A Comprehensive 1,000 Genomes-based Genome-wide Association Meta-analysis of Coronary Artery Disease

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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References

Welter D, MacArthur J, Morales J, Burdett T, Hall P, Junkins H . The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. 2013; 42(Database issue):D1001-6. PMC: 3965119. DOI: 10.1093/nar/gkt1229. View

Peloso G, Auer P, Bis J, Voorman A, Morrison A, Stitziel N . Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks. Am J Hum Genet. 2014; 94(2):223-32. PMC: 3928662. DOI: 10.1016/j.ajhg.2014.01.009. View

Fairfax B, Humburg P, Makino S, Naranbhai V, Wong D, Lau E . Innate immune activity conditions the effect of regulatory variants upon monocyte gene expression. Science. 2014; 343(6175):1246949. PMC: 4064786. DOI: 10.1126/science.1246949. View

Crosby J, Peloso G, Auer P, Crosslin D, Stitziel N, Lange L . Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med. 2014; 371(1):22-31. PMC: 4180269. DOI: 10.1056/NEJMoa1307095. View

Stitziel N, Won H, Morrison A, Peloso G, Do R, Lange L . Inactivating mutations in NPC1L1 and protection from coronary heart disease. N Engl J Med. 2014; 371(22):2072-82. PMC: 4335708. DOI: 10.1056/NEJMoa1405386. View

Ashcroft G, Yang X, Glick A, Weinstein M, Letterio J, Mizel D . Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat Cell Biol. 1999; 1(5):260-6. DOI: 10.1038/12971. View

Devlin B, Roeder K . Genomic control for association studies. Biometrics. 2001; 55(4):997-1004. DOI: 10.1111/j.0006-341x.1999.00997.x. View

Mallat Z, Gojova A, Marchiol-Fournigault C, Esposito B, Kamate C, Merval R . Inhibition of transforming growth factor-beta signaling accelerates atherosclerosis and induces an unstable plaque phenotype in mice. Circ Res. 2001; 89(10):930-4. DOI: 10.1161/hh2201.099415. View

Hanayama R, Tanaka M, Miwa K, Shinohara A, Iwamatsu A, Nagata S . Identification of a factor that links apoptotic cells to phagocytes. Nature. 2002; 417(6885):182-7. DOI: 10.1038/417182a. View

10.

Higgins J, Thompson S . Quantifying heterogeneity in a meta-analysis. Stat Med. 2002; 21(11):1539-58. DOI: 10.1002/sim.1186. View

11.

Kim J, Ahn H, Ryu J, Suk K, Park J . BH3-only protein Noxa is a mediator of hypoxic cell death induced by hypoxia-inducible factor 1alpha. J Exp Med. 2003; 199(1):113-24. PMC: 1887730. DOI: 10.1084/jem.20030613. View

12.

DerSimonian R, Laird N . Meta-analysis in clinical trials. Control Clin Trials. 1986; 7(3):177-88. DOI: 10.1016/0197-2456(86)90046-2. View

13.

Howie B, Fuchsberger C, Stephens M, Marchini J, Abecasis G . Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat Genet. 2012; 44(8):955-9. PMC: 3696580. DOI: 10.1038/ng.2354. View

14.

Voight B, Kang H, Ding J, Palmer C, Sidore C, Chines P . The metabochip, a custom genotyping array for genetic studies of metabolic, cardiovascular, and anthropometric traits. PLoS Genet. 2012; 8(8):e1002793. PMC: 3410907. DOI: 10.1371/journal.pgen.1002793. View

15.

Morris A, Voight B, Teslovich T, Ferreira T, V Segre A, Steinthorsdottir V . Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet. 2012; 44(9):981-90. PMC: 3442244. DOI: 10.1038/ng.2383. View

16.

Scott R, Lagou V, Welch R, Wheeler E, Montasser M, Luan J . Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. Nat Genet. 2012; 44(9):991-1005. PMC: 3433394. DOI: 10.1038/ng.2385. View

17.

. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012; 489(7414):57-74. PMC: 3439153. DOI: 10.1038/nature11247. View

18.

Maurano M, Humbert R, Rynes E, Thurman R, Haugen E, Wang H . Systematic localization of common disease-associated variation in regulatory DNA. Science. 2012; 337(6099):1190-5. PMC: 3771521. DOI: 10.1126/science.1222794. View

19.

Grundberg E, Small K, Hedman A, Nica A, Buil A, Keildson S . Mapping cis- and trans-regulatory effects across multiple tissues in twins. Nat Genet. 2012; 44(10):1084-9. PMC: 3784328. DOI: 10.1038/ng.2394. View

20.

Abecasis G, Auton A, Brooks L, DePristo M, Durbin R, Handsaker R . An integrated map of genetic variation from 1,092 human genomes. Nature. 2012; 491(7422):56-65. PMC: 3498066. DOI: 10.1038/nature11632. View