Genome-phenome wide association study of broadly defined headache

Hsu et al. conducted a genome-wide association study on headaches in East Asians, followed by a phenome-wide association analysis using the UK Biobank. Single-nucleotide polymorphism rs8072917 of gene RNF213 was the causal variant for broadly defined headaches, which was also associated with cellulitis, neck and face abscesses and muscular symptoms. Until 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 x 10(-8)), mapped to two protein-coding genes RNF213 and ENDOV. 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 x 10(-9)), mapped to gene RP11-1101K5.1. We then conducted a conditional analysis and a statistical fine-mapping of the broadly defined headache-associated loci and identified a single credible set of loci with rs8072917 supporting that this lead variant was the true causal variant on RNF213 gene region. RNF213 replicated 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.

Automated summary

Hsu et al. conducted a genome-wide association study on headaches in East Asians, which revealed that a single-nucleotide polymorphism (rs8072917) of the RNF213 gene is the causal variant for broadly defined headaches. This study also found associations between the causal variant and other medical conditions such as cellulitis, neck and face abscesses, and muscular symptoms. This research sheds light on the genetic architecture of headaches in individuals of East Asian ancestry and has potential implications for the development of genetic tests and treatments.