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. 2024 Jun;11(6):1393-1404.
doi: 10.1002/acn3.52025. Epub 2024 May 7.

Polygenic liability for anxiety in association with comorbid anxiety in multiple sclerosis

Kaarina Kowalec  1   2 , Arvid Harder  2 , Casandra Dolovich  3 , Kathryn C Fitzgerald  4 , Amber Salter  5 , Yi Lu  2 , Charles N Bernstein  3 , James M Bolton  6 , Gary Cutter  7 , John D Fisk  8 , Joel Gelernter  9   10 , Lesley A Graff  11 , Sara Hägg  2 , Carol A Hitchon  12 , Daniel F Levey  9   10 , Fred D Lublin  13 , Kyla A McKay  14 , Scott Patten  15 , Amit Patki  7 , Murray B Stein  6   16 , Hemant K Tiwari  7 , Jerry S Wolinsky  17 , Ruth A Marrie  3   18
Affiliations

Polygenic liability for anxiety in association with comorbid anxiety in multiple sclerosis

Kaarina Kowalec et al. Ann Clin Transl Neurol. 2024 Jun.

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.

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Conflict of interest statement

Dr. Salter receives research funding from the Multiple Sclerosis Society of Canada, the National Multiple Sclerosis Society, CMSC, and the US Department of Defense and is a member of the editorial board for Neurology. She serves as a consultant for Gryphon Bio, LLC. She is a member of the Data and Safety Monitoring Board for Premature Infants Receiving Milking or Delayed Cord Clamping (PREMOD2), Central Vein Sign: A Diagnostic Biomarker in Multiple Sclerosis (CAVS‐MS), Ocrelizumab for Preventing Clinical Multiple Sclerosis in Individuals with Radiologically Isolated Disease (CELLO) and Methotrexate treatment of Arthritis caused by Chikungunya virus (MARCH). Dr. Bernstein is supported by the Bingham Chair in Gastroenterology. He has served on advisory Boards for AbbVie Canada, Amgen Canada, Bristol Myers Squibb Canada, Eli Lilly Canada, Ferring Canada, JAMP Pharmaceuticals, Janssen Canada, Pendopharm, Sandoz Canada, Takeda Canada, and Pfizer Canada; Consultant for Mylan Pharmaceuticals and Takeda; Received educational grants from Abbvie Canada, Amgen Canada, Bristol Myers Squibb Canada, Eli Lilly Canada, Ferring Canada, Pfizer Canada, Takeda Canada, and Janssen Canada. Received research funding from Abbvie Canada, Amgen Canada, Pfizer Canada, Sandoz Canada, and Takeda Canada. Dr. Fisk receives research grant support from the Canadian Institutes of Health Research, the National Multiple Sclerosis Society, MS Canada, Crohn's and Colitis Canada, Research Nova Scotia; and consultation and distribution royalties from MAPI Research Trust. Dr. Graff has received research funding from Pfizer Canada and Takeda Canada. Dr. Hitchon has served on advisory boards for Astra‐Zeneca and received research funding from Pfizer. Dr. Gelernter is named as an inventor on PCT patent application #15/878,640 entitled: “Genotype‐guided dosing of opioid agonists,” filed on January 24, 2018, and issued on January 26, 2021 as U.S. Patent No. 10,900,082. Dr. Gelernter is paid for editorial work for the journal Complex Psychiatry. Dr. Cutter has the following disclosures: Data and Safety Monitoring Boards for Applied Therapeutics, AI therapeutics, AMO Pharma, Astra‐Zeneca, Avexis Pharmaceuticals, Bristol Meyers Squibb/Celgene, CSL Behring, Cynata Therapeutics, Horizon Pharmaceuticals, Immunic, Karuna Therapeutics, Kezar Life Sciences, Mapi Pharmaceuticals LTD, Merck, Mitsubishi Tanabe Pharma Holdings, Opko Biologics, Prothena Biosciences, Novartis, Regeneron, Sanofi‐Aventis, Reata Pharmaceuticals, Teva Pharmaceuticals, NHLBI (Protocol Review Committee), University of Texas Southwestern, University of Pennsylvania, Visioneering Technologies, Inc; and Consulting or Advisory Boards for Alexion, Antisense Therapeutics, Avotres, Biogen, Clene Nanomedicine, Clinical Trial Solutions LLC, Endra Life Sciences, Entelexo Biotherapeutics, Inc., Genzyme, Genentech, GW Pharmaceuticals, Hoya Corporation, Immunic, Immunosis Pty Ltd, Klein‐Buendel Incorporated, Linical, Merck/Serono, Novartis, Perception Neurosciences, Protalix Biotherapeutics, Regeneron, Roche, SAB Biotherapeutics. Dr. Cutter is employed by the University of Alabama at Birmingham and President of Pythagoras, Inc. a private consulting company located in Birmingham, AL. Dr. K McKay receives research funding from StratNeuro and has received speaker honoraria from Biogen and Sanofi. Dr. MB Stein has stock options in Oxeia Biopharmaceuticals and EpiVario. He has been paid for his editorial work on Depression and Anxiety (Editor‐in‐Chief), Biological Psychiatry (Deputy Editor), and UpToDate (Co‐Editor‐in‐Chief for Psychiatry). He has also received research support from NIH, Department of Veterans Affairs, and the Department of Defense. He is on the scientific advisory board for the Brain and Behavior Research Foundation and the Anxiety and Depression Association of America. Dr. J. Wolinsky received compensation for consulting, scientific advisory boards, or other activities with the Cleveland Clinic Foundation, EMD Serono, Inmagene, Novartis, Roche/Genentech, Sandoz, University of Alabama, and Zenas BioPharm. Royalties are received for our licensed monoclonal antibodies through UTHealth to Millipore (Chemicon International) Corporation. Dr Kowalec, Mr. Harder, Ms. Dolovich, Dr. KC Fitzgerald, Dr. Y Lu, Dr. JM Bolton, Dr. S Hägg, Dr. DF Levey, Dr. FD Lublin, Dr. S Patten, Dr. A Patki, Dr HK Tiwari, and Dr. RA Marrie report no disclosures related to this work.

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