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; Christina L. Wassel; Christophe Tzourio; Cristiano Fava; Damiano Baldassarre; Daniel H. O’leary; Daniel Teupser; Diana Kuh; Elena Tremoli; Elmo Mannarino; Enzo Grossi; Eric Boerwinkle; Eric E. Schadt; Erik Ingelsson; Fabrizio Veglia; Fernando Rivadeneira; Frank Beutner; Ganesh Chauhan; Gerardo Heiss; Harold Snieder; Harry Campbell; Henry Völzke; Hugh S. Markus; Ian J. Deary; J. Wouter Jukema; Jacqueline De Graaf; Jacqueline Price; Janne Pott; Jemma C. Hopewell; Jingjing Liang; Joachim Thiery; Jorgen Engmann; Karl Gertow; Kenneth Rice; Kent D. Taylor; Klodian Dhana; Lambertus A. L. M. Kiemeney; Lars Lind; Laura M. Raffield; Lenore J. Launer; Lesca M. Holdt; Marcus Dörr; Martin Dichgans; Matthew Traylor; Matthias Sitzer; Meena Kumari; Mika Kivimaki; Mike A. Nalls; Olle Melander; Olli Raitakari; Oscar H. Franco; Oscar L. Rueda-ochoa; Panos Roussos; Peter H. Whincup; Philippe Amouyel; Philippe Giral; Pramod Anugu; Quenna Wong; Rainer Malik; Rainer Rauramaa; Ralph Burkhardt; Rebecca Hardy; Reinhold Schmidt; Renée De Mutsert; Richard W. Morris; Rona J. Strawbridge; S. Goya Wannamethee; Sara Hägg; Sonia Shah; Stela Mclachlan; Stella Trompet; Sudha Seshadri; Sudhir Kurl; Susan R. Heckbert; Susan Ring; Tamara B. Harris; Terho Lehtimäki; Tessel E. Galesloot; Tina Shah; Ulf De Faire; Vincent Plagnol; Wayne D. Rosamond; Wendy Post; Xiaofeng Zhu; Xiaoling Zhang; Xiuqing Guo; Yasaman Saba; Abbas Dehghan; Adrie Seldenrijk; Alanna C. Morrison; Anders Hamsten; Bruce M. Psaty; Cornelia M. Van Duijn; Deborah A. Lawlor; Dennis O. Mook-kanamori; Donald W. Bowden; Helena Schmidt; James G. Wilson; Jerome I. Rotter; Joanna M. Wardlaw; John Deanfield; Julian Halcox; Leo-pekka Lyytikäinen; Markus Loeffler; Michele K. Evans; Stéphanie Debette; Steve E. Humphries; Uwe Völker; Vilmundur Gudnason; Aroon D. Hingorani; Johan L. M. Björkegren; Juan P. Casas; Christopher J. O’donnell

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, Christina L. Wassel, Christophe Tzourio, Cristiano Fava, Damiano Baldassarre, Daniel H. O’leary, Daniel Teupser, Diana Kuh, Elena Tremoli, Elmo Mannarino, Enzo Grossi, Eric Boerwinkle, Eric E. Schadt, Erik Ingelsson, Fabrizio Veglia, Fernando Rivadeneira, Frank Beutner, Ganesh Chauhan, Gerardo Heiss, Harold Snieder, Harry Campbell, Henry Völzke, Hugh S. Markus, Ian J. Deary, J. Wouter Jukema, Jacqueline De Graaf, Jacqueline Price, Janne Pott, Jemma C. Hopewell, Jingjing Liang, Joachim Thiery, Jorgen Engmann, Karl Gertow, Kenneth Rice, Kent D. Taylor, Klodian Dhana, Lambertus A. L. M. Kiemeney, Lars Lind, Laura M. Raffield, Lenore J. Launer, Lesca M. Holdt, Marcus Dörr, Martin Dichgans, Matthew Traylor, Matthias Sitzer, Meena Kumari, Mika Kivimaki, Mike A. Nalls, Olle Melander, Olli Raitakari, Oscar H. Franco, Oscar L. Rueda-ochoa, Panos Roussos, Peter H. Whincup, Philippe Amouyel, Philippe Giral, Pramod Anugu, Quenna Wong, Rainer Malik, Rainer Rauramaa, Ralph Burkhardt, Rebecca Hardy, Reinhold Schmidt, Renée De Mutsert, Richard W. Morris, Rona J. Strawbridge, S. Goya Wannamethee, Sara Hägg, Sonia Shah, Stela Mclachlan, Stella Trompet, Sudha Seshadri, Sudhir Kurl, Susan R. Heckbert, Susan Ring, Tamara B. Harris, Terho Lehtimäki, Tessel E. Galesloot, Tina Shah, Ulf De Faire, Vincent Plagnol, Wayne D. Rosamond, Wendy Post, Xiaofeng Zhu, Xiaoling Zhang, Xiuqing Guo, Yasaman Saba, Abbas Dehghan, Adrie Seldenrijk, Alanna C. Morrison, Anders Hamsten, Bruce M. Psaty, Cornelia M. Van Duijn, Deborah A. Lawlor, Dennis O. Mook-kanamori, Donald W. Bowden, Helena Schmidt, James G. Wilson, Jerome I. Rotter, Joanna M. Wardlaw, John Deanfield, Julian Halcox, Leo-pekka Lyytikäinen, Markus Loeffler, Michele K. Evans, Stéphanie Debette, Steve E. Humphries, Uwe Völker, Vilmundur Gudnason, Aroon D. Hingorani, Johan L. M. Björkegren, Juan P. Casas, Christopher J. O’donnell

Research output: Contribution to journal › Article › peer-review

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 - 3 Dec 2018

Keywords / Materials (for Non-textual outputs)

cardiovascular diseases
cardiovascular genetics
genome-wide association studies
quantitative trait loci

Access to Document

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FranceschiniEtalNC2018GWASAndColocalizationFinal published version, 1.63 MBLicence: Creative Commons: Attribution (CC-BY)

http://www.nature.com/articles/s41467-018-07340-5Licence: Creative Commons: Attribution (CC-BY)

The Disconnected Mind Phase 3
Wardlaw, J. (Principal Investigator)
UK-based charities
1/04/16 → 30/09/20
Project: Research
Brain imaging and cognitive ageing in the Lothian Birth Cohort 1936: III
Wardlaw, J. (Principal Investigator), Bastin, M. (Co-investigator) & Deary, I. (Co-investigator)
MRC
1/05/15 → 30/04/19
Project: Research
RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.
Deary, I. (Principal Investigator), Gale, C. (Co-investigator), Holmes, M. (Co-investigator), Logie, P. (Co-investigator), Maclullich, A. (Co-investigator), Porteous, D. (Co-investigator), Seckl, J. (Co-investigator), Starr, J. (Co-investigator), Wardlaw, J. (Co-investigator) & Okely, J. (Researcher)
1/09/13 → 31/08/19
Project: Research

Cite this

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., ... O’donnell, C. J. (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{d23e9102304747e592abb92e412ecd85,

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 = "cardiovascular diseases, cardiovascular genetics, genome-wide association studies, quantitative trait loci",

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 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, {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{\textquoteright}leary, {Daniel H.} and Daniel Teupser and Diana Kuh and Elena Tremoli and Elmo Mannarino and Enzo Grossi and Eric Boerwinkle and Schadt, {Eric E.} and Erik Ingelsson and Fabrizio Veglia and Fernando Rivadeneira and Frank Beutner and Ganesh Chauhan and Gerardo Heiss and Harold Snieder and Harry Campbell and Henry V{\"o}lzke and Markus, {Hugh S.} and Deary, {Ian J.} and Jukema, {J. Wouter} and {De Graaf}, Jacqueline and Jacqueline Price and Janne Pott and Hopewell, {Jemma C.} and Jingjing Liang and Joachim Thiery and Jorgen Engmann and Karl Gertow and Kenneth Rice and Taylor, {Kent D.} and Klodian Dhana and Kiemeney, {Lambertus A. L. M.} and Lars Lind and Raffield, {Laura M.} and Launer, {Lenore J.} and Holdt, {Lesca M.} and Marcus D{\"o}rr and Martin Dichgans and Matthew Traylor and Matthias Sitzer and Meena Kumari and Mika Kivimaki and Nalls, {Mike A.} and Olle Melander and Olli Raitakari and Franco, {Oscar H.} and Rueda-ochoa, {Oscar L.} and Panos Roussos and Whincup, {Peter H.} and Philippe Amouyel and Philippe Giral and Pramod Anugu and Quenna Wong and Rainer Malik and Rainer Rauramaa and Ralph Burkhardt and Rebecca Hardy and Reinhold Schmidt and {De Mutsert}, Ren{\'e}e and Morris, {Richard W.} and Strawbridge, {Rona J.} and Wannamethee, {S. Goya} and Sara H{\"a}gg and Sonia Shah and Stela Mclachlan and Stella Trompet and Sudha Seshadri and Sudhir Kurl and Heckbert, {Susan R.} and Susan Ring and Harris, {Tamara B.} and Terho Lehtim{\"a}ki and Galesloot, {Tessel E.} and Tina Shah and {De Faire}, Ulf and Vincent Plagnol and Rosamond, {Wayne D.} and Wendy Post and Xiaofeng Zhu and Xiaoling Zhang and Xiuqing Guo and Yasaman Saba and Abbas Dehghan and Adrie Seldenrijk and Morrison, {Alanna C.} and Anders Hamsten and Psaty, {Bruce M.} and {Van Duijn}, {Cornelia M.} and Lawlor, {Deborah A.} and Mook-kanamori, {Dennis O.} and Bowden, {Donald W.} and Helena Schmidt and Wilson, {James G.} and Rotter, {Jerome I.} and Wardlaw, {Joanna M.} and John Deanfield and Julian Halcox and Leo-pekka Lyytik{\"a}inen and Markus Loeffler and Evans, {Michele K.} and St{\'e}phanie Debette and Humphries, {Steve E.} and Uwe V{\"o}lker and Vilmundur Gudnason and Hingorani, {Aroon D.} and Bj{\"o}rkegren, {Johan L. M.} and Casas, {Juan P.} and O{\textquoteright}donnell, {Christopher J.}",

note = "Published Gold",

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",

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, S, 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, Fava, C, Baldassarre, D, O’leary, DH, Teupser, D, Kuh, D, Tremoli, E, Mannarino, E, Grossi, E, Boerwinkle, E, Schadt, EE, Ingelsson, E, Veglia, F, Rivadeneira, F, Beutner, F, Chauhan, G, Heiss, G, Snieder, H, Campbell, H, Völzke, H, Markus, HS, Deary, IJ, Jukema, JW, De Graaf, J, Price, J, Pott, J, Hopewell, JC, Liang, J, Thiery, J, Engmann, J, Gertow, K, Rice, K, Taylor, KD, Dhana, K, Kiemeney, LALM, Lind, L, Raffield, LM, Launer, LJ, Holdt, LM, Dörr, M, Dichgans, M, Traylor, M, Sitzer, M, Kumari, M, Kivimaki, M, Nalls, MA, Melander, O, Raitakari, O, Franco, OH, Rueda-ochoa, OL, Roussos, P, Whincup, PH, Amouyel, P, Giral, P, Anugu, P, Wong, Q, Malik, R, Rauramaa, R, Burkhardt, R, Hardy, R, Schmidt, R, De Mutsert, R, Morris, RW, Strawbridge, RJ, Wannamethee, SG, Hägg, S, Shah, S, Mclachlan, S, Trompet, S, Seshadri, S, Kurl, S, Heckbert, SR, Ring, S, Harris, TB, Lehtimäki, T, Galesloot, TE, Shah, T, De Faire, U, Plagnol, V, Rosamond, WD, Post, W, Zhu, X, Zhang, X, Guo, X, Saba, Y, Dehghan, A, Seldenrijk, A, Morrison, AC, Hamsten, A, Psaty, BM, Van Duijn, CM, Lawlor, DA, Mook-kanamori, DO, Bowden, DW, Schmidt, H, Wilson, JG, Rotter, JI, Wardlaw, JM, Deanfield, J, Halcox, J, Lyytikäinen, L, Loeffler, M, Evans, MK, Debette, S, Humphries, SE, Völker, U, Gudnason, V, Hingorani, AD, Björkegren, JLM, Casas, JP & O’donnell, CJ 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 - Wassel, Christina L.

AU - Tzourio, Christophe

AU - Fava, Cristiano

AU - Baldassarre, Damiano

AU - O’leary, Daniel H.

AU - Teupser, Daniel

AU - Kuh, Diana

AU - Tremoli, Elena

AU - Mannarino, Elmo

AU - Grossi, Enzo

AU - Boerwinkle, Eric

AU - Schadt, Eric E.

AU - Ingelsson, Erik

AU - Veglia, Fabrizio

AU - Rivadeneira, Fernando

AU - Beutner, Frank

AU - Chauhan, Ganesh

AU - Heiss, Gerardo

AU - Snieder, Harold

AU - Campbell, Harry

AU - Völzke, Henry

AU - Markus, Hugh S.

AU - Deary, Ian J.

AU - Jukema, J. Wouter

AU - De Graaf, Jacqueline

AU - Price, Jacqueline

AU - Pott, Janne

AU - Hopewell, Jemma C.

AU - Liang, Jingjing

AU - Thiery, Joachim

AU - Engmann, Jorgen

AU - Gertow, Karl

AU - Rice, Kenneth

AU - Taylor, Kent D.

AU - Dhana, Klodian

AU - Kiemeney, Lambertus A. L. M.

AU - Lind, Lars

AU - Raffield, Laura M.

AU - Launer, Lenore J.

AU - Holdt, Lesca M.

AU - Dörr, Marcus

AU - Dichgans, Martin

AU - Traylor, Matthew

AU - Sitzer, Matthias

AU - Kumari, Meena

AU - Kivimaki, Mika

AU - Nalls, Mike A.

AU - Melander, Olle

AU - Raitakari, Olli

AU - Franco, Oscar H.

AU - Rueda-ochoa, Oscar L.

AU - Roussos, Panos

AU - Whincup, Peter H.

AU - Amouyel, Philippe

AU - Giral, Philippe

AU - Anugu, Pramod

AU - Wong, Quenna

AU - Malik, Rainer

AU - Rauramaa, Rainer

AU - Burkhardt, Ralph

AU - Hardy, Rebecca

AU - Schmidt, Reinhold

AU - De Mutsert, Renée

AU - Morris, Richard W.

AU - Strawbridge, Rona J.

AU - Wannamethee, S. Goya

AU - Hägg, Sara

AU - Shah, Sonia

AU - Mclachlan, Stela

AU - Trompet, Stella

AU - Seshadri, Sudha

AU - Kurl, Sudhir

AU - Heckbert, Susan R.

AU - Ring, Susan

AU - Harris, Tamara B.

AU - Lehtimäki, Terho

AU - Galesloot, Tessel E.

AU - Shah, Tina

AU - De Faire, Ulf

AU - Plagnol, Vincent

AU - Rosamond, Wayne D.

AU - Post, Wendy

AU - Zhu, Xiaofeng

AU - Zhang, Xiaoling

AU - Guo, Xiuqing

AU - Saba, Yasaman

AU - Dehghan, Abbas

AU - Seldenrijk, Adrie

AU - Morrison, Alanna C.

AU - Hamsten, Anders

AU - Psaty, Bruce M.

AU - Van Duijn, Cornelia M.

AU - Lawlor, Deborah A.

AU - Mook-kanamori, Dennis O.

AU - Bowden, Donald W.

AU - Schmidt, Helena

AU - Wilson, James G.

AU - Rotter, Jerome I.

AU - Wardlaw, Joanna M.

AU - Deanfield, John

AU - Halcox, Julian

AU - Lyytikäinen, Leo-pekka

AU - Loeffler, Markus

AU - Evans, Michele K.

AU - Debette, Stéphanie

AU - Humphries, Steve E.

AU - Völker, Uwe

AU - Gudnason, Vilmundur

AU - Hingorani, Aroon D.

AU - Björkegren, Johan L. M.

AU - Casas, Juan P.

AU - O’donnell, Christopher J.

N1 - Published Gold

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 - cardiovascular diseases

KW - cardiovascular genetics

KW - genome-wide association studies

KW - quantitative trait loci

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

IS - 1

M1 - 5141

ER -

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

Abstract

Keywords / Materials (for Non-textual outputs)

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Projects

The Disconnected Mind Phase 3

Brain imaging and cognitive ageing in the Lothian Birth Cohort 1936: III

RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.

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