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

MEGASTROKE Consortium

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Article number5141
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 01-12-2018

Fingerprint

Carotid Intima-Media Thickness
genome
Genome-Wide Association Study
loci
arteries
Carotid Arteries
heart diseases
Genes
strokes
Coronary Disease
arteriosclerosis
Tissue
Stroke
genes
Atherosclerosis
Myocardial Ischemia
Blood Vessels
Meta-Analysis
regression analysis
magnetic permeability

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

@article{eedcb832be1949859f5a2626f9cf8d46,
title = "GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes",
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.",
author = "{MEGASTROKE Consortium} and Nora Franceschini and Claudia Giambartolomei and {de Vries}, {Paul S.} and Chris Finan and Bis, {Joshua C.} and Huntley, {Rachael P.} and Lovering, {Ruth C.} and Tajuddin, {Salman M.} and Winkler, {Thomas W.} and Misa Graff and Maryam Kavousi and Caroline Dale and Smith, {Albert V.} and Edith Hofer and {van Leeuwen}, {Elisabeth M.} and Nolte, {Ilja M.} and Lingyi Lu and Markus Scholz and Muralidharan Sargurupremraj and Niina Pitk{\"a}nen and Oscar Franz{\'e}n and Joshi, {Peter K.} and Raymond Noordam and Marioni, {Riccardo E.} and Hwang, {Shih Jen} and Musani, {Solomon K.} and Ulf Schminke and Walter Palmas and Aaron Isaacs and Adolfo Correa and Zonderman, {Alan B.} and Albert Hofman and Alexander Teumer and Cox, {Amanda J.} and Uitterlinden, {Andr{\'e} G.} and Andrew Wong and Smit, {Andries J.} and Newman, {Anne B.} and Annie Britton and Arno Ruusalepp and Bengt Sennblad and Bo Hedblad and Bogdan Pasaniuc and Penninx, {Brenda W.} and Langefeld, {Carl D.} and Wassel, {Christina L.} and Christophe Tzourio and Cristiano Fava and Damiano Baldassarre and O’Leary, {Daniel H.}",
year = "2018",
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doi = "10.1038/s41467-018-07340-5",
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GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes. / MEGASTROKE Consortium.

In: Nature Communications, Vol. 9, No. 1, 5141, 01.12.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

AU - MEGASTROKE Consortium

AU - Franceschini, Nora

AU - Giambartolomei, Claudia

AU - de Vries, Paul S.

AU - Finan, Chris

AU - Bis, Joshua C.

AU - Huntley, Rachael P.

AU - Lovering, Ruth C.

AU - Tajuddin, Salman M.

AU - Winkler, Thomas W.

AU - Graff, Misa

AU - Kavousi, Maryam

AU - Dale, Caroline

AU - Smith, Albert V.

AU - Hofer, Edith

AU - van Leeuwen, Elisabeth M.

AU - Nolte, Ilja M.

AU - Lu, Lingyi

AU - Scholz, Markus

AU - Sargurupremraj, Muralidharan

AU - Pitkänen, Niina

AU - Franzén, Oscar

AU - Joshi, Peter K.

AU - Noordam, Raymond

AU - Marioni, Riccardo E.

AU - Hwang, Shih Jen

AU - Musani, Solomon K.

AU - Schminke, Ulf

AU - Palmas, Walter

AU - Isaacs, Aaron

AU - Correa, Adolfo

AU - Zonderman, Alan B.

AU - Hofman, Albert

AU - Teumer, Alexander

AU - Cox, Amanda J.

AU - Uitterlinden, André G.

AU - Wong, Andrew

AU - Smit, Andries J.

AU - Newman, Anne B.

AU - Britton, Annie

AU - Ruusalepp, Arno

AU - Sennblad, Bengt

AU - Hedblad, Bo

AU - Pasaniuc, Bogdan

AU - Penninx, Brenda W.

AU - Langefeld, Carl D.

AU - Wassel, Christina L.

AU - Tzourio, Christophe

AU - Fava, Cristiano

AU - Baldassarre, Damiano

AU - O’Leary, Daniel H.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

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