Shared Genetic Variants Account for Overlap in Migraine and Multiple Sclerosis

Lisa F. Barcellos, PhD, MPH

Recently published data from 2 large-scale genome-wide association studies found no evidence for migraine as a causal risk factor of multiple sclerosis (MS); however, data revealed several genetic variants, particularly those in the major histocompatibility complex (MHC) loci, that may account for some of the overlap observed between the conditions.

Published in Neurology, the analysis included 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 = 1991). Led by Lisa F. Barcellos, PhD, MPH, professor of epidemiology, Berkeley Public Health, investigators implanted a 2-sample Mendelian randomization to test whether a migraine genetic instrumental variable was associated with MS.

All told, findings on an inverse variance-weighted MR analysis did not reveal a causal association between migraine instrumental variable (IV) and MS (ß = 0.09; SE, 0.08; P = .29). Effects from weighted median, weighted mode, and mode estimation methods did not differ considerably from the inverse variance-weighted method. Although there was no evidence of global genetic correlation between MS and migraine (r = 0.01; SE, 0.05; P = .88), there were 4 non-MHC genomic regions that showed associations between the 2 conditions.

A closer look at non-MHC regions showed a positive statistic on chromosome 12, signifying that alleles in this region affect MS and migraine in the same region. The other non-MHC regions had negative statistics, with genes in/near these regions involved in RNA polymerase II binding and transcription, lipid homeostasis, fatty acid ß oxidation, meiotic cell cycle, and cytokine-mediated signaling pathway. These genes were not significantly enriched in specific tissue types.

"Given the well-documented strong association between MS and migraine, it seems likely that migraine within the context of MS is a symptom or consequence of MS,” the study authors wrote. "If it were possible to define an "MS-type headache” occurring because of MS processes but before MS diagnosis, it might be possible to initiate MS treatment earlier and slow disease progression. In addition, identifying PwMS most at risk of migraines might allow clinicians to recommend treatments that improve quality of life."

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In total, 18,803 genetic variants in the MHC region shared between MS and migraine were significantly associated with MS (P <5 x 10^-8). More specifically, 98 variants were significantly associated with migraine (P <1.25 x 10^-3) and were in 4 high-linkage disequilibrium (LD) regions of the MHC. Investigators clumped these into 4 independent loci: HCG20, HLA-B, TNXA, and TNXB, all of which had the major allele, rather than the minor, confer the risk of MS and migraine. Evidence for LD between these 4 loci and HLA-DRB1*15:01, the strongest genetic risk factor of MS, was not observed (r² <.07).

In the study, nearly 40% (38.9%) of patients with MS experienced migraine; however, they were more likely to be female (88.6%) than non-migraine patients with MS (70.3%) and had a lower educational attainment. Specifically, 40.4% had bachelor’s degree or higher vs 48.3% of non-migraine patients with MS. Migraine appeared to be more common earlier in MS onset for those affected (31.5 years vs 32.8%), and was associated with more frequent depression (45.0% vs 35.0%) and use of interferon beta treatment (54.1% vs 50.7%).

The only 2 clinical characteristics of higher odds of migraine were a history of depression (OR, 1.48; 95% CI, 1.22-1.80) or higher Perceived Deficits Questionnaire (PDQ) score (OR, 1.04; 95% CI, 1.02-1.06) after adjusting for potential confounders such as age, sex, disease duration, and interferon beta use. Smoking, the only environmental or behavioral risk factor identified, boosted the odds of migraine in patients with MS by 1.30 times (95% CI, 1.08-1.57) when in comparison with never smokers. Notably, investigators found no association with migraine status and MS in HLA-DRB1*15:01, HLA-A*02, MS polygenic risk scores (PRS), and migraine PRSs.

REFERENCE
1. Horton MK, Robinson SC, Shao X, et al. Cross-train Mendelian randomization study to investigate whether migraine is a risk factor for multiple sclerosis. Neurology. Published online January 11, 2023. doi:10.1212/WNL.00000000000206791