If these results are used please cite:
Howson JMM et al.
Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms.
Nat Genet. 49(7): 1113-1119. doi: 10.1038/ng.3874.

In brief, the European (EUR) studies comprised 16,093 CAD cases and 16,616 controls from EPIC-CVD 
(a case-cohort study embedded in the pan-European EPIC prospective study), the Copenhagen City Heart 
Study (CCHS), the Copenhagen Ischemic Heart Disease Study (CIHDS) and the Copenhagen General Population 
Study (CGPS) all recruited within Copenhagen, Denmark. The South Asian (SAS) studies comprised up to 7,654 
CAD cases and 7,014 controls from the Pakistan Risk of Myocardial Infarction Study (PROMIS) a case-control 
study that recruited samples from 9 sites in Pakistan, and the Bangladesh Risk of Acute Vascular Events (BRAVE) 
study based in Dhaka, Bangladesh. The East Asian (EA) studies comprised 4,129 CAD cases and 6,369 controls 
recruited from 7 studies across Taiwan that collectively comprise the TAIwan metaboCHIp (TAICHI) Consortium. 
The African American (AA) studies comprised 2,100 CAD cases and 5,746 controls from the Atherosclerosis Risk 
in Communities Study (ARIC), Women’s Health Initiative (WHI) and six studies from the Myocardial Infarction 
Genetics Consortium (MIGen).

Samples from EPIC-CVD, CCHS, CIHDS, CGPS, BRAVE and PROMIS were genotyped on a customised version of the 
Illumina CardioMetabochip (referred to as the “Metabochip+”, Illumina, San Diego, USA), in two Illumina-certified 
laboratories located in Cambridge, UK, and Copenhagen, Denmark, by technicians masked to the phenotypic status of 
samples. The remaining studies were genotyped using the standard CardioMetabochip in Hudson-Alpha and Cedars 
Sinai (TAICHI50, WHI, ARIC51) and the Broad Institute (MIGen).

In brief, studies genotyped on the Metabochip+ had genotypes assigned using the Illumina GenCall software in 
Genome Studio. Samples were removed if they had a call rate < 0.97, average heterozygosity >±3 standard 
deviations away from the overall mean heterozygosity or their genotypic sex did not match their reported sex. 
One of each pair of duplicate samples and first degree relatives (assessed with a kinship co-efficient > 0.2) 
were removed.

Across all studies, SNP exclusions were based on minor allele frequency (MAF) < 0.01, P < 1x10-6 for Hardy 
Weinberg Equilibrium or call rate (CR) less than 0.97 (full details are given in Supplementary Table 2 of the paper). 
These exclusions were also applied centrally to studies genotyped on the CardioMetabochip, namely the ARIC, 
WHI, MIGen and TAICHI studies. Principal component analysis (PCA) was applied to identify and remove ancestral 
outliers. More stringent thresholds were adopted for SNPs used in the PCA for TAICHI and those studies genotyped 
on the Metabochip+, namely, CR < 0.99, PHWE < 1x10-4 and MAF < 0.05. In addition, one of each pair of SNPs in LD 
(r2> 0.2) was removed, as were variants in regions known to be associated with CAD.

Association with CAD was assessed in studies with de novo genotyping from EUR, SAS, and EA, using the 
Genome-wide Efficient mixed model analysis (GEMMA) approach53. This model includes both fixed effects and 
random effects of genetic inheritance. CAD (coded 0/1) was the outcome variable, up to five principal components 
and the test SNP, coded additively, were included as fixed effects. P-values from the score test are reported. 
The AA studies were analysed using a logistic model in PLINK, with CAD as the outcome variable and SNP coded 
additively as predictor. The covariates used by each study, including the number of principal components are 
reported in the Supplementary Information.

Fixed effects inverse variance weighted meta-analysis was used to combine results across studies in METAL. 
Heterogeneity P-values and I2 values were calculated and any SNP with P < 0.0001 for heterogeneity was removed. 
We performed two meta-analyses, the first involved just the European studies with de novo genotyping and the 
CARDIoGRAMplusC4D results to minimize ancestral diversity. The second involved all studies with de novo genotyping 
and the CARDIoGRAMplusC4D results to maximize sample size and statistical power. 

Abstract
Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic 
regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that 
additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale 
evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we 
genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed 
meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 
162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10-8, in fixed-effects meta-analysis) 
from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration 
and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and 
vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with 
cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.

There are 2 results files, one for European ancestry alone and one for All samples/Mixed.

The Column headings are as follows:

rsid	chrpos_b37	effect_allele	other_allele	effect_allele_freq	beta	se	p	n	unit