ADRA2AandIRX1are putative risk genes for Raynaud’s phenomenon

Raynaud’s phenomenon (RP) is a common vasospastic disorder that causes severe pain and ulcers, but despite its high reported heritability, no causal genes have been robustly identified. We conducted a genome-wide association study including 5,147 RP cases and 439,294 controls, based on diagnoses from electronic health records, and identified three unreported genomic regions associated with the risk of RP ( p< 5×10 −8 ). We prioritized ADRA2A (rs7090046, odds ratio (OR) per allele: 1.26; 95%-CI: 1.20-1.31; p<9.6×10 -27 ) and IRX1 (rs12653958, OR: 1.17; 95%-CI: 1.12-1.22, p<4.8×10 -13 ) as candidate causal genes through integration of gene expression in disease relevant tissues. We further identified a likely causal detrimental effect of low fasting glucose levels on RP risk (r G =-0.21; p-value=2.3×10 -3 ), and systematically highlighted drug repurposing opportunities, like the antidepressant mirtazapine. Our results provide the first robust evidence for a strong genetic contribution to RP and highlight a so far underrated role of α 2A -adrenoreceptor signalling, encoded at ADRA2A , as a possible mechanism for hypersensitivity to catecholamine-induced vasospasms.