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Meta-Analysis
. 2018 Dec 3;9(1):5141.
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  1 Claudia Giambartolomei  2 Paul S de Vries  3 Chris Finan  4 Joshua C Bis  5 Rachael P Huntley  4 Ruth C Lovering  4 Salman M Tajuddin  6 Thomas W Winkler  7 Misa Graff  1 Maryam Kavousi  8 Caroline Dale  9 Albert V Smith  10   11 Edith Hofer  12   13 Elisabeth M van Leeuwen  8 Ilja M Nolte  14 Lingyi Lu  15 Markus Scholz  16   17 Muralidharan Sargurupremraj  18 Niina Pitkänen  19 Oscar Franzén  20   21 Peter K Joshi  22 Raymond Noordam  23 Riccardo E Marioni  24   25 Shih-Jen Hwang  26   27 Solomon K Musani  28 Ulf Schminke  29 Walter Palmas  30 Aaron Isaacs  8   31 Adolfo Correa  28 Alan B Zonderman  6 Albert Hofman  8   32 Alexander Teumer  33   34 Amanda J Cox  35   36 André G Uitterlinden  8   37 Andrew Wong  38 Andries J Smit  39 Anne B Newman  40 Annie Britton  41 Arno Ruusalepp  21   42   43 Bengt Sennblad  44   45 Bo Hedblad  46 Bogdan Pasaniuc  2   47 Brenda W Penninx  48 Carl D Langefeld  15 Christina L Wassel  49 Christophe Tzourio  18 Cristiano Fava  46   50 Damiano Baldassarre  51   52 Daniel H O'Leary  53 Daniel Teupser  17   54 Diana Kuh  38 Elena Tremoli  52   55 Elmo Mannarino  56 Enzo Grossi  57 Eric Boerwinkle  3   58 Eric E Schadt  20   21 Erik Ingelsson  59   60   61 Fabrizio Veglia  52 Fernando Rivadeneira  8   37 Frank Beutner  62 Ganesh Chauhan  18   63 Gerardo Heiss  1 Harold Snieder  14 Harry Campbell  22 Henry Völzke  33   34 Hugh S Markus  64 Ian J Deary  24   65 J Wouter Jukema  66 Jacqueline de Graaf  67 Jacqueline Price  22 Janne Pott  16   17 Jemma C Hopewell  68 Jingjing Liang  69 Joachim Thiery  17   70 Jorgen Engmann  4 Karl Gertow  44 Kenneth Rice  71 Kent D Taylor  72 Klodian Dhana  73 Lambertus A L M Kiemeney  74 Lars Lind  75 Laura M Raffield  76 Lenore J Launer  6 Lesca M Holdt  17   54 Marcus Dörr  34   77 Martin Dichgans  78   79 Matthew Traylor  64 Matthias Sitzer  80 Meena Kumari  41   81 Mika Kivimaki  41 Mike A Nalls  82   83 Olle Melander  46 Olli Raitakari  19   84 Oscar H Franco  8   85 Oscar L Rueda-Ochoa  8   86 Panos Roussos  20   87   88 Peter H Whincup  89 Philippe Amouyel  90   91   92 Philippe Giral  93 Pramod Anugu  28 Quenna Wong  94 Rainer Malik  78 Rainer Rauramaa  95   96 Ralph Burkhardt  17   97   98 Rebecca Hardy  38 Reinhold Schmidt  12 Renée de Mutsert  99 Richard W Morris  100 Rona J Strawbridge  44   101 S Goya Wannamethee  102 Sara Hägg  103 Sonia Shah  4 Stela McLachlan  22 Stella Trompet  23   66 Sudha Seshadri  104 Sudhir Kurl  105 Susan R Heckbert  5   106 Susan Ring  107   108 Tamara B Harris  6 Terho Lehtimäki  109   110 Tessel E Galesloot  74 Tina Shah  4 Ulf de Faire  111   112 Vincent Plagnol  113 Wayne D Rosamond  1 Wendy Post  114 Xiaofeng Zhu  69 Xiaoling Zhang  27   115 Xiuqing Guo  72   116 Yasaman Saba  117 MEGASTROKE ConsortiumAbbas Dehghan  8   118 Adrie Seldenrijk  119 Alanna C Morrison  3 Anders Hamsten  44 Bruce M Psaty  106   120 Cornelia M van Duijn  8   68 Deborah A Lawlor  107   108 Dennis O Mook-Kanamori  99   121 Donald W Bowden  122 Helena Schmidt  117 James F Wilson  22   123 James G Wilson  124 Jerome I Rotter  72   116 Joanna M Wardlaw  24   125 John Deanfield  4 Julian Halcox  126 Leo-Pekka Lyytikäinen  109   110 Markus Loeffler  16   17 Michele K Evans  6 Stéphanie Debette  18 Steve E Humphries  127 Uwe Völker  34   128 Vilmundur Gudnason  10   11 Aroon D Hingorani  4 Johan L M Björkegren  129   130   131   132 Juan P Casas  9 Christopher J O'Donnell  133   134   135
Collaborators, Affiliations
Free PMC article
Meta-Analysis

GWAS and Colocalization Analyses Implicate Carotid Intima-Media Thickness and Carotid Plaque Loci in Cardiovascular Outcomes

Nora Franceschini et al. Nat Commun. .
Free PMC article

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.

Conflict of interest statement

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.

Figures

Fig. 1
Fig. 1
Overall study design. a GWAS meta-analyses of cIMT and carotid plaque for gene discovery. b Local and genome-wide shared genetic basis using gene expression and clinical outcomes GWAS data
Fig. 2
Fig. 2
Pairwise colocalization results for genes identified for cIMT and carotid plaque GWAS meta-analysis with STARNET expression datasets. Red indicates a high posterior probability of colocalization and blue a high probability of no colocalization of the same SNP with tissue eQTLs
Fig. 3
Fig. 3
Association results at the CCDC71L locus (chromosome 7), showing a high posterior probability of a shared variant for cIMT and carotid plaque in AOR and MAM eQTLs. −log10(p) SNP association p-values for cIMT (plot A) and carotid plaque (plot B), and eQTL in AOR (plot C) and eQTL in SF (plot D). Association results in SF tissue have a low probability of a shared signal with cIMT and carotid plaque, possibly indicating a different mechanism in this tissue. eQTLs in MAM are identical to AOR and not shown. The p-values were calculated by fitting a linear regression model with cIMT or plaque as dependent variable and imputed SNPs as independent variables. Each dot is an SNP and the color indicates linkage disequilibrium (r2) with the best hit (in purple)

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