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

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., Sargurupremraj, M., Pitkanen, N., Franzen, O., Joshi, P. K., Noordam, R., Marioni, R. E., Hwang, S-J., Musani, S. K., Schminke, U., Palmas, W., Isaacs, A., Correa, A., Zonderman, A. B., Hofman, A., Teumer, A., Cox, A. J., Uitterlinden, A. G., Wong, A., Smit, A. J., Newman, A. B., Britton, A., Ruusalepp, A., Sennblad, B., Hedblad, B., Pasaniuc, B., Penninx, B. W., Langefeld, C. D., Wassel, C. L., Tzourio, C., Snieder, H., Kumari, M. & Post, W., 3-Dec-2018, In : Nature Communications. 9, 14 p., 5141.

Research output: Contribution to journalArticleAcademicpeer-review

  • 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

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 languageEnglish
Article number5141
Number of pages14
JournalNature Communications
Volume9
Publication statusPublished - 3-Dec-2018

    Keywords

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

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