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Abstract
Background and Objectives Migraine is common among people with multiple sclerosis (MS), but the reasons for this are unknown. We tested 3 hypothesized mechanisms for this observed comorbidity, including migraine is a risk factor of MS, genetic variants are shared between the conditions, and migraine is because of MS.
Methods Data were from 2 sources: publicly available summary statistics from genome-wide association studies of MS (N = 115,748) and migraine (N = 375,752 and N = 361,141) and a case-control study of MS recruited from the Kaiser Permanente Northern California Health Plan (N = 1,991). For the latter participants, migraine status was ascertained using a validated electronic health record migraine probability algorithm or self-report. Using the public summary statistics, we used 2-sample Mendelian randomization to test whether a migraine genetic instrumental variable was associated with MS. We used linkage disequilibrium score regression and LOGODetect to ascertain whether MS and migraine shared genetic variants across the genome and regionally. Using the Northern California MS cohort, we used logistic regression to identify whether people with both MS and migraine had different odds of clinical characteristics (e.g., age at MS onset, Perceived Deficits Questionnaire, and depression) or MS-specific risk factors (e.g., body mass index, smoking status, and infectious mononucleosis status) compared with people with MS without migraine.
Results We did not find evidence supporting migraine as a causal risk factor of MS (p = 0.29). We did, however, identify 4 major histocompatibility complex (MHC) loci shared between MS and migraine. Among the Northern California MS cohort, 774 (39%) experienced migraine. People with both MS and migraine from this cohort were more likely to ever smoke (odds ratio [OR] = 1.30, 95% CI: 1.08–1.57), have worse self-reported cognitive deficits (OR = 1.04, 95% CI: 1.02–1.06), and ever experience depression (OR = 1.48, 95% CI: 1.22–1.80).
Discussion Our findings do not support migraine as a causal risk factor of MS. Several genetic variants, particularly in the MHC, may account for some of the overlap. It seems likely that migraine within the context of MS is because of MS. Identifying what increases the risk of migraine within MS might lead to an improved treatment and quality of life.
Glossary
- BMI=
- body mass index;
- CATI=
- computer-assisted telephone interview;
- EHR=
- electronic health record;
- GWAS=
- genome-wide association study;
- IMSGC=
- International Multiple Sclerosis Genetic Consortium;
- IHGC=
- International Headache Genetic Consortium;
- IV=
- instrumental variable;
- KPNC=
- Kaiser Permanente Northern California;
- LD=
- linkage disequilibrium;
- LDSC=
- LD score regression;
- LRP1=
- lipoprotein receptor–related protein-1;
- MAF=
- minor allele frequency;
- MHC=
- major histocompatibility complex;
- MPA=
- migraine probability algorithm;
- MR=
- Mendelian randomization;
- MS=
- multiple sclerosis;
- MSSS=
- Multiple Sclerosis Severity Scale;
- OR=
- odds ratio;
- PDQ=
- Perceived Deficits Questionnaire;
- PITS-M=
- Modified Telephone Interview for Cognitive Status;
- PRS=
- polygenic risk score;
- PwMS=
- people with MS;
- SNP=
- single nucleotide polymorphism
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Submitted and externally peer reviewed. The handling editor was Associate Editor Rebecca Burch, MD.
- Received June 28, 2022.
- Accepted in final form November 21, 2022.
- © 2023 American Academy of Neurology
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