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

Mult Scler. 2021 Nov;27(13):2077-2084. doi: 10.1177/1352458521993075. Epub 2021 Feb 16.


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.

Keywords: Mendelian randomization; Multiple sclerosis; genetic epidemiology; major depressive disorder.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Depression
  • Depressive Disorder, Major* / epidemiology
  • Depressive Disorder, Major* / genetics
  • Genome-Wide Association Study
  • Humans
  • Mendelian Randomization Analysis
  • Multiple Sclerosis* / epidemiology
  • Multiple Sclerosis* / genetics
  • Polymorphism, Single Nucleotide