| Title: | ADRA2A and IRX1 are putative risk genes for Raynaud's phenomenon |
| Journal: | Nature Communications |
| Published: | 12 Oct 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/37828025/ |
| DOI: | https://doi.org/10.1038/s41467-023-41876-5 |
| URL: | https://www.nature.com/articles/s41467-023-41876-5.pdf |
Publication 9387
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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 × 10−8). 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 (rG = −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 α2A-adrenoreceptor signalling, encoded at ADRA2A, as a possible mechanism for hypersensitivity to catecholamine-induced vasospasms.</p>
10 Authors
- Sylvia Hartmann
- Summaira Yasmeen
- Benjamin M. Jacobs
- Spiros Denaxas
- Munir Pirmohamed
- Eric R. Gamazon
- Mark J. Caulfield
- Harry Hemingway
- Maik Pietzner
- Claudia Langenberg
1 Application
| Application ID | Title |
|---|---|
| 44448 | The genetic and environmental determinants of cardiometabolic and related disorders. |
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