Hartmann, Sylvia, Yasmeen, Summaira 
ORCID: 0000-0001-5470-2081, Jacobs, Benjamin M ORCID: 0000-0002-6023-6010, Denaxas, Spiros, Pirmohamed, Munir ORCID: 0000-0002-7534-7266, Gamazon, Eric R ORCID: 0000-0003-4204-8734, Caulfield, Mark J ORCID: 0000-0001-9295-3594, Genes & Health Research Team, , Hemingway, Harry ORCID: 0000-0003-2279-0624, Pietzner, Maik ORCID: 0000-0003-3437-9963 et al (show 1 more authors)
(2023)
ADRA2A and IRX1 are putative risk genes for Raynaud's phenomenon.
Nature communications, 14 (1).
6156-.
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ADRA2A and IRX1 are putative risk genes for Raynauds phenomenon.pdf - Open Access published version Download (1MB) | Preview |
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<sup>-8</sup>). We prioritized ADRA2A (rs7090046, odds ratio (OR) per allele: 1.26; 95%-CI: 1.20-1.31; p < 9.6 × 10<sup>-27</sup>) and IRX1 (rs12653958, OR: 1.17; 95%-CI: 1.12-1.22, p < 4.8 × 10<sup>-13</sup>) 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<sub>G</sub> = -0.21; p-value = 2.3 × 10<sup>-3</sup>), 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<sub>2A</sub>-adrenoreceptor signalling, encoded at ADRA2A, as a possible mechanism for hypersensitivity to catecholamine-induced vasospasms.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Genes & Health Research Team, Humans, Pain, Raynaud Disease, Ulcer, Homeodomain Proteins, Receptors, Adrenergic, alpha-2, Transcription Factors, Genome-Wide Association Study |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 13 Dec 2023 11:45 |
| Last Modified: | 13 Dec 2023 11:45 |
| DOI: | 10.1038/s41467-023-41876-5 |
| Open Access URL: | https://doi.org/10.1038/s41467-023-41876-5 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3177309 |
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