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.