Transformer-based deep learning enhances discovery in migraine GWAS

Migraine is a complex neurological disorder with substantial heritability, yet genome-wide association studies (GWAS) have explained only a fraction of its genetic component. We developed InsightGWAS, a Transformer-based model, to enhance genetic discovery for migraine by integrating functional annotations and leveraging transfer learning from GWAS datasets of major depressive disorder (MDD). Applying InsightGWAS to migraine GWAS datasets comprising 53,109 cases and 230,876 controls, we identified 293 previously unreported loci, influencing genes such as CACNA1D, HTR3C, and NLGN1, respectively. Furthermore, two loci rs4320030 (SCN11A) and rs5763529 (HORMAD2) were validated in independent sequencing studies, demonstrating the model's precision in uncovering migraine-associated loci. Compared to traditional GWAS results, enrichment analyses of InsightGWAS-predicted loci uncovered new signaling pathways, including nitrogen compound metabolism and cation binding, offering novel insights into the metabolic and ionic mechanisms underlying migraine susceptibility. These findings demonstrate the impact of InsightGWAS in complementing conventional approaches and advancing our understanding of migraine genetics.