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

MEGASTROKE Consortium; Nora Franceschini; Claudia Giambartolomei; Paul S. de Vries; Chris Finan; Joshua C. Bis; Rachael P. Huntley; Ruth C. Lovering; Salman M. Tajuddin; Thomas W. Winkler; Misa Graff; Maryam Kavousi; Caroline Dale; Albert V. Smith; Edith Hofer; Elisabeth M. van Leeuwen; Ilja M. Nolte; Lingyi Lu; Markus Scholz; Muralidharan Sargurupremraj; Niina Pitkanen; Oscar Franzen; Peter K. Joshi; Raymond Noordam; Riccardo E. Marioni; Shih-Jen Hwang; Solomon K. Musani; Ulf Schminke; Walter Palmas; Aaron Isaacs; Adolfo Correa; Alan B. Zonderman; Albert Hofman; Alexander Teumer; Amanda J. Cox; Andre G. Uitterlinden; Andrew Wong; Andries J. Smit; Anne B. Newman; Annie Britton; Arno Ruusalepp; Bengt Sennblad; Bo Hedblad; Bogdan Pasaniuc; Brenda W. Penninx; Carl D. Langefeld; Christina L. Wassel; Christophe Tzourio; Harold Snieder; Meena Kumari; Wendy Post

doi:10.1038/s41467-018-07340-5

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

MEGASTROKE Consortium, Nora Franceschini, Claudia Giambartolomei, Paul S. de Vries, Chris Finan, Joshua C. Bis, Rachael P. Huntley, Ruth C. Lovering, Salman M. Tajuddin, Thomas W. Winkler, Misa Graff, Maryam Kavousi, Caroline Dale, Albert V. Smith, Edith Hofer, Elisabeth M. van Leeuwen, Ilja M. Nolte, Lingyi Lu, Markus Scholz, Muralidharan SargurupremrajNiina Pitkanen, Oscar Franzen, Peter K. Joshi, Raymond Noordam, Riccardo E. Marioni, Shih-Jen Hwang, Solomon K. Musani, Ulf Schminke, Walter Palmas, Aaron Isaacs, Adolfo Correa, Alan B. Zonderman, Albert Hofman, Alexander Teumer, Amanda J. Cox, Andre G. Uitterlinden, Andrew Wong, Andries J. Smit, Anne B. Newman, Annie Britton, Arno Ruusalepp, Bengt Sennblad, Bo Hedblad, Bogdan Pasaniuc, Brenda W. Penninx, Carl D. Langefeld, Christina L. Wassel, Christophe Tzourio, Harold Snieder, Meena Kumari, Wendy Post

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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 language	English
Article number	5141
Number of pages	14
Journal	Nature Communications
Volume	9
DOIs	https://doi.org/10.1038/s41467-018-07340-5
Publication status	Published - 3-Dec-2018

Keywords

GENOME-WIDE ASSOCIATION
CORONARY-ARTERY-DISEASE
INTEGRATIVE ANALYSIS
GENE-PRODUCT
METAANALYSIS
VARIANTS
HEART

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MEGASTROKE Consortium, Franceschini, N., Giambartolomei, C., de Vries, P. S., Finan, C., Bis, J. C., Huntley, R. P., Lovering, R. C., Tajuddin, S. M., Winkler, T. W., Graff, M., Kavousi, M., Dale, C., Smith, A. V., Hofer, E., van Leeuwen, E. M., Nolte, I. M., Lu, L., Scholz, M., ... Post, W. (2018). GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes. Nature Communications, 9, Article 5141. https://doi.org/10.1038/s41467-018-07340-5

@article{8f612906219e4004b372223422c0bf23,

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.",

keywords = "GENOME-WIDE ASSOCIATION, CORONARY-ARTERY-DISEASE, INTEGRATIVE ANALYSIS, GENE-PRODUCT, METAANALYSIS, VARIANTS, HEART",

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 Pitkanen and Oscar Franzen and Joshi, {Peter K.} and Raymond Noordam and Marioni, {Riccardo E.} and Shih-Jen Hwang 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, {Andre 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 Harold Snieder and Meena Kumari and Wendy Post",

year = "2018",

month = dec,

day = "3",

doi = "10.1038/s41467-018-07340-5",

language = "English",

volume = "9",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

MEGASTROKE Consortium, Franceschini, N, Giambartolomei, C, de Vries, PS, Finan, C, Bis, JC, Huntley, RP, Lovering, RC, Tajuddin, SM, Winkler, TW, Graff, M, Kavousi, M, Dale, C, Smith, AV, Hofer, E, van Leeuwen, EM, Nolte, IM, Lu, L, Scholz, M, Sargurupremraj, M, Pitkanen, N, Franzen, O, Joshi, PK, Noordam, R, Marioni, RE, Hwang, S-J, Musani, SK, Schminke, U, Palmas, W, Isaacs, A, Correa, A, Zonderman, AB, Hofman, A, Teumer, A, Cox, AJ, Uitterlinden, AG, Wong, A, Smit, AJ, Newman, AB, Britton, A, Ruusalepp, A, Sennblad, B, Hedblad, B, Pasaniuc, B, Penninx, BW, Langefeld, CD, Wassel, CL, Tzourio, C, Snieder, H, Kumari, M & Post, W 2018, 'GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes', Nature Communications, vol. 9, 5141. https://doi.org/10.1038/s41467-018-07340-5

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 - Pitkanen, Niina

AU - Franzen, 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, Andre 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 - Snieder, Harold

AU - Kumari, Meena

AU - Post, Wendy

PY - 2018/12/3

Y1 - 2018/12/3

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.

KW - GENOME-WIDE ASSOCIATION

KW - CORONARY-ARTERY-DISEASE

KW - INTEGRATIVE ANALYSIS

KW - GENE-PRODUCT

KW - METAANALYSIS

KW - VARIANTS

KW - HEART

U2 - 10.1038/s41467-018-07340-5

DO - 10.1038/s41467-018-07340-5

M3 - Article

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

M1 - 5141

ER -

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

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Keywords

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