) had polyneuropathy. Polygenic scores (PGSs) for diabetes, BMI, vitamin B12 levels, and alcohol intake were calculated at multiple significance thresholds based on published genome-wide association studies. Results: Higher PGSs of diabetes, BMI, and alcohol intake were associated with higher prevalence of chronic axonal polyneuropathy, whereas higher PGS of vitamin B12 levels was associated with lower prevalence of polyneuropathy. These effects were most pronounced for PGSs with lenient significance thresholds for diabetes and BMI (odds ratio [OR]_{diabetes, p < 1.0} = 1.21, 95% confidence interval [CI] = 1.05–1.39 and OR_{BMI, p < 1.0} = 1.21, 95% CI = 1.04–1.41) and for the strictest significance thresholds for vitamin B12 level and alcohol intake (OR _{vitamin B12, p < 5e-6} = 0.79, 95% CI = 0.68–0.92 and OR_{alcohol, p < 5e-8} = 1.17, 95% CI = 1.02–1.35). We did not find an association between different PGSs and sural sensory nerve action potential amplitude, nor between individual lead variants of PGS_p< 5e-8 and polyneuropathy. Conclusions: This study provides evidence for polygenic associations of diabetes, BMI, vitamin B12 level, and alcohol intake with chronic axonal polyneuropathy. This supports the hypothesis of causal associations between well-known clinical risk factors and polyneuropathy.