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

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 Pitkänen; Oscar Franzén; 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; André 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; Oscar H. Franco; Sander W. van der Laan; Paul I.W. de Bakker; Sara L. Pulit; Pim van der Harst

doi:10.1038/s41467-018-07340-5

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

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 PitkänenOscar Franzén, 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, André 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, Oscar H. Franco, Sander W. van der Laan, Paul I.W. de Bakker, Sara L. Pulit, Pim van der Harst,

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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
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-07340-5
Publication status	Published - 1 Dec 2018

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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., Sargurupremraj, M. (2018). GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes. Nature Communications, 9(1), Article 5141. https://doi.org/10.1038/s41467-018-07340-5

@article{b821e36460ee4bfabaff75626b70ca17,

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 = "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 Franco, {Oscar H.} and {van der Laan}, {Sander W.} and {de Bakker}, {Paul I.W.} and Pulit, {Sara L.} and {van der Harst}, Pim",

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.{\textquoteright}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: {\textcopyright} 2018, The Author(s).",

year = "2018",

month = dec,

day = "1",

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

language = "English",

volume = "9",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

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, Pitkänen, N, Franzén, O, Joshi, PK, Noordam, R, Marioni, RE, Hwang, SJ, 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, Franco, OH , van der Laan, SW, de Bakker, PIW, Pulit, SL, van der Harst, P 2018, 'GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes', Nature Communications, vol. 9, no. 1, 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 - 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 - Franco, Oscar H.

AU - van der Laan, Sander W.

AU - de Bakker, Paul I.W.

AU - Pulit, Sara L.

AU - van der Harst, Pim

N1 - 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).

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.

UR - http://www.scopus.com/inward/record.url?scp=85057617727&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-07340-5

DO - 10.1038/s41467-018-07340-5

M3 - Article

C2 - 30510157

AN - SCOPUS:85057617727

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5141

ER -

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

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