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

Noor E. Taams, Maria J. Knol, Rens Hanewinckel, Judith Drenthen, Hieab H.H. Adams, Pieter A. van Doorn, Mohammad Arfan Ikram*

*Corresponding author for this work

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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 ORBMI, 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 ORalcohol, 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 PGSp< 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.

Original languageEnglish
Pages (from-to)2066-2073
Number of pages8
JournalEuropean Journal of Neurology
Issue number7
Early online date5 Mar 2022
Publication statusPublished - Jul 2022

Bibliographical note

Funding Information:
P.A.v.D. and M.A.I. received a grant from Prinses Beatrix Spierfonds for neuromuscular diseases (W.OR17-10) to conduct this study. The funding source had no role in the study design, collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication.

Publisher Copyright:
© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.


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