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.

雷诺现象 （RP） 是一种常见的血管痉挛性疾病，可引起严重疼痛和溃疡，但尽管其报道的遗传性很高，但尚未明确确定致病基因。我们根据电子健康记录的诊断进行了一项全基因组关联研究，包括 5,147 例 RP 病例和 439,294 例对照，并确定了与 RP 风险相关的三个未报告的基因组区域 （p < 5 × 10⁻⁸）。我们优先考虑 ADRA2A （rs7090046，每个等位基因的比值比 （OR）：1.26;95%-CI：1.20-1.31;p < 9.6 × ^10-27）和 IRX1 （rs12653958，OR：1.17;95%-CI：1.12-1.22，p < 4.8 × ^10-13）作为候选致病基因，通过在疾病相关组织中整合基因表达。我们进一步确定了低空腹血糖水平对 RP 风险的可能因果不利影响 （r_G = -0.21;p 值 = 2.3 × ^10-3），并系统地强调了药物再利用的机会，如抗抑郁药米氮平。我们的结果为对 RP 的强烈遗传贡献提供了第一个强有力的证据，并强调了迄今为止被低估的 α_2A 肾上腺素受体信号传导的作用，由 ADRA2A 编码，是对儿茶酚胺诱导的血管痉挛过敏的可能机制。