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Multiple Sclerosis and Depression: Are Links Causal?

Relationships between multiple sclerosis (MS) and depression did not appear to be causal, a Mendelian randomization study suggested.

Genetic liability to major depressive disorder had no effect on the odds of MS, reported Adil Harroud, MD, of the University of California San Francisco, and colleagues, at ACTRIMS Forum 2021, the annual meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis.

Susceptibility to MS also had no effect on the odds of major depressive order, but a genetic predisposition toward higher BMI increased the likelihood of each disease, they added. The findings were published in Multiple Sclerosis Journal.

“Depression is common in people with MS and is associated with accelerated disability progression. Individuals with comorbid MS and depression have synergistically higher mortality rates compared to those with depression or MS alone,” Harroud said.

“We aimed to determine whether this association reflects a causal relationship between depression and MS,” he told MedPage Today. “We undertook a Mendelian randomization approach, which uses natural genetic variation to proxy an exposure and minimize the effects of confounders.”

This is because genetic variants are randomly allocated at conception and generally more selective in their associations, Harroud noted. “Mendelian randomization is also robust to reverse causality, which is significant because the incidence of depression rises as early as 5 to 10 years before MS diagnosis,” he said.

“The intuition behind Mendelian randomization is that if depression is causal in MS, then genetic variants which reliably increase the risk of depression in the population should also increase the risk of MS.”

The study used genetic summary results for major depressive disorder from a genome-wide meta-analysis of three cohorts: the Psychiatric Genomics Consortium, UK Biobank, and 23andMe. Depression was self-reported in the UK Biobank and 23andMe cohorts; it was based on clinically diagnosed major depressive disorder in the Psychiatric Genomics Consortium group. The researchers found a strong genetic correlation (0.85-0.87) between data sets, despite different case definitions for depression.

In reverse, with major depressive order as the outcome, estimates were restricted to Psychiatric Genomics Consortium and UK Biobank data due to 23andMe restrictions.

The researchers found no effect of genetic liability to major depressive disorder on the odds of MS (OR 1.07 per doubling in odds of major depressive disorder, 95% CI 0.90–1.28, P=0.43), and no support for a causal effect in the other direction (OR 1.00 per doubling in odds of MS, 95% CI 0.99–1.01, P=0.51). Sensitivity analyses indicated that bias from pleiotropy was unlikely.

A genetic predisposition toward higher BMI increased the odds of MS (OR 1.34 per SD increase in BMI, 95% CI 1.09–1.65 P=0.005) and of major depressive disorder (OR 1.08, 95% CI 1.01–1.15, P=0.02). “Genetic evidence suggesting commonality of obesity to both conditions may partly explain the increased incidence of depression pre-MS diagnosis,” the researchers wrote.

It’s important to note that this study focused on MS susceptibility and not MS disease course, Harroud pointed out. “It does not address whether MS-related inflammation modifies the risk of depression and vice versa,” he said. Identifying and treating depression in MS remains an important clinical objective, as people with MS and comorbid depression have worse outcomes than MS patients without depression, he added.


Harroud disclosed support from the National Multiple Sclerosis Society and the Multiple Sclerosis Society of Canada.

The researchers disclosed no relevant relationships with industry.