Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque
Open accessAbstract
Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10(-8)). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events.
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Causal common variants associated with continuous endophenotypes have been associated with disease in many cases.
“In many cases, causal common variants associated with a continuous endophenotype have been associated with disease [eg80–82]”
From Rare and common variants: twenty arguments (2012) · cites this paper as [81]
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- Authors
- the CARDIoGRAM Consortium, Bis, J. C., Kavousi, M., Franceschini, N., Isaacs, A., Abecasis, G. R., Schminke, U., Post, W. S., Smith, A. V., Cupples, L. A., Markus, H. S., Schmidt, R., Huffman, J. E., Lehtimäki, T., Baumert, J., Münzel, T., Heckbert, S. R., Dehghan, A., North, K., Oostra, B., Bevan, S., Stoegerer, E.-M., Hayward, C., Raitakari, O., Meisinger, C., Schillert, A., Sanna, S., Völzke, H., Cheng, Y.-C., Thorsson, B., Fox, C. S., Rice, K., Rivadeneira, F., Nambi, V., Halperin, E., Petrovic, K. E., Peltonen, L., Wichmann, H. E., Schnabel, R. B., Dörr, M., Parsa, A., Aspelund, T., Demissie, S., Kathiresan, S., Reilly, M. P., Taylor, K., Uitterlinden, A., Couper, D. J., Sitzer, M., Kähönen, M., Illig, T., Wild, P. S., Orru, M., Lüdemann, J., Shuldiner, A. R., Eiriksdottir, G., White, C. C., Rotter, J. I., Hofman, A., Seissler, J., Zeller, T., Usala, G., Ernst, F., Launer, L. J., D'Agostino, R. B., O'Leary, D. H., Ballantyne, C., Thiery, J., Ziegler, A., Lakatta, E. G., Chilukoti, R. K., Harris, T. B., Wolf, P. A., Psaty, B. M., Polak, J. F., Li, X., Rathmann, W., Uda, M., Boerwinkle, E., Klopp, N., Schmidt, H., Wilson, J. F., Viikari, J., Koenig, W., Blankenberg, S., Newman, A. B., Witteman, J., Heiss, G., van Duijn, C., Scuteri, A., Homuth, G., Mitchell, B. D., Gudnason, V., & O'Donnell, C. J.
- Affiliations
- University of Washington (US)
- Erasmus MC (NL)
- University of North Carolina at Chapel Hill (US)
- University of Michigan (US)
- Universität Greifswald (DE)
- Johns Hopkins University (US)
- Icelandic Heart Association (IS)
- Boston University (US)
- St George's, University of London (GB)
- Medical University of Graz (AT)
- Western General Hospital (GB)
- Tampere University Hospital (FI)
- Helmholtz Munich (DE)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- Kaiser Permanente Washington Health Research Institute (US)
- University of Turku (FI)
- University Hospital Schleswig-Holstein (DE)
- Institute of Genetic and Biomedical Research (IT)
- University of Maryland, Baltimore (US)
- Brigham and Women's Hospital (US)
- Houston Methodist (US)
- International Computer Science Institute (US)
- University of Helsinki (FI)
- University of Iceland (IS)
- Broad Institute (US)
- University of Pennsylvania (US)
- Cedars-Sinai Medical Center (US)
- Herford Hospital (DE)
- Ludwig-Maximilians-Universität München (DE)
- National Institutes of Health (US)
- Baylor College of Medicine (US)
- University Hospital Leipzig (DE)
- National Institute on Aging (US)
- Tufts University (US)
- Deutsches Diabetes-Zentrum e.V. (DE)
- The University of Texas Health Science Center at Houston (US)
- University of Edinburgh (GB)
- University of Pittsburgh (US)
- Corresponding author
- Bis, Joshua C
- ORCID
- Bis, Joshua C
- Kavousi, Maryam
- Franceschini, Nora
- Isaacs, Aaron
- Abecasis, Gonçalo R
- Schminke, Ulf
- Post, Wendy S
- Smith, Albert V
- Cupples, L Adrienne
- Markus, Hugh S
- Schmidt, Reinhold
- Huffman, Jennifer E
- Lehtimäki, Terho
- Baumert, Jens
- Münzel, Thomas
- Heckbert, Susan R
- Dehghan, Abbas
- North, Kari
- Bevan, Steve
- Hayward, Caroline
- Raitakari, Olli
- Meisinger, Christa
- Schillert, Arne
- Sanna, Serena
- Völzke, Henry
- Cheng, Yu-Ching
- Fox, Caroline S
- Rice, Kenneth
- Rivadeneira, Fernando
- Nambi, Vijay
- Halperin, Eran
- Peltonen, Leena
- Wichmann, H Erich
- Schnabel, Renate B
- Dörr, Marcus
- Aspelund, Thor
- Demissie, Serkalem
- Kathiresan, Sekar
- Reilly, Muredach P
- Taylor, Kent
- Couper, David J
- Kähönen, Mika
- Wild, Philipp S
- Shuldiner, Alan R
- White, Charles C
- Rotter, Jerome I
- Seissler, Jochen
- Zeller, Tanja
- Ernst, Florian
- Launer, Lenore J
- Ballantyne, Christie
- Thiery, Joachim
- Ziegler, Andreas
- Lakatta, Edward G
- Chilukoti, Ravi Kumar
- Harris, Tamara B
- Wolf, Philip A
- Psaty, Bruce M
- Polak, Joseph F
- Li, Xia
- Rathmann, Wolfgang
- Uda, Manuela
- Boerwinkle, Eric
- Schmidt, Helena
- Wilson, James F
- Viikari, Jorma
- Blankenberg, Stefan
- Newman, Anne B
- Heiss, Gerardo
- Scuteri, Angelo
- Homuth, Georg
- Mitchell, Braxton D
- Gudnason, Vilmundur
- Venue
- Nature Genetics
- Published
- 2011-09-11
- Volume
- 43
- Issue
- 10
- Pages
- 940-947
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC3257519
- OpenAlex
- W2169832447
- Cited by
- 212
- References
- 90
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 7 · 2023: 7 · 2022: 8 · 2021: 9 · 2020: 13 · 2019: 15 · 2018: 16 · 2017: 19 · 2016: 19 · 2015: 23 · 2014: 18 · 2013: 23 · 2012: 26
- FWCI
- 2.32
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- St George's Online Research Archive (St George's University of London) (acceptedVersion)
- PubMed Central (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- UNICA IRIS Institutional Research Information System (University of Cagliari) (submittedVersion)
- UnissResearch (Università degli Studi di Sassari) (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- OPUS (Augsburg University) (submittedVersion)
- Hirsla (Landspítali University Hospital) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion)
- Funders
- Wellcome Trust
- European Commission (201668)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (918-76–619)
- National Institutes of Health (n01hc085082-026, n01hc085081-021, n01hc045133-001, n01ag12100-57-0-2, n01hc085079-024, n01hc015103-009, n01hc085084-005, n01hc55021-47-0-1, n01hc085085-011, n01hc085083-027, n01hc55020-39-0-0, n01hc085080-026, n01hc55016-37-0-0, n01hc055022-024, n01hc085086-022, n01hc55019-35-0-1, Z99 HL999999, UL1TR000005, n01hc55018-38-0-1, n01hc25195-41-0-1, n01hc55222-0-0-0, n01hc075150-004, n01hc035129-010, n01hc55015-48-0-1)
- U.S. Public Health Service (268200625226C)
- National Institute on Aging (R01-AG-18728, AG-16495, N01-AG-12109, AG 20098, R56AG023629, N01-AG012100, R01AG018728, R01AG020098, AG08122, AG033193, AG023629, AG027058, R56AG020098, R01AG016495, R01AG023629, R01AG033193, R01AG015928, R01AG027058, R01AG008122)
- National Heart, Lung, and Blood Institute (N01-HC-85081, N01HC85085, N01-HC55022, N01 HC085086, N01HC-85083, N01 HC055016, N01-HC-55018, N0-1-HC-85239, U01HL084729, N01 HC 55020, HL-105756, N01 HC085079, N01‐HC25195, HL-087652, N01 HC 55019, N01HC85082, N01HC‐75150, N01 HC85086, R01 HL-59367, R01HL087652, N01 HC055020, N01 HC035129, HL-075366, N01HC85080, N02- HL-64278, N01 HC055018, N01 HC015103, N01 HC55222, R01HL075366, HL-084729, N01-HC-025195, N01-HC55016, R01HL087641, N01 HC055022, R01HL059367, R01HL105756, U01HL080295, U01HL072515, N01 HC055019, N01 HC055222, R01HL088119, Z01HL006002, HL080295, R01HL080295, N01‐HC‐55015, N01-HC55021, N01 HC075150, N01 HC055021, N01 HC055015, N01 HC045133, R01HL086694, N01-HC85079, N01-HC85084)
- National Human Genome Research Institute (HG005581, U01HG004402, RC2HG005581)
- National Institute of General Medical Sciences (U01GM074518)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK063491, P30DK072488, P30DK063491)
- National Institute of Neurological Disorders and Stroke (NS17950, R01NS017950)
- National Center for Research Resources (UL1RR025005, M01 RR00069, M01RR016500, M01RR000069, M01RR 16500)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Keywords
- carotid intima-media thickness, carotid plaque, subclinical atherosclerosis, genetic loci, single nucleotide polymorphisms, cardiovascular risk, coronary artery disease, lipid metabolism, blood pressure homeostasis, signal transduction, CHARGE consortium, cardiogram
- MeSH terms
- Adult, Aged, Aging, Coronary Artery Disease, Genotype, Heart, Humans, Middle Aged, Phenotype, Risk Factors, Cohort Studies, Genome, Human, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, White People, Atherosclerosis, Genome-Wide Association Study, Genetic Loci, Plaque, Atherosclerotic, Carotid Intima-Media Thickness
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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