Polygenicity of Comorbid Depression in Multiple Sclerosis

Area of Science:

• Neurogenetics
• Psychiatric Epidemiology
• Multiple Sclerosis Research

Background:

• Depression is a common comorbidity in multiple sclerosis (MS), often accelerating disability progression.
• The precise causes of depression in MS are not fully understood, necessitating novel identification strategies.
• Existing genetic studies on depression may not accurately reflect its occurrence as a comorbidity in MS.

Purpose of the Study:

• To investigate the association between polygenic scores (PGS) for depression and the risk of comorbid depression in individuals with MS.
• To determine if genetic predisposition for depression differs when it occurs with MS compared to when it is a primary condition.

Main Methods:

• Utilized data from 106,682 individuals of European genetic ancestry across Canada, UK Biobank, and the United States.
• Categorized participants into cases (MS with depression) and compared them with controls (MS without depression, depression without immune disease, healthy individuals).
• Employed three definitions of depression: clinical diagnoses, self-reported diagnoses, and depressive symptoms, analyzing PGS association using regression.

Main Results:

• Individuals with MS and depression exhibited a significantly higher depression PGS compared to those with MS but no depression (OR range 1.29-1.38) and healthy controls (OR range 1.49-1.53).
• The association between higher depression PGS and depression in MS was consistent across different depression definitions and sex stratification.
• A polygenic score for body mass index (BMI) was associated with depressive symptoms (p ≤ 0.001), and depression PGS did not significantly differ between comorbid and primary depression.

Conclusions:

• A heightened genetic predisposition for depression is linked to a 30%-40% increased likelihood of depression in European ancestry individuals with MS.
• The genetic underpinnings of depression in MS appear similar to those of primary depression, suggesting shared genetic factors.
• This research supports the potential utility of polygenic scores for assessing psychiatric disorder risk in MS populations and warrants further investigation in diverse ancestries.