Genetic Overlap Analysis Identifies a Shared Etiology between Migraine and Headache with Type 2 Diabetes

Migraine and headache frequently co-occur with type 2 diabetes (T2D), suggesting a shared aetiology between the two conditions. We used genome-wide association study (GWAS) data to investigate the genetic overlap and causal relationship between migraine and headache with T2D. Using linkage disequilibrium score regression (LDSC), we found a significant genetic correlation between migraine and T2D (r(g) = 0.06, p = 1.37 × 10(−5)) and between headache and T2D (r(g) = 0.07, p = 3.0 × 10(−4)). Using pairwise GWAS (GWAS-PW) analysis, we identified 11 pleiotropic regions between migraine and T2D and 5 pleiotropic regions between headache and T2D. Cross-trait SNP meta-analysis identified 23 novel SNP loci (P(meta) < 5 × 10(−8)) associated with migraine and T2D, and three novel SNP loci associated with headache and T2D. Cross-trait gene-based overlap analysis identified 33 genes significantly associated (P(gene-based) < 3.85 × 10(−6)) with migraine and T2D, and 11 genes associated with headache and T2D, with 7 genes (EHMT2, SLC44A4, PLEKHA1, CFDP1, TMEM170A, CHST6, and BCAR1) common between them. There was also a significant overlap of genes nominally associated (P(gene-based) < 0.05) with both migraine and T2D (P(binomial-test) = 2.83 × 10(−46)) and headache and T2D (P(binomial-test) = 4.08 × 10(−29)). Mendelian randomisation (MR) analyses did not provide consistent evidence for a causal relationship between migraine and T2D. However, we found headache was causally associated (inverse-variance weighted, OR(IVW) = 0.90, P(ivw) = 7 × 10(−3)) with T2D. Our findings robustly confirm the comorbidity of migraine and headache with T2D, with shared genetically controlled biological mechanisms contributing to their co-occurrence, and evidence for a causal relationship between headache and T2D.