Mendelian randomization provides no evidence for a causal role in the bidirectional relationship between depression and multiple sclerosis

Abstract

Background: Major depressive disorder (MDD) is common in multiple sclerosis (MS) and its incidence rises before MS diagnosis. However, the causality and direction of this association remain unclear. Objective: The objective is to investigate the bidirectional relationship between MS and MDD using Mendelian randomization (MR). Methods: We selected genetic instruments associated with risk of MDD ( n = 660,937 cases; 1,453,489 controls) and MS ( n = 47,429 cases; 68,374 controls). Using two-sample MR, we examined putative causal effects in either direction, with sensitivity analyses to assess pleiotropy. Also, we adjusted for body mass index (BMI) in multivariable MR. Results: We found no effect of genetic liability to MDD on the odds of MS (OR = 1.07/doubling in odds, 95% CI = 0.90–1.28). Similarly, our findings did not support a causal effect of genetic liability to MS on MDD (OR = 1.00/doubling in odds, 95% CI = 0.99–1.01). Despite heterogeneity, sensitivity analyses indicated that bias from pleiotropy was unlikely. Conversely, genetic predisposition toward higher BMI increased the odds of MS (OR = 1.34/SD increase, 95% CI = 1.09–1.65) and MDD (OR = 1.08, 95% CI = 1.01–1.15). Conclusion: This study does not support a causal association between MDD genetic liability and MS susceptibility, and vice versa. Genetic evidence suggesting commonality of obesity to both conditions may partly explain the increased incidence of depression pre-MS diagnosis.

Depressive symptom trajectories and polygenic risk scores in individuals with an immune-mediated inflammatory disease

“…In addition, PRS for BMI was the only trait which remained statistically significant following the adjustment for additional potential confounders, such as age and sex. The link between BMI and depression in the general population is well-established, with a Mendelian randomization study suggesting that higher BMI partly causes depression [ 23 , 24 , 43 ]. Our stratified regression analysis further identified that the BMI PRS was significantly associated with the higher depressive symptom group in the IMID sample but was no longer significant in the non-IMID/psychiatric sample.…”

“…We performed complementary mediation analysis to test whether IMID mediates the association between BMI PRS and depressive symptoms trajectories. We expected that we would not observe mediation based on prior Mendelian randomization studies suggesting BMI is causally related to IMID and to MDD, but IMID is not causally associated to MDD [ 24 – 28 ] ( Fig. S2 ).…”

“…The relationship between MDD and the immune system is complex [ 22 ] and is further complicated by a risk factor common to both MDD [ 23 ] and IMID [ 24 – 26 ]: body mass index. Studies employing Mendelian randomization, a method used to examine causal effects of a modifiable exposure on an outcome, have shown BMI, but not MDD, play a causal role in determining the likelihood of developing two IMID: multiple sclerosis [ 24 ] and rheumatoid arthritis [ 27 ]. Other Mendelian randomization studies have shown both BMI [ 26 ] and MDD as risk factors for inflammatory bowel disease, but the investigation into MDD did not account for BMI [ 28 ].…”

A metabolome-wide Mendelian randomization study prioritizes causal circulating metabolites for multiple sclerosis

“…MR has been applied to MS, providing evidence for causal roles of high BMI [10][11][12][13] , increased interleukin-6 (IL-6) signaling 11 , and low vitamin D 10,13 . On the other hand, MR did not support the causal roles of uric acid 14 , leptin 13 , adiponectin 13 , and depression 15,16 . A systemic MR study of 65 possible risk factors for MS revealed robust evidence of causality for four of them, high childhood and adult BMI, low vitamin D, and low physical activity.…”

Comparing underlying mechanisms of depression in multiple sclerosis and rheumatoid arthritis

“…Apolipoprotein ε*2 has been attributed to have a protective role since this allele has been found to correlate with less depressive symptoms [33], but these findings have not been validated further. A recent study investigating the relationship between depression and MS using mendelian randomization came to conclusion that there is no causal contribution between depression genetic liability and MS susceptibility and vice versa [34].…”