A comprehensive 1000 Genomes–based genome-wide association meta-analysis of coronary artery disease

Abstract

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association studies (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of 185 thousand CAD cases and controls, interrogating 6.7 million common (MAF>0.05) as well as 2.7 million low frequency (0.005<MAF<0.05) variants. In addition to confirmation of most known CAD loci, we identified 10 novel loci, eight additive and two recessive, that contain candidate genes that newly implicate biological processes in vessel walls. We observed intra-locus 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.

Variants at the APOE/C1/C2/C4 Locus Modulate Cholesterol Efflux Capacity Independently of High‐Density Lipoprotein Cholesterol

“…Because not all variants could be retrieved by LDlink, we selected α=1×10 −4 to declare significance in this secondary analysis (an effective Bonferroni correction for 500 tests). We also looked up CEC association results for variants associated with blood lipid levels (n=160 single‐nucleotide polymorphisms [SNPs]) or CAD risk (n=86 SNPs) by GWAS,22, 23, 24, 25, 26 using a statistical threshold of α=2.1×10 −4 (Bonferroni correction for 239 different variants). For these secondary analyses of candidate variants, we did not correct for the number of CEC phenotypes and statistical models to assess statistical significance.…”

Mendelian randomization with fine‐mapped genetic data: Choosing from large numbers of correlated instrumental variables

“…The associations of 325 individual SNPs with testosterone in 3,225 men of European ancestry are reported by Jin et al. (2012); associations of 322 of these variants with CAD risk in 60,801 CAD cases and 123,504 controls are reported by the CARDIoGRAMplusC4D Consortium (2015). Previously, in an independent dataset, Coviello et al.…”

The impact of genome‐wide association studies on the pathophysiology and therapy of cardiovascular disease

“…The joint forces of the CARDIoGRAM (Schunkert et al , 2011), C4D (Coronary Artery Disease C4D Genetics Consortium, 2011) and finally the CARDIoGRAMplusC4D (CARDIoGRAMplusC4D Consortium et al , 2013; Nikpay et al , 2015) consortium allowed the analysis of up to 180,000 individuals, about half of which had CAD. Interestingly, consequent studies revealed a strong relationship between the numbers of individuals investigated and the numbers of genome‐wide significant variants detected by the GWAS approach (Fig 1).…”

“…(B) The number of SNP s detected with genome‐wide significance after replication correlates with the number of individuals included in the discovery studies. Symbols denote the numbers of genotyped SNP s [dots: ≤ 500,000 SNP s (Samani et al , 2007; McPherson et al , 2007; Helgadottir et al , 2007; Myocardial Infarction Genetics Consortium, 2009; Erdmann et al , 2009; Tregouet et al , 2009; IBC 50K CAD Consortium, 2011; Lu et al , 2012); asterisks: 2,500,000 SNP s (Coronary Artery Disease C4D Genetics Consortium, 2011; Schunkert et al , 2011; CARDIoGRAMplusC4D Consortium et al , 2013); arrow: 940,000 SNP s (Nikpay et al , 2015)].…”

“…distinct SNPs in human DNA for association with disease. Denser genotyping and higher numbers of study subjects increased the number of loci with genome‐wide significant association for CAD to 56 (CARDIoGRAMplusC4D Nikpay et al , 2015). Table 2 gives an overview about the loci thus far identified to be genome‐wide significantly associated with CAD by GWAS.…”