P18.031.A Decoding syncope: genetic loci linked to sleep, psychiatric disorders, cardiovascular and autonomic dysregulation

Background: Syncope and collapse (i.e. fainting) is a transient loss of consciousness, usually caused by reduced cerebral perfusion due to vasodilatation. Syncope is common, more frequent in females with a lifetime prevalence of 35% but the understanding of its genetic background remain incomplete. Matherials and Methods: To address this gap, we performed a new genome-wide association study (GWAS) meta-analysis for syncope and collapse across four European cohorts (FinnGen, VA Million Veteran Program, Estonian BioBank, DeCODE Genetics), encompassing a total of 1,545,493 participants.  Results: We identified 75 genomic risk loci (P<5.0×10-8), of which 57 were not previously reported, mapping near 487 different genes. The strongest association was observed on chromosome 2, with the lead intergenic variant rs12465214 (P=3.45×10-⁷⁵) near ZNF804A, the risk gene for schizophrenia, previously reported as implicated in syncope risk. New associations were discovered: e.g., a locus was identified near PAX8 (rs62158163, P=6.88×10-¹⁰), a gene involved in circadian rhythm and sleep duration. Functional analyses reported that several loci mapped to genes involved in sleep regulation (e.g., insomnia, nightmares, long sleep), psychiatric traits (e.g., mood instability, smoking, neuroticism), and autonomic dysregulation. Genetic correlation results also showed a shared genetic background between syncope and these traits. Stratified linkage disequilibrium score regression (sLDSC) also suggested which brain regions and cell types may be implicated in syncope through genetic regulation mechanisms, revealing a multifaceted pathway underlying the genetic architecture of syncope. Conclusion: This study highlights the previously reported complex genetic architecture of syncope, and reveals novel promising associations with sleep, psychiatric, and autonomic-related traits for further investigation.