Genetic Predisposition for Elevated BMI May Increase Risk of MS, Depression

A causal relationship between major depressive disorder (MDD) and multiple sclerosis (MS), and vice versa, was not found in a recent Mendelian randomization study, while higher body mass index (BMI) was shown to increase the risk for both.

A genetic correlation between major depressive disorder (MDD) and multiple sclerosis (MS), and vice versa, was not found in a recent Mendelian randomization (MR) study, while higher body mass index (BMI) was shown to increase the risk for both.

Their findings were published recently online in Multiple Sclerosis Journal.

“MDD is common in MS, and its incidence rises before MS diagnosis,” the authors noted. “However, the causality and direction of this association remain unclear.” They added that an MR-designed study “is robust to reverse causality as genotypes are not influenced by disease onset.”

Comparing the causal effects of either relationship (MDD on MS or MS on MDD), the authors compared 660,937 cases of MDD with 1.4 million controls and 47,429 cases of MS with 68,374 controls. The selected genetic instruments associated with risk of either disease and used sensitivity analyses to assess pleiotropy, while adjusting for BMI.

Genetic liability toward MDD or MS was not found to increase the risk of developing the other, according to the authors’ findings:

  • Genetic liability to MDD on MS: odds ratio (OR), 1.07/doubling in odds (95% CI, 0.90-1.28; P = .43)
  • Genetic liability to MS on MDD: OR, 1.00/doubling in odds (95% CI, 0.99-1.01; P = .51)

However, having a genetic predisposition to a higher BMI did increase the odds of both conditions:

  • MDD: OR, 1.34/SD increase in BMI (95% CI, 1.09-1.65; P = .005)
  • MS: OR, 1.08/SD increase in BMI (95% CI, 1.01-1.15; P = .02)

The investigators extracted their genetic summary data for MDD from a recent genome-wide association study (GWAS) among of individuals from the Psychiatric Genomics Consortium, UK Biobank, and 23andMe. Depression was both self-reported or clinically diagnosed. Ninety-eight genome-wide significant single nucleotide polymorphisms (SNPs) were included for contributing to MDD risk.

For MS, genetic summary data came from the latest International MS Genetic Consortium GWAS meta-analysis, and 175 SNPs were included for contributing to MS risk.

The GIANT Consortium provided summary statistics for BMI.

“This study did not find any evidence to suggest that genetic liability to MDD is associated with MS risk, nor was genetic liability to MS associated with MDD,” the authors concluded.“In contrast, the multivariable MR analyses showed a clear effect of higher BMI on increased odds of both MS and MDD, with a stronger magnitude for MS. The contribution of obesity to both conditions may partly explain the increased incidence of depression pre-MS diagnosis.”

They added that observational studies failing to consider obesity’s effects on MDD in patients with MS could skew results because confounders could be missed, as well as that their results echo findings from previous MR studies that elevated BMI is a risk factor for both conditions.

Reference

Harroud A, Marrie RA, Fitzgerald KC, et al. Mendelian randomization provides no evidence for a causal role in the bidirectional relationship between depression and multiple sclerosis. Mult Scler. Published online February 16, 2021. doi:10.1177/1352458521993075