Genomewide association analysis of coronary artery disease

Background - Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease. Methods - We first identified chromosomal loci that were strongly associated with coronary artery disease in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1926 case subjects with coronary artery disease and 2938 controls) and looked for replication in the German MI [Myocardial Infarction] Family Study (which involved 875 case subjects with myocardial infarction and 1644 controls). Data on other single-nucleotide polymorphisms (SNPs) that were significantly associated with coronary artery disease in either study (P<0.001) were then combined to identify additional loci with a high probability of true association. Genotyping in both studies was performed with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix). Results - Of thousands of chromosomal loci studied, the same locus had the strongest association with coronary artery disease in both the WTCCC and the German studies: chromosome 9p21.3 (SNP, rs1333049) (P=1.80x10–14 and P=3.40x10–6, respectively). Overall, the WTCCC study revealed nine loci that were strongly associated with coronary artery disease (P80%) of a true association: chromosomes 1p13.3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212). Conclusions - We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease

Schematic approach.

<p>1) Identification of reported adverse effect of GA 2) Identify genes reported to interact with GA. 3) Establish a link between the genes identified in 2. and the adverse effect identified in 1).</p

TGFB1 locus.

<p>TGFB1 locus.</p

GA interacts with CCR, TGFB1, IFNAR1 and HLA-DRB1 (solid line).

<p>Moreover, it is known that GA affects CAD (Coronary Artery Disease) risk (dashed line). In this work, we searched for SNPs associated with CAD in the gene regions representing the GA off target effects (dotted lines). We found a genome-wide significant association for the TGFB1 locus with a p-value of 1.58 × 10⁻¹² (red dotted line). n.s.: non-significant; TGFB1: Transforming Growth Factor, Beta 1; CCR5: Chemokine (C-C Motif) Receptor 5 (Gene/Pseudogene); IFNAR1: Interferon (Alpha, Beta And Omega) Receptor 1; HLA-DRB1: Major Histocompatibility Complex, Class II, DR Beta 1.</p

Association sub-loci signal for the TGFB1 locus.

<p>The three lead SNPs are shown with the corresponding high-LD blocks (SNPs within r2>0.2.) depicted in orange, red and green. Independent sub-loci were identified with the GCTA conditional analysis tool (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0182999#sec002" target="_blank">methods</a>). The LD between the lead SNPs indicated and under r²<0.1. The three individual LocusZoom plots are found in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0182999#pone.0182999.s002" target="_blank">S2 Fig</a>.</p