Purpose: We investigated whether common genetic variants predispose to syncope and collapse.
Methods: We used genome-wide association data on syncope and collapse for 408,961 individuals with European ancestry from the UK Biobank study. In a replication study, the Integrative Psychiatric Research Consortium (iPSYCH) cohort (n = 86,189) was used to investigate the risk of incident syncope stratified by genotype carrier status.
Results: We report on a genome-wide significant locus on chromosome 2q32.1 with the lead SNP rs12465214 (odds ratio [OR]= 1.13, 95% confidence interval [CI] = 1.10 - 1.17, P = 5.8 x 10^-15; Figure 1a). This association was replicated in the iPSYCH cohort, where homozygous carriers of the C allele conferred an increased hazard ratio (HR = 1.30, CI = 1.15 - 1.46, P = 1.68 x 10^-5; Figure 1b). LD score regression demonstrated a significant genetic correlation (rg) with coronary artery disease (rg = 0.41, P = 6.99 x 10^-15) and related phenotypes such as angina and hypertension (Figure 1c). Analyses of eQTL (P = 4 x 10^-8) and epigenetic chromatin states revealed that variation in this locus likely affects expression of the gene ZNF804A, which resides in its proximity (Figure 1d). A qPCR analysis showed that ZNF804A was mostly expressed in the brain. A lower level of ZNF804A expression was also detected in the cerebral arteries. ZNF804A was not expressed in heart tissue.
Conclusion: rs12465214 is associated with syncope and collapse. Variation in this locus likely modulates the expression of the nearby gene ZNF804A through eQTLs and chromatin interactions. ZNF804A is mainly expressed in the brain and cerebral arteries. However, the precise function of ZNF804A is unknown. Furthermore, syncope and collapse is a polygenetic trait and share a significant genetic overlap with coronary artery disease, angina and hypertension.