Genome-wide association study identifiesADRA2AandIRX1as novel risk genes for Raynaud’s phenomenon

Abstract

AbstractBackgroundRaynaud’s phenomenon (RP) is a common vasospastic disorder that causes severe pain and ulcers in fingers and toes triggered by cold or emotional stress. Despite its high reported heritability, no causal genes have been robustly identified, limiting mechanistic understanding and treatment options.AimTo investigate the genetic architecture of RP to better understand its aetiology and identify new potential therapeutic targets.MethodsWe conducted a genome-wide association study including 9,084 RP cases and 435,357 controls, based on diagnoses from electronic health records, among participants of the UK Biobank study. We identified candidate causal variants and genes using Bayesian fine-mapping and colocalization with gene expression across 49 tissues. We performed phenome-wide association analyses for all significant RP loci and computed genetic correlations followed by latent causal variable analyses between RP and a total of 205 selected phenotypes.ResultsWe identified eight unreported genomic regions associated with the risk of RP atp<5×10−8and assignedADRA2A(rs7090046, odds ratio (OR) per allele: 1.27; 95%-CI: 1.23-1.31; p<2.52×10−47) andIRX1(rs11748327, OR: 1.20; 95%-CI: 1.16-1.23, p<9.71×10−28) as the candidate causal genes at the two strongest loci. Higher expression ofADRA2Ain tibial artery andIRX1in skeletal muscle was thereby associated with a higher RP risk. We identified a likely causal detrimental effect of low fasting glucose levels on RP risk (rG=-0.12; p-value=0.01), while significant positive genetic correlations with reported comorbidities like migraine, depression, or peripheral artery disease are likely explained by shared risk factors.ConclusionOur results provide the first robust evidence for a strong genetic contribution to RP, highlighting a so far underrated role of α2A-adrenoreceptor signalling, encoded atADRA2A, as an important mechanism for hypersensitivity to catecholamine-induced vasospasms even at thermoneutral conditions.