GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

Smith, Albert Vernon; Gudnason, Vilmundur; Grétarsdóttir, Sólveig; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Stefansson, Kari

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dc.contributor	Háskóli Íslands
dc.contributor	University of Iceland
dc.contributor.author	orcid.org/0000-0003-1942-5845 Smith, Albert Vernon
dc.contributor.author	orcid.org/0000-0001-5696-0084 Gudnason, Vilmundur
dc.contributor.author	Grétarsdóttir, Sólveig
dc.contributor.author	orcid.org/0000-0003-4623-9087 Thorleifsson, Gudmar
dc.contributor.author	Thorsteinsdottir, Unnur
dc.contributor.author	orcid.org/0000-0003-1676-864X Stefansson, Kari
dc.date.accessioned	2020-03-05T15:27:48Z
dc.date.available	2020-03-05T15:27:48Z
dc.date.issued	2018-12
dc.identifier.citation	Franceschini, N., Giambartolomei, C., de Vries, P.S. et al. GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes. Nat Commun 9, 5141 (2018). https://doi.org/10.1038/s41467-018-07340-5
dc.identifier.issn	2041-1723
dc.identifier.uri	https://hdl.handle.net/20.500.11815/1582
dc.description	Publisher's version (útgefin grein)
dc.description.abstract	Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.
dc.description.sponsorship	The work was supported by the following grants: National Institute of Health grants: R21HL123677, R21-HL140385, DK104806-01A1, R01-MD012765-01A1 (NF), National Institutes of Health awards R01HG009120, R01HG006399, U01CA194393, T32NS048004 (CG), the American Heart Association Grant #17POST33350042 (PV), the British Heart Foundation (RG/13/5/30112) and the National Institute for Health Research University College London Hospitals Biomedical Research Centre (RCL and RPH), the British Heart Foundation FS/14/55/30806 (JCH), the German Federal Ministry of Education and Research (BMBF) in the context of the e:Med program (e:AtheroSysMed), the DFG as part of the CRC 1123 (B3), and the FP7/2007-2103 European Union project CVgenes@target (grant agreement number Health-F2-2013-601456). We thank Li-Ming Gan for assistance with the STARNET study and Jon White for assistance with UCLEB analyses. Additional acknowledgements are included in Supplementary Note 2.
dc.format.extent	5141
dc.language.iso	en
dc.publisher	Springer Science and Business Media LLC
dc.relation.ispartofseries	Nature Communications;9(1)
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	Cardiovascular diseases
dc.subject	Cardiovascular genetics
dc.subject	Genome-wide association studies
dc.subject	Quantitative trait loci
dc.subject	Blóðrásarsjúkdómar
dc.subject	Erfðafræði
dc.subject	Erfðarannsóknir
dc.subject	hjarta
dc.title	GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes
dc.type	info:eu-repo/semantics/article
dcterms.license	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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.
dc.description.version	Peer Reviewed
dc.identifier.journal	Nature Communications
dc.identifier.doi	10.1038/s41467-018-07340-5
dc.contributor.department	Faculty of Medicine (UI)
dc.contributor.department	Læknadeild (HÍ)
dc.contributor.school	Heilbrigðisvísindasvið (HÍ)
dc.contributor.school	School of Health Sciences (UI)