AbstractUntil recently, most genetic studies of headache have been conducted on participants with European ancestry. We therefore conducted a large-scale genome-wide association study of self-reported headache in individuals of East Asian ancestry (specifically those who were identified as Han Chinese). In this study, 108 855 participants were enrolled, including 12 026 headache cases from the Taiwan Biobank. For broadly defined headache phenotype, we identified a locus on Chromosome 17, with the lead single-nucleotide polymorphism rs8072917 (odds ratio 1.08,P= 4.49 × 10−8), mapped to two protein-coding genesRNF213andENDOV. For severe headache phenotype, we found a strong association on Chromosome 8, with the lead single-nucleotide polymorphism rs13272202 (odds ratio 1.30,P= 1.02 × 10−9), mapped to geneRP11-1101K5.1. We then conducted a conditional analysis and a statistical fine-mapping of the broadly defined headache-associatedlociand identified a single credible set oflociwith rs8072917 supporting that this lead variant was the true causal variant onRNF213gene region.RNF213replicated the result of previous studies and played important roles in the biological mechanism of broadly defined headache. On the basis of the previous results found in the Taiwan Biobank, we conducted phenome-wide association studies for the lead variants using data from the UK Biobank and found that the causal variant (single-nucleotide polymorphism rs8072917) was associated with muscle symptoms, cellulitis and abscess of face and neck, and cardiogenic shock. Our findings foster the genetic architecture of headache in individuals of East Asian ancestry. Our study can be replicated using genomic data linked to electronic health records from a variety of countries, therefore affecting a wide range of ethnicities globally. Our genome–phenome association study may facilitate the development of new genetic tests and novel drug mechanisms.