An Integrative Migraine Polygenic Risk Score Is Associated with Age at Onset But Not Chronification

Background/Objective: Genome-wide association studies (GWASs) demonstrate a complex genetic landscape for migraine risk. Migraine polygenic risk scores (PRSs) developed from GWAS data may have utility for predicting disease course. We analyzed the strength of association between an integrative migraine PRS and age at onset and chronification. Methods: In this retrospective clinical/genetic case-control study, PGS004799 was calculated for adults with European ancestry from two real-world community cohorts. In the DodoNA cohort, 1653 treated, deeply phenotyped migraine cases, diagnosed using International Classification of Headache Disorders 3rd edition criteria, were followed for a mean (range) of 2.3 (1-10) years and compared to 3460 controls (without migraine diagnosis). In the GHI cohort, 2443 cases were identified using the first migraine ICD code as a proxy for migraine onset and compared to 8576 controls (without migraine ICD codes). PRS associations with age at onset (DodoNA) or first migraine ICD code (GHI) and chronification (DodoNA) were evaluated. Results: In both cohorts, PRS was higher in cases (DodoNA mean (range) cases: 0.82 (0.07-1.76), controls: 0.78 (0.04-1.56); t (5111) = -6.1, p = 1.4 × 10^-9, GHI: cases: 0.79 (0.003-1.68), controls: 0.75 (-0.06-1.53); t (11,017) = -7.69, p = 1.6 × 10^-14), and a higher PRS was associated with earlier onset in females (HR [95% CI] DodoNA: 2.1 [1.6-2.6, p < 0.001; GHI: 1.8 [1.4-2.1], p < 0.001) and in males (DodoNA: 2.5 [1.3-4.7], p = 0.005; GHI: 1.6 [1.1-2.6], p = 0.027). PRS was not different in cases with or without chronification (t (1651) = -1.67, p = 0.094) and was not associated with earlier chronification (1.2 [0.8-1.6], p = 0.424). Conclusions: Higher genetic risk was associated with earlier onset and increased risk of migraine well into adulthood, but not with chronification. This suggests that the PRS quantifies genetic susceptibility that is distinct from factors influencing disease course.