Large differences in adiponectin levels have no clear effect on multiple sclerosis risk: A Mendelian randomization study

Background: Mendelian randomization (MR) studies have demonstrated strong support for an association between genetically increased body mass index and risk of multiple sclerosis (MS). The adipokine adiponectin may be a potential mechanism linking body mass to risk of MS. Objective: To evaluate whether genetically increased adiponectin levels influence risk of MS. Methods: Using genome-wide significant single nucleotide polymorphisms (SNPs) for adiponectin, we undertook an MR study to estimate the effect of adiponectin on MS. This method prevents bias due to reverse causation and minimizes bias due to confounding. Sensitivity analyses were performed to evaluate the assumptions of MR. Results: MR analyses did not support a role for genetically elevated adiponectin in risk of MS (odds ratio (OR)=0.93 per unit increase in natural-log-transformed adiponectin, equivalent to a two-standard deviation increase in adiponectin on the absolute scale; 95% confidence interval (CI)=0.66-1.33; p=0.61). Further MR analysis suggested that genetic variation at the adiponectin gene, which influences adiponectin level, does not impact MS risk. Sensitivity analyses, including MR-Egger regression, suggested no bias due to pleiotropy. Conclusion: Lifelong genetically increased adiponectin levels in humans have no clear effect on risk of MS. Other biological factors driving the association between body mass and MS should be investigated.