Genome-wide cross-trait analysis identified shared etiology between Alzheimer’s disease and migraine

Abstract

Aim: Alzheimer’s disease (AD) and migraine are both common and heritable neurological disorders. Epidemiological studies repeatedly report an association between migraine and an increased risk of AD. However, whether this co-occurrence reflects shared molecular etiology remains unclear. Methods: We integrated large-scale genome-wide association study (GWAS) summary statistics, AD (Ncase = 21,982 and Ncontrol = 41,944), overall migraine (Ncase = 26,894 and Ncontrol = 374,605), migraine with aura (MA, Ncase = 11,757 and Ncontrol = 374,605), and migraine without aura (MO, Ncase = 9,690 and Ncontrol = 374,605), to perform genome-wide cross-trait meta-analysis (CPASSOC), functional annotation and transcriptome-wide association studies (TWAS) to elucidate the genetic etiology between AD and migraine in detail. Results: Genome-wide cross-trait analysis revealed that 11 independent suggestive shared loci (PCPASSOC < 5 × 10-8 and Psingle-trait < 0.05) and 3 significant shared loci (PCPASSOC < 5 × 10-8 and Psingle-trait < 5 × 10-3) for AD and migraine, with substantial subtype specificity. In addition, after global false discovery rate (FDR) correction across 49 tissues, we identified C2 as a highly significant shared pleiotropic gene in the brain cerebellar hemisphere, and TSBP1-AS1 in the thyroid for AD and MA. Finally, drug-target prioritization highlighted C2 as a candidate therapeutic target, while PheWAS analysis revealed no significant associations between C2 and major disease categories, supporting its limited phenotypic pleiotropy. Conclusion: This study clarified the pleiotropic loci and shared genes underlying AD and migraine by integrating multi-omics. These findings provide important insights into the molecular mechanisms between AD and migraine, and potential candidate genes for further functional validation.