Polygenicity of Comorbid Depression in Multiple Sclerosis

BACKGROUND AND OBJECTIVES: Depression is common in multiple sclerosis (MS) and is associated with faster disability progression. The etiology of comorbid depression in MS remains poorly understood. Identification of individuals with a high risk of depression, through polygenic scores (PGS), may facilitate earlier identification. Previous genetic studies of depression considered depression as a primary disorder, not a comorbidity, and thus, findings may not generalize to MS. Body mass index (BMI) is a risk factor of both MS and depression, and its association may highlight differences in depression in MS. To improve the understanding of comorbid depression in MS, we will investigate PGS in people with MS, with the hypothesis that a higher depression PGS is associated with increased odds for comorbid depression in MS. METHODS: Samples from 3 sources (Canada, UK Biobank, and the United States) were used. Individuals were grouped into cases (MS/comorbid depression) and compared with 3 control groups: MS/no depression, depression/no immune disease, and healthy persons. We used 3 depression definitions: lifetime clinical diagnoses, self-reported diagnoses, and depressive symptoms. The PGS were tested in association with depression using regression. RESULTS: A total of 106,682 individuals of European genetic ancestry were used: Canada (n = 370; 213 with MS), UK Biobank (n = 105,734; 1,390 with MS), and the United States (n = 578 with MS). Meta-analyses revealed individuals with MS and depression had a higher depression PGS compared with both individuals with MS without depression (odds ratio range per SD 1.29-1.38, DISCUSSION: A higher depression genetic burden was associated with approximately 30%-40% increased odds of depression in European genetic ancestry participants with MS compared with those without depression and was no different compared with those with depression and no comorbid immune disease. This study paves the way for further investigations into the possible use of PGS for assessing psychiatric disorder risk in MS and its application to non-European genetic ancestries

Polygenic Liability for Anxiety in Association With Comorbid Anxiety in Multiple Sclerosis

OBJECTIVE: Comorbid anxiety occurs often in MS and is associated with disability progression. Polygenic scores offer a possible means of anxiety risk prediction but often have not been validated outside the original discovery population. We aimed to investigate the association between the Generalized Anxiety Disorder 2-item scale polygenic score with anxiety in MS. METHODS: Using a case-control design, participants from Canadian, UK Biobank, and United States cohorts were grouped into cases (MS/comorbid anxiety) or controls (MS/no anxiety, anxiety/no immune disease or healthy). We used multiple anxiety measures: current symptoms, lifetime interview-diagnosed, and lifetime self-report physician-diagnosed. The polygenic score was computed for current anxiety symptoms using summary statistics from a previous genome-wide association study and was tested using regression. RESULTS: A total of 71,343 individuals of European genetic ancestry were used: Canada (n = 334; 212 MS), UK Biobank (n = 70,431; 1,390 MS), and the USA (n = 578 MS). Meta-analyses identified that in MS, each 1-SD increase in the polygenic score was associated with ~50% increased odds of comorbid moderate anxious symptoms compared to those with less than moderate anxious symptoms (OR: 1.47, 95% CI: 1.09-1.99). We found a similar direction of effects in the other measures. MS had a similar anxiety genetic burden compared to people with anxiety as the index disease. INTERPRETATION: Higher genetic burden for anxiety was associated with significantly increased odds of moderate anxious symptoms in MS of European genetic ancestry which did not differ from those with anxiety and no comorbid immune disease. This study suggests a genetic basis for anxiety in MS

Predicting Pre-transplant Abstinence in Patients with Alcohol-Induced Liver Disease

Background: Some patients with alcohol-induced liver failure will succumb to their disease prior to demonstrating compliance with the six months abstinence rule for liver transplantation. Purpose: The purpose of this study was to determine whether a patient’s self-reported, longest period of abstinence predicts subsequent abstinence. Methods: Adult patients (n=63) with alcohol-induced liver disease were asked to recall their longest period of abstinence prior to their initial hepatology visit. Compliance with instructions to remain abstinent was then documented. Results: Nineteen patients (30%) achieved abstinence and 44 (70%) relapsed within six months of seeing their hepatologist. Relapses were more common in patients who self-reported previous periods of abstinence exceeding six months (19/44, 43%) compared with 2/19 (11%) in those with periods of less than six months (p=0.01). Serum albumin levels were lower in relapsers but other tests of liver function (bilirubin level and international ratio of prothrombin time) and predictors of post-transplant recidivism did not associate with relapses. On multivariate analysis, self-reported abstinence (OR: 0.11, 95% CI: 0.02-0.57, p=0.008) and serum albumin levels (regression coefficient 0.113, p=0.02) predicted relapses. Conclusions: A self-reported period of abstinence in excess of six months was associated with an increased risk of subsequent relapse following a hepatologist’s instructions to remain abstinent. These counter-intuitive findings should be confirmed by larger, prospective studies