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

Authors

Kaarina Kowalec
Arvid Harder
Casandra Dolovich
Kathryn C Fitzgerald
Amber Salter
Yi Lu
Charles N Bernstein
James M Bolton
Gary Cutter
John D Fisk
Joel Gelernter
Lesley A Graff
Sara Hägg
Carol A Hitchon
Daniel F Levey
Fred D Lublin
Kyla A McKay
Scott Patten
Amit Patki
Murray B Stein
Hemant K Tiwari
Jerry S Wolinsky
Ruth A Marrie

Publication Date

6-1-2024

Journal

Annals of Clinical and Translational Neurology

Abstract

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.

Keywords

Humans, Multiple Sclerosis, Male, Female, Adult, Middle Aged, Multifactorial Inheritance, Comorbidity, Case-Control Studies, Anxiety Disorders, Anxiety, Canada, United States, United Kingdom, Aged, Genome-Wide Association Study, Genetic Predisposition to Disease