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A comprehensive 1000 Genomes–based genome-wide association meta-analysis of coronary artery disease
Open accessAbstract
Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.
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“Numerous epidemiological studies, Mendelian randomization studies, and RCTs have consistently demonstrated a log-linear relationship between the absolute changes in plasma LDL-C and the risk of ASCVD [34,45-50].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [46]
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“as well as with many physical diseases, such as obesity186, type 2 diabetes mellitus187, and heart disease188.”
From Comorbidity between major depressive disorder and physical diseases: a comprehensive review of epidemiology, mechanisms and management (2023) · cites this paper as [188]
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“The FGF5 locus has been linked to cardiovascular conditions in previous GWASs67,75.”
From Genetic determinants of plasma protein levels in the Estonian population (2024) · cites this paper as [75]
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“We detected a cis signal for the FGF5 level and associated variants in the region, which overlapped with previous GWAS findings for cardiovascular diseases and medications used to treat them.”
From Genetic determinants of plasma protein levels in the Estonian population (2024) · cites this paper as [75]
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“Since 2007, genomewide association analyses have identified more than 50 independent loci associated with the risk of coronary artery disease.7–15”
From Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease (2016) · cites this paper as [15]
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Mach, F., Baigent, C., Catapano, A. L., Koskinas, K. C., Casula, M., Badimon, L., Chapman, M. J., De Backer, G. G., Delgado, V., Ference, B. A., et al. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehz455 · Cited by 8,961
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Tsao, C. W., Aday, A. W., Almarzooq, Z. I., Anderson, C. A. M., Arora, P., Avery, C. L., Baker-Smith, C. M., Beaton, A. Z., Boehme, A. K., Buxton, A. E., et al. (2023) · Circulation · doi:10.1161/cir.0000000000001123 · Cited by 8,300
The MR-Base platform supports systematic causal inference across the human phenome
Hemani, G., Zheng, J., Elsworth, B., Wade, K. H., Haberland, V., Baird, D., Laurin, C., Burgess, S., Bowden, J., Langdon, R., et al. (2018) · eLife · doi:10.7554/elife.34408 · Cited by 7,959
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Tsao, C. W., Aday, A. W., Almarzooq, Z. I., Alonso, A., Beaton, A. Z., Bittencourt, M. S., Boehme, A. K., Buxton, A. E., Carson, A. P., Commodore-Mensah, Y., et al. (2022) · Circulation · doi:10.1161/cir.0000000000001052 · Cited by 5,987
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Virani, S. S., Alonso, A., Aparicio, H. J., Benjamin, E. J., Bittencourt, M. S., Callaway, C. W., Carson, A. P., Chamberlain, A. M., Cheng, S., Delling, F. N., et al. (2021) · Circulation · doi:10.1161/cir.0000000000000950 · Cited by 5,784
Metadata
- Authors
- the CARDIoGRAMplusC4D Consortium
- Venue
- Nature Genetics
- Published
- 2015-09-07
- Volume
- 47
- Issue
- 10
- Pages
- 1121-1130
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC4589895
- OpenAlex
- W2238851414
- Cited by
- 2,447
- References
- 84
- Citations by year
- 2026: 98 · 2025: 178 · 2024: 259 · 2023: 263 · 2022: 336 · 2021: 277 · 2020: 255 · 2019: 239 · 2018: 243 · 2017: 181 · 2016: 115 · 2015: 2
- FWCI
- 22.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Site cant be reached (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion, other-oa)
- Leicester Research Archive (University of Leicester) (submittedVersion, other-oa)
- Lund University Publications (Lund University) (submittedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- Funders
- Donald W. Reynolds Foundation
- Amgen
- School of Medicine, Boston University
- Foundation for Cardiovascular Research
- University of Oklahoma
- Wellcome Trust
- National Institute for Health and Care Research (NF-SI-0512-10165, NF-SI-0611-10170, HHSN268200625226C, NF-SI-0508-10235)
- British Heart Foundation (FS/14/55/30806, QLG2-CT-2002-01254, RE/13/1/30181, RG/08/014/24067, RG/14/5/30893)
- European Commission (QLG2-CT-2002-01254, 213506, 01254)
- National Natural Science Foundation of China (81370002)
- ZonMw (050-060-810)
- Erasmus Universiteit Rotterdam
- Erasmus Medisch Centrum (014-93-015)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (050.060.810, 916.12.154, 911-03-012, 175.010.2005.011)
- Hjärt-Lungfonden (20120197)
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet (2009-02298, 2012-01397, M-2005-1112)
- Sydäntutkimussäätiö
- Hjartavernd (HHSN271201200022C, N01-AG-1-2100)
- Nestec
- National Institutes of Health (HHSN268201100012C, HHSN271201200022C, HHSN268201100008C, HHSN268201100006C, N01-AG-1-2100, DK U01-066134, HHSN26820- 1100005C, HHSN268201100007C, HHSN268201100011C, EU/QLRT-2001-01254, HHSN268201100010C, HHSN268201100009C, HHSN268200625226C, HL-043851)
- University of Oklahoma Health Sciences Center
- Medical Research Council (MR/L01629X/1, MR/L003120/1)
- Uppsala Multidisciplinary Center for Advanced Computational Science
- National Heart, Lung, and Blood Institute (HHSN268201 100012C, R01HL080467, R01HL127564, HHSN268201100007C, HHSN2682 01100008C, HL043851, HH-SN-268201100006C, HHSN268201100011C, HL099355, R01 HL-59367, HHSN268201100005C, HHSN268201100010C, HHSN268200625226C, R01HL087641, R01HL059367, HHSN26820 1100009C, RC1HL099355, HL080467, R33HL120757, CA047988, R01HL117078, R01HL086694)
- National Human Genome Research Institute (U01HG004402)
- National Cancer Institute (HL-080467, HL-099355, HL-043851, CA 047988, UM1CA182913, R01CA047988)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK089256, R01DK082766, R01DK107437, NOT-HG-11-009)
- National Center for Research Resources (UL1RR025005)
- NHLBI Division of Intramural Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
- Keywords
- coronary artery disease, genetic susceptibility, genetic susceptibility loci, single nucleotide polymorphisms, low-frequency variants, phased haplotypes, allelic heterogeneity, genetic architecture
- MeSH terms
- Coronary Artery Disease, Humans, Phenotype, Genome, Human, Genome-Wide Association Study
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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