Elucidating the susceptibility genes between insomnia and migraine by integrating genetic data and transcriptomes

Insomnia is a sleep disorder commonly occurring in the general population. Migraine is a severe neurological disease with a high morbidity rate. Insomnia can increase the risk of developing migraines. However, the full biological mechanisms underlying this condition remain incompletely understood. Based on summary statistics from genome-wide association studies (GWAS) on insomnia (Ncase = 109,548 and Ncontrol = 277,440), overall migraine (Ncase = 26,894 and Ncontrol = 374,605), including its subtypes migraine with aura (MA) (Ncase = 11,757 and Ncontrol = 374,605), and migraine without aura (MO) (Ncase = 9,690 and Ncontrol = 374,605), we performed a large-scale genome-wide cross-trait analysis for each trait pair, followed by functional annotation, transcriptome-wide association studies (TWAS) and Mendelian randomization (MR) to investigate the genetic relationship between the development of insomnia and migraine. There was a significant positive genetic correlation between insomnia and migraine (rg = 0.3187, P = 5.64E-16), as well as MA (rg = 0.2843, P = 6.752E-09) and MO (rg = 0.292, P = 1.121E-11). By segmenting the entire genome into 1,703 largely independent regions and diverse functional categories, we identified notable local genetic correlations within several specific regions and functional categories. We identified 8 independent loci shared by insomnia and overall migraine, 2 independent pleiotropic loci for insomnia and MA, and 7 independent shared loci for insomnia and MO, by genome-wide cross-trait analysis. In addition, TWAS analysis revealed 7, 2, and 2 shared genes for insomnia and migraine, as well as MA and MO, respectively. 3 shared genes are located in the pleiotropic loci for insomnia and migraine. 1 shared gene is located in the pleiotropic loci for insomnia and MO. Bi-directional MR indicated a potential causal risk of insomnia to MA at a marginally significant level, but migraine, including MA and MO, was not causally associated with the risk of insomnia. This study demonstrated a shared genetic architecture, pleiotropic loci, shared genes, and a potential putative relationship underlying insomnia and migraine by integrating genetic data and transcriptomes, providing important insights into the genetic mechanisms between insomnia and migraine comorbidities, and implications for intervention and treatment targets.