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

Journal article
Authors N. Franceschini
C. Giambartolomei
P. S. de Vries
C. Finan
J. C. Bis
R. P. Huntley
R. C. Lovering
S. M. Tajuddin
T. W. Winkler
M. Graff
M. Kavousi
C. Dale
A. V. Smith
E. Hofer
E. M. van Leeuwen
I. M. Nolte
L. Lu
M. Scholz
M. Sargurupremraj
N. Pitkänen
O. Franzén
P. K. Joshi
R. Noordam
R. E. Marioni
S. J. Hwang
S. K. Musani
U. Schminke
W. Palmas
A. Isaacs
A. Correa
A. B. Zonderman
A. Hofman
A. Teumer
A. J. Cox
A. G. Uitterlinden
A. Wong
A. J. Smit
A. B. Newman
A. Britton
A. Ruusalepp
B. Sennblad
B. Hedblad
B. Pasaniuc
B. W. Penninx
C. D. Langefeld
C. L. Wassel
C. Tzourio
C. Fava
D. Baldassarre
D. H. O’Leary
D. Teupser
D. Kuh
E. Tremoli
E. Mannarino
E. Grossi
E. Boerwinkle
E. E. Schadt
E. Ingelsson
F. Veglia
F. Rivadeneira
F. Beutner
G. Chauhan
G. Heiss
H. Snieder
H. Campbell
H. Völzke
H. S. Markus
I. J. Deary
J. W. Jukema
J. de Graaf
J. Price
J. Pott
J. C. Hopewell
J. Liang
J. Thiery
J. Engmann
K. Gertow
K. Rice
K. D. Taylor
K. Dhana
L. A. L. M. Kiemeney
L. Lind
L. M. Raffield
L. J. Launer
L. M. Holdt
M. Dörr
M. Dichgans
M. Traylor
M. Sitzer
M. Kumari
M. Kivimaki
M. A. Nalls
O. Melander
O. Raitakari
O. H. Franco
O. L. Rueda-Ochoa
P. Roussos
P. H. Whincup
P. Amouyel
P. Giral
P. Anugu
Q. Wong
R. Malik
R. Rauramaa
R. Burkhardt
R. Hardy
R. Schmidt
R. de Mutsert
R. W. Morris
R. J. Strawbridge
S. G. Wannamethee
S. Hägg
S. Shah
S. McLachlan
S. Trompet
S. Seshadri
S. Kurl
S. R. Heckbert
S. Ring
T. B. Harris
T. Lehtimäki
T. E. Galesloot
T. Shah
U. de Faire
V. Plagnol
W. D. Rosamond
W. Post
X. Zhu
X. Zhang
X. Guo
Y. Saba
Y. Okada
A. Mishra
L. Rutten-Jacobs
A. K. Giese
S. W. van der Laan
S. Gretarsdottir
C. D. Anderson
M. Chong
H. H. H. Adams
T. Ago
P. Almgren
P. Amouyel
H. Ay
T. M. Bartz
O. R. Benavente
S. Bevan
G. B. Boncoraglio
Jr. Brown
A. S. Butterworth
C. Carrera
C. L. Carty
D. I. Chasman
W. M. Chen
J. W. Cole
I. Cotlarciuc
C. Cruchaga
J. Danesh
P. I. W. de Bakker
A. L. DeStefano
M. den Hoed
Q. Duan
S. T. Engelter
G. J. Falcone
R. F. Gottesman
R. P. Grewal
S. Gustafsson
J. Haessler
T. B. Harris
A. Hassan
A. S. Havulinna
E. G. Holliday
G. Howard
F. C. Hsu
H. I. Hyacinth
M. A. Ikram
M. R. Irvin
X. Jian
J. Jiménez-Conde
J. A. Johnson
J. W. Jukema
M. Kanai
K. L. Keene
B. M. Kissela
D. O. Kleindorfer
C. Kooperberg
M. Kubo
L. Lange
C. D. Langefeld
C. Langenberg
J. M. Lee
R. Lemmens
D. Leys
C. M. Lewis
W. Y. Lin
A. G. Lindgren
Erik Lorentzen
P. K. Magnusson
J. Maguire
A. Manichaikul
P. F. McArdle
J. F. Meschia
T. H. Mosley
T. Ninomiya
M. J. O’Donnell
S. L. Pulit
K. Rannikmäe
A. P. Reiner
K. M. Rexrode
S. S. Rich
P. M. Ridker
N. S. Rost
P. M. Rothwell
T. Rundek
R. L. Sacco
S. Sakaue
M. M. Sale
V. Salomaa
B. R. Sapkota
R. Schmidt
C. O. Schmidt
U. Schminke
P. Sharma
A. Slowik
C. L. M. Sudlow
C. Tanislav
Turgut Tatlisumak
V. N. S. Thijs
G. Thorleifsson
U. Thorsteinsdottir
S. Tiedt
S. Trompet
M. Walters
N. J. Wareham
S. Wassertheil-Smoller
K. L. Wiggins
Q. Yang
S. Yusuf
T. Pastinen
A. Ruusalepp
E. E. Schadt
S. Koplev
V. Codoni
M. Civelek
N. Smith
D. A. Trégouët
I. E. Christophersen
C. Roselli
S. A. Lubitz
P. T. Ellinor
E. S. Tai
J. S. Kooner
N. Kato
J. He
P. van der Harst
P. Elliott
J. C. Chambers
F. Takeuchi
A. D. Johnson
D. K. Sanghera
O. Melander
Christina Jern
D. Strbian
I. Fernandez-Cadenas
Jr. Longstreth
A. Rolfs
J. Hata
D. Woo
J. Rosand
G. Pare
D. Saleheen
K. Stefansson
B. B. Worrall
S. J. Kittner
J. M. M. Howson
Y. Kamatani
A. Dehghan
A. Seldenrijk
A. C. Morrison
A. Hamsten
B. M. Psaty
C. M. van Duijn
D. A. Lawlor
D. O. Mook-Kanamori
D. W. Bowden
H. Schmidt
J. F. Wilson
J. G. Wilson
J. I. Rotter
J. M. Wardlaw
J. Deanfield
J. Halcox
L. P. Lyytikäinen
M. Loeffler
M. K. Evans
S. Debette
S. E. Humphries
U. Völker
V. Gudnason
A. D. Hingorani
J. L. M. Björkegren
J. P. Casas
C. J. O’Donnell
Published in Nature Communications
Volume 9
Issue 1
ISSN 20411723 (ISSN)
Publication year 2018
Published at Institute of Biomedicine, Department of Pathology
Core Facilities, Bioinformatics
Institute of Neuroscience and Physiology, Department of Clinical Neuroscience
Language en
Links dx.doi.org/10.1038/s41467-018-07340...
Keywords ADAMTS9 protein, apolipoprotein E, loxl4 protein, protein, unclassified drug, cardiovascular disease, cell, cell component, gene expression, genetic analysis, genomics, stroke, adipose derived stem cell, arterial wall thickness, artery wall, Article, B scan, brain ischemia, cardiovascular system, carotid atherosclerosis, cell adhesion, cerebrovascular accident, CFDP1-TMEM170A gene, chromosome 7, chromosome 8, clinical outcome, coronary artery disease, disease association, EDNRA gene, epigenetics, expression quantitative trait locus, gene, gene control, gene frequency, gene locus, genetic correlation, genetic epidemiology, genetic regulation, genetic risk, genetic susceptibility, genetic variability, genome-wide association study, heart atrium appendage, human, human cell, internal mammary artery, ischemic heart disease, mesenchymal stem cell, nonhuman, PIK3CG gene, regulatory mechanism, single nucleotide polymorphism, STEAP2-AS1 gene, tibial artery, TMCO5B gene
Subject categories Medical Genetics

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. © 2018, The Author(s).

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