ADRA2A and IRX1 are putative risk genes for Raynaud's phenomenon

被引：13

作者：

Hartmann, Sylvia ^{[1
]}

Yasmeen, Summaira ^{[1
]}

Jacobs, Benjamin M. ^{[2
]}

Denaxas, Spiros ^{[3
,4
,5
,6
]}

Pirmohamed, Munir ^{[7
]}

Gamazon, Eric R. ^{[8
,9
]}

Caulfield, Mark J. ^{[10
]}

Hemingway, Harry ^{[3
,4
,6
]}

Pietzner, Maik ^{[1
,11
,12
]}

Langenberg, Claudia ^{[1
,11
,12
]}

机构：

[1] Charite, Berlin Inst Hlth, Computat Med, Berlin, Germany

[2] Queen Mary Univ London, Wolfson Inst Populat Hlth, Prevent Neurol Unit, London, England

[3] UCL, Inst Hlth Informat, London, England

[4] Hlth Data Res UK, London, England

[5] British Heart Fdn, Data Sci Ctr, London, England

[6] Univ Coll London Hosp, Biomed Res Ctr, Natl Inst Hlth Res, London, England

[7] Univ Liverpool, Wolfson Ctr Personalised Med, Dept Pharmacol & Therapeut, Liverpool, Merseyside, England

[8] Vanderbilt Univ, Med Ctr, Div Genet Med, Nashville, TN 37232 USA

[9] Vanderbilt Univ, Med Ctr, Vanderbilt Genet Inst, Nashville, TN 37232 USA

[10] Queen Mary Univ London, William Harvey Res Inst, London, England

[11] Univ Cambridge, MRC Epidemiol Unit, Cambridge, England

[12] Queen Mary Univ London, Precis Healthcare Univ Res Inst, London, England

来源：

NATURE COMMUNICATIONS | 2023年 / 14卷 / 01期

基金：

美国国家卫生研究院; 英国医学研究理事会;

关键词：

QUALITY-OF-LIFE; ALPHA(2)-ADRENOCEPTOR SUBTYPES; COLD; VASOCONSTRICTION; RESPONSIVENESS; RESOURCE; ATTACKS; TRAITS;

D O I：

10.1038/s41467-023-41876-5

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 x 10(-8)). We prioritized ADRA2A (rs7090046, odds ratio (OR) per allele: 1.26; 95%-CI: 1.20-1.31; p < 9.6 x 10(-27)) and IRX1 (rs12653958, OR: 1.17; 95%-CI: 1.12-1.22, p < 4.8 x 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 x 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 alpha 2A-adrenoreceptor signalling, encoded at ADRA2A, as a possible mechanism for hypersensitivity to catecholamine-induced vasospasms.

引用

页数：11

共 65 条

[1] The GTEx Consortium atlas of genetic regulatory effects across human tissues [J].

Aguet, Francois ;

Barbeira, Alvaro N. ;

Bonazzola, Rodrigo ;

Brown, Andrew ;

Castel, Stephane E. ;

Jo, Brian ;

Kasela, Silva ;

Kim-Hellmuth, Sarah ;

Liang, Yanyu ;

Parsana, Princy ;

Flynn, Elise ;

Fresard, Laure ;

Gamazon, Eric R. ;

Hamel, Andrew R. ;

He, Yuan ;

Hormozdiari, Farhad ;

Mohammadi, Pejman ;

Munoz-Aguirre, Manuel ;

Ardlie, Kristin G. ;

Battle, Alexis ;

Bonazzola, Rodrigo ;

Brown, Christopher D. ;

Cox, Nancy ;

Dermitzakis, Emmanouil T. ;

Engelhardt, Barbara E. ;

Garrido-Martin, Diego ;

Gay, Nicole R. ;

Getz, Gad ;

Guigo, Roderic ;

Hamel, Andrew R. ;

Handsaker, Robert E. ;

He, Yuan ;

Hoffman, Paul J. ;

Hormozdiari, Farhad ;

Im, Hae Kyung ;

Jo, Brian ;

Kasela, Silva ;

Kashin, Seva ;

Kim-Hellmuth, Sarah ;

Kwong, Alan ;

Lappalainen, Tuuli ;

Li, Xiao ;

Liang, Yanyu ;

MacArthur, Daniel G. ;

Mohammadi, Pejman ;

Montgomery, Stephen B. ;

Munoz-Aguirre, Manuel ;

Rouhana, John M. ;

Hormozdiari, Farhad ;

Im, Hae Kyung .

SCIENCE, 2020, 369 (6509) :1318-1330

[2] SNPs on chromosome 5p15.3 associated with myocardial infarction in Japanese population [J].

Aoki, Asako ;

Ozaki, Kouichi ;

Sato, Hiroshi ;

Takahashi, Atsushi ;

Kubo, Michiaki ;

Sakata, Yasuhiko ;

Onouchi, Yoshihiro ;

Kawaguchi, Takahisa ;

Lin, Tsung-Hsien ;

Takano, Hitoshi ;

Yasutake, Masahiro ;

Hsu, Po-Chao ;

Ikegawa, Shiro ;

Kamatani, Naoyuki ;

Tsunoda, Tatsuhiko ;

Juo, Suh-Hang H. ;

Hori, Masatsugu ;

Komuro, Issei ;

Mizuno, Kyoichi ;

Nakamura, Yusuke ;

Tanaka, Toshihiro .

JOURNAL OF HUMAN GENETICS, 2011, 56 (01) :47-51

[3]

Aragam K.G., 2021, bioRxiv, DOI [DOI 10.1101/2021.05.24.21257377, 10.1101/2021.05.24.21257377]

[4] Using Phecodes for Research with the Electronic Health Record: From PheWAS to PheRS [J].

Bastarache, Lisa .

ANNUAL REVIEW OF BIOMEDICAL DATA SCIENCE, VOL 4, 2021, 4 :1-19

[5] VENODILATION IN RAYNAUDS-DISEASE [J].

BEDARIDA, GV ;

KIM, D ;

BLASCHKE, TF ;

HOFFMAN, BB .

LANCET, 1993, 342 (8885) :1451-1454

[6] ESVM guidelines - the diagnosis and management of Raynaud's phenomenon [J].

Belch, Jill ;

Carlizza, Anita ;

Carpentier, Patrick H. ;

Constans, Joel ;

Khan, Faisel ;

Wautrecht, Jean-Claude ;

Visona, Adriana ;

Heiss, Christian ;

Brodeman, Marianne ;

Pecsvarady, Zsolt ;

Roztocil, Karel ;

Colgan, Mary-Paula ;

Vasic, Dragan ;

Gottsater, Anders ;

Amann-Vesti, Beatrice ;

Chraim, Ali ;

Poredos, Pavel ;

Olinic, Dan-Mircea ;

Madaric, Juraj ;

Nikol, Sigrid ;

Herrick, Ariane L. ;

Sprynger, Muriel ;

Klein-Weigel, Peter ;

Hafner, Franz ;

Staub, Daniel ;

Zeman, Zan .

VASA-EUROPEAN JOURNAL OF VASCULAR MEDICINE, 2017, 46 (06) :413-423

[7] LD Score regression distinguishes confounding from polygenicity in genome-wide association studies [J].

Bulik-Sullivan, Brendan K. ;

Loh, Po-Ru ;

Finucane, Hilary K. ;

Ripke, Stephan ;

Yang, Jian ;

Patterson, Nick ;

Daly, Mark J. ;

Price, Alkes L. ;

Neale, Benjamin M. .

NATURE GENETICS, 2015, 47 (03) :291-+

[8] The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019 [J].

Buniello, Annalisa ;

MacArthur, Jacqueline A. L. ;

Cerezo, Maria ;

Harris, Laura W. ;

Hayhurst, James ;

Malangone, Cinzia ;

McMahon, Aoife ;

Morales, Joannella ;

Mountjoy, Edward ;

Sollis, Elliot ;

Suveges, Daniel ;

Vrousgou, Olga ;

Whetzel, Patricia L. ;

Amode, Ridwan ;

Guillen, Jose A. ;

Riat, Harpreet S. ;

Trevanion, Stephen J. ;

Hall, Peggy ;

Junkins, Heather ;

Flicek, Paul ;

Burdett, Tony ;

Hindorff, Lucia A. ;

Cunningham, Fiona ;

Parkinson, Helen .

NUCLEIC ACIDS RESEARCH, 2019, 47 (D1) :D1005-D1012

[9] The UK Biobank resource with deep phenotyping and genomic data [J].

Bycroft, Clare ;

Freeman, Colin ;

Petkova, Desislava ;

Band, Gavin ;

Elliott, Lloyd T. ;

Sharp, Kevin ;

Motyer, Allan ;

Vukcevic, Damjan ;

Delaneau, Olivier ;

O'Connell, Jared ;

Cortes, Adrian ;

Welsh, Samantha ;

Young, Alan ;

Effingham, Mark ;

McVean, Gil ;

Leslie, Stephen ;

Allen, Naomi ;

Donnelly, Peter ;

Marchini, Jonathan .

NATURE, 2018, 562 (7726) :203-+

[10] Beta-blocker-associated hypoglycaemia: New insights from a real-world pharmacovigilance study [J].

Carnovale, Carla ;

Gringeri, Michele ;

Battini, Vera ;

Mosini, Giulia ;

Invernizzi, Elena ;

Mazhar, Faizan ;

Bergamaschi, Francesco ;

Fumagalli, Mara ;

Zuccotti, Gianvincenzo ;

Clementi, Emilio ;

Radice, Sonia ;

Fabiano, Valentina .

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 2021, 87 (08) :3320-3331

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