<b>Genome-wide association study reveals a locus in </b><b><i>ADARB2</i></b><b> for complete freedom from headache in Danish Blood Donors</b>

Headache disorders are the most common disorders of the nervous system. The lifetime prevalence of headache disorders show that some individuals never experience headache. The etiology of complete freedom from headache is not known. To assess genetic variants associated with complete freedom from headache, we performed a genome-wide association study of individuals who have never experienced a headache. We included 63,992 individuals (2,998 individuals with complete freedom from headache and 60,994 controls) from the Danish Blood Donor Study Genomic Cohort. Participants were included in two rounds, from November 2015 to March 2018 and from May 2020 to August 2020. We discovered a genome-wide significant association, with the lead variant rs7904615[G] in ADARB2 (EAF=27%, OR=1.20 [1.13–1.27], p=3.92x10-9). The genomic locus was replicated in a non-overlapping cohort of 13,032 individuals (539 individuals with complete freedom from headache and 12,493 controls) from the Danish Blood Donor Study Genomic Cohort (p&lt;0.05, two-sided). Participants for the replication were included from November 2015 to August 2020. In conclusion, we show that complete freedom from headache has a genetic component, and we suggest that ADARB2 is involved in complete freedom from headache. The genomic locus was specific for complete freedom from headache and was not associated with any primary headache disorders. Further studies are needed before ADARB2 can be proven as a gene contributing to protection from headache.