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

Association of haplotypes derived from rs2856650, rs3740689 and rs10769258 with VT risk in two GWAS.

<p>The meta-analysis of the AGT haplotype-associated ORs obtained in the two GWAS samples lead to an overall OR of 2.78 [2.01–3.81] (p = 4.72 10⁻¹⁰). In a combined analysis of the individual-level genotype data of the two GWAS, the AGT haplotype frequency was estimated to 0.054 and 0.019 in cases and controls, respectively. This led to a combined OR of 3.03 [2.23–4.10] (p = 8.96 10⁻¹³) compared to the most frequent GGT haplotype (with estimated frequency 0.330 and 0.343 in cases and controls, respectively).</p

Box-Plot representation of the imputed dose at rs1799963 (FII G20210A) according to measured genotypes in a sample of 1,961 VT cases.

<p>The imputed dose in the 419 VT cases of the first GWAS is shown in blue while results obtained in the 1,542 VT part of the second GWAS are shown in red.</p

Pairwise linkage disequilibrium r² between genotyped SNPs mapping from <i>F2</i> to <i>PTPRJ</i> genes at the 11p11.2 locus in a sample of 1,542 VT cases.

<p>Pairwise linkage disequilibrium r² between genotyped SNPs mapping from <i>F2</i> to <i>PTPRJ</i> genes at the 11p11.2 locus in a sample of 1,542 VT cases.</p

Genome-wide significant association (p<1.×10⁻⁸) observed at the 11p11.2 locus.

<p>(a) SNPs for which no rsID has yet been allocated are named according to their position on chromosome 11.</p><p>(b) Minor Allele Frequency.</p><p>(c) P-value of the association between imputed SNPs and VT risk, after adjusting for principal components.</p><p>(d) Imputation quality criterion (r²).</p><p>(e) Combined meta-analysis p-value obtained using the Mantel-Haenszel inverse-variance weighting method.</p

Pairwise linkage disequilibrium r² between genotyped SNPs at the 11p11.2 locus over the 47,373,425–48,064,194 bp region in the second GWAS study (Germain et al. Plos One 2011).

<p>Pairwise linkage disequilibrium r² between genotyped SNPs at the 11p11.2 locus over the 47,373,425–48,064,194 bp region in the second GWAS study (Germain et al. Plos One 2011).</p

Genotype distribution of the <i>MYPBC3</i> rs2856656 according to VT status and carrier-ship of F5/F2 mutations in the MARTHA and FARIVE studies.

(a)<p>Minor Allele Frequencies.</p

Association of the imputed rs2856656 with VT risk in two GWAS datasets.

<p>Association of the imputed rs2856656 with VT risk in two GWAS datasets.</p

Case-control samples available in this work.

<p>⁽¹⁾ These individuals were typed with the Illumina Sentrix HumanHap300 beadchip containing 317,319 SNPs among which 291,872 satisfied the quality control (QC) criteria (Trégouët et al. (2009) Blood 113: 5298–5303). ⁽²⁾ These individuals were typed with the Illumina 610-Quad and Illumina 660W-Quad beadchips. Among the 551,141 SNPs common to both assays, 491,258 SNPs satisfied the QC criteria (Germain et al (2011) Plos One 6: e25581). ^(a) 812 VT patients of the MARTHA study were part of the GWAS⁽²⁾ VT sample. ^(b) The FV Leiden and FII G20210A mutations were genotyped in the GWAS patients as part of the study design where patients homozygous for these mutations were excluded.</p

Box-Plot representation of the imputation quality (r²) according to the minor allele frequency of the SNPs inferred from 1000G 2010-08 release.

<p>Box-plot derived from the imputation analysis of the largest GWAS ⁽²⁾.</p