ADRA2A and IRX1 are putative risk genes for Raynaud's phenomenon.
Nature communications 2023 ; 14: 6156.
Hartmann S, Yasmeen S, Jacobs BM, Denaxas S, Pirmohamed M, Gamazon ER, Caulfield MJ, Genes & Health Research Team Genes & Health Research Team, Hemingway H, Pietzner M, Langenberg C
DOI : 10.1038/s41467-023-41876-5
PubMed ID : 37828025
PMCID : PMC10570309
URL : https://www.nature.com/articles/s41467-023-41876-5
Abstract
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). We prioritized ADRA2A (rs7090046, odds ratio (OR) per allele: 1.26; 95%-CI: 1.20-1.31; p < 9.6 × 10) and IRX1 (rs12653958, OR: 1.17; 95%-CI: 1.12-1.22, p < 4.8 × 10) 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 = -0.21; p-value = 2.3 × 10), 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-adrenoreceptor signalling, encoded at ADRA2A, as a possible mechanism for hypersensitivity to catecholamine-induced vasospasms.