GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes
Franceschini, Nora; Giambartolomei, Claudia; de Vries, Paul S.; Finan, Chris; Bis, Joshua C.; Huntley, Rachael P.; Lovering, Ruth C.; Tajuddin, Salman M.; Winkler, Thomas W.; Graff, Misa; Kavousi, Maryam; Dale, Caroline; Smith, Albert V.; Hofer, Edith; van Leeuwen, Elisabeth M.; Nolte, Ilja M.; Lu, Lingyi; Scholz, Markus; Sargurupremraj, Muralidharan; Pitkänen, Niina; Franzén, Oscar; Joshi, Peter K.; Noordam, Raymond; Marioni, Riccardo E.; Hwang, Shih Jen; Musani, Solomon K.; Schminke, Ulf; Palmas, Walter; Isaacs, Aaron; Correa, Adolfo; Zonderman, Alan B.; Hofman, Albert; Teumer, Alexander; Cox, Amanda J.; Uitterlinden, André G.; Wong, Andrew; Smit, Andries J.; Newman, Anne B.; Britton, Annie; Ruusalepp, Arno; Sennblad, Bengt; Hedblad, Bo; Pasaniuc, Bogdan; Penninx, Brenda W.; Langefeld, Carl D.; Franco, Oscar H.; van der Laan, Sander W.; de Bakker, Paul I.W.; Pulit, Sara L.; van der Harst, Pim; MEGASTROKE Consortium
(2018) Nature Communications, volume 9, issue 1
(Article)
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
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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.
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Keywords: General Chemistry, General Biochemistry,Genetics and Molecular Biology, General Physics and Astronomy
ISSN: 2041-1723
Publisher: Nature Publishing Group
Note: Funding Information: Competing interests: C.F. received a fee for speaking at a course by Springer Healthcare/ Malesci. E.I. is a scientific advisor for Precision Wellness, Cellink and Olink Proteomics for work unrelated to the present project. M.A.N.’s participation in this project was supported by a consulting contract between Data Tecnica International and the National Institute on Aging, NIH, Bethesda, MD, USA. M.A.N. also consults for Illumina Inc., the Michael J. Fox Foundation, and University of California Healthcare. B.M.P. serves on the DSMB of a clinical trial funded by Zoll LifeCor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. D.A.L. has received support from Roche Diagnostics and Medtronic for biomarker research unrelated to this paper. J.P.C. has received funding from GSK regarding methodological work around electronic health records, and -omics for drug discovery. All remaining authors declare no competing interests. Funding Information: 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:Ather-oSysMed), 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. Publisher Copyright: © 2018, The Author(s).
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