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ADRA2A and IRX1 are 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 fro...

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Autores principales: Hartmann, Sylvia, Yasmeen, Summaira, Jacobs, Benjamin M., Denaxas, Spiros, Pirmohamed, Munir, Gamazon, Eric R., Caulfield, Mark J., Hemingway, Harry, Pietzner, Maik, Langenberg, Claudia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10570309/
https://www.ncbi.nlm.nih.gov/pubmed/37828025
http://dx.doi.org/10.1038/s41467-023-41876-5
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author Hartmann, Sylvia
Yasmeen, Summaira
Jacobs, Benjamin M.
Denaxas, Spiros
Pirmohamed, Munir
Gamazon, Eric R.
Caulfield, Mark J.
Hemingway, Harry
Pietzner, Maik
Langenberg, Claudia
author_facet Hartmann, Sylvia
Yasmeen, Summaira
Jacobs, Benjamin M.
Denaxas, Spiros
Pirmohamed, Munir
Gamazon, Eric R.
Caulfield, Mark J.
Hemingway, Harry
Pietzner, Maik
Langenberg, Claudia
author_sort Hartmann, Sylvia
collection PubMed
description 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.
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spelling pubmed-105703092023-10-14 ADRA2A and IRX1 are putative risk genes for Raynaud’s phenomenon Hartmann, Sylvia Yasmeen, Summaira Jacobs, Benjamin M. Denaxas, Spiros Pirmohamed, Munir Gamazon, Eric R. Caulfield, Mark J. Hemingway, Harry Pietzner, Maik Langenberg, Claudia Nat Commun Article 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. Nature Publishing Group UK 2023-10-12 /pmc/articles/PMC10570309/ /pubmed/37828025 http://dx.doi.org/10.1038/s41467-023-41876-5 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Hartmann, Sylvia
Yasmeen, Summaira
Jacobs, Benjamin M.
Denaxas, Spiros
Pirmohamed, Munir
Gamazon, Eric R.
Caulfield, Mark J.
Hemingway, Harry
Pietzner, Maik
Langenberg, Claudia
ADRA2A and IRX1 are putative risk genes for Raynaud’s phenomenon
title ADRA2A and IRX1 are putative risk genes for Raynaud’s phenomenon
title_full ADRA2A and IRX1 are putative risk genes for Raynaud’s phenomenon
title_fullStr ADRA2A and IRX1 are putative risk genes for Raynaud’s phenomenon
title_full_unstemmed ADRA2A and IRX1 are putative risk genes for Raynaud’s phenomenon
title_short ADRA2A and IRX1 are putative risk genes for Raynaud’s phenomenon
title_sort adra2a and irx1 are putative risk genes for raynaud’s phenomenon
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10570309/
https://www.ncbi.nlm.nih.gov/pubmed/37828025
http://dx.doi.org/10.1038/s41467-023-41876-5
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