Evidence of symptom specificity for depression in multiple sclerosis: A two sample Mendelian randomization study

Background: Depression is common and phenotypically heterogenous in multiple sclerosis (MS). MS may increase risk of some but not all affective symptoms or certain symptoms may predispose individuals to higher MS risk. Objective: To assess the existence and direction of causality between distinct depressive symptoms and MS using two-sample Mendelian randomization (MR). Methods: Using summary data from genome-wide association studies, we selected genetic instrument variables (IV) for MS (n = 115,776) and IVs for depressive symptoms (average n = 117,713): anhedonia, altered appetite, concentration, depressed mood, fatigue, inadequacy, psychomotor changes, sleeping problems and suicidality. We performed two-sample MR in either direction using inverse-variance models. Sensitivity analyses included weighted-median and MR-Egger regression. Obesity is a known risk factor for MS and depression; we adjusted for body mass index in multivariable-MR. Results: Genetic liability to MS was associated with anhedonia (IVW estimate per 10²: 0.69; 95 % CI: 0.24–1.13; p = 0.002), concentration difficulty (0.66; 0.19–1.13; p = 0.006) and psychomotor changes (0.37; 0.08–0.65; p = 0.01). Results were similar in sensitivity analyses. In the opposite direction, we found no evidence of a causal relationship for any affective symptom on MS risk. Conclusions: Genetic susceptibility to MS was associated with anhedonia, concentration, and psychomotor-related symptoms, suggesting a specific phenotype of depression in MS.