Genome-wide association meta-analysis of spontaneous coronary artery dissection identifies risk variants and genes related to artery integrity and tissue-mediated coagulation

Figures

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  Fig. 1. GWAS meta-analysis main association results and gene prioritization at-risk loci. a, Manhattan plot representation of SNP-based association meta-analysis in SCAD. The x axis shows the genomic coordinates and the y axis shows the −log10[P value] obtained by two-sided Wald test. SNPs located around genome-wide significant signals (±500 kb) are highlighted. The labels show the rsIDs for the lead SNPs, with newly identified loci in red and previously known loci in black. The dashed red line represents genome-wide significance (P = 5 × 10−8) and the gray line suggestive association (P = 10−5). b, Summary of the strategy for the annotation of gene prioritization. The dots indicate genes fulfilling one of the following eight criteria: (1) colocalization of SCAD association signal and eQTL association in the aorta, coronary artery, tibial artery, fibroblasts or whole blood samples (GTEx version 8 release); (2) a TWAS hit in any of the above-mentioned tissues; (3) a cardiovascular (CV) phenotype in the gene knockout mouse; (4) existing evidence of gene function in cardiovascular disease (CVD) pathophysiology in humans; (5) the gene is an eGene for a nearby lead SNP in the above-mentioned…

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  Fig. 2. Enrichment of SCAD SNPs in open chromatin regions from arterial cells and genetically predicted expression changes of nearby genes. a, Top, representation of the fold-enrichment of SCAD SNPs (top y axis) and enrichment P value (log scale; bottom y axis) among the open chromatin regions of seven single-cell subclusters contributing to >1% of cells in artery tissue24. The SCAD 95% credible set of causal SNPs and their linkage disequilibrium proxies were matched to random pools of neighboring SNPs using the GREGOR package43. Enrichment represents the ratio of the number of SCAD SNPs overlapping open chromatin regions over the average number of matched SNPs overlapping the same regions. P values were evaluated by binomial one-sided test, with greater enrichment as the alternative hypothesis43. The bottom dashed line represents significance (P < 0.05) after adjustment for 105 subclusters. Higher opacity is used to identify significant associations (adjusted P < 0.05). Bottom, composition of artery tissues relative to 105 single-cell subclusters, as determined by snATAC-seq in 30 adult tissues24. Only subclusters representing >1% of cells from either the aorta or tibial artery were…

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  Fig. 3. Colocalization and genetic correlation of SCAD genetic association with cardiovascular diseases and traits. a, Heatmap representing the colocalization of SCAD signals with GWAS analysis of the following cardiovascular diseases or traits: cervical artery dissection (CeAD), multifocal FMD, migraine, blood pressure (SBP and DBP), LDL cholesterol blood concentration, hemoglobin concentration (HGB), any stroke (AS), intracranial aneurysm (IA) and CAD. The tile color represents the H4 coefficient of approximate Bayes factor (ABF) colocalization (that is, the posterior probability of the two traits sharing one causal variant at the locus (PP.H4.ABF; 0–1)) multiplied by the sign of colocalization (+1 if both traits have the same risk or higher mean allele and −1 if opposite allele)). b, Forest plot representing genetic correlations with SCAD. The Rho coefficient of genetic correlation (rg), obtained using linkage disequilibrium score regression, is represented on the x axis (center of the error bar). The range of each bar represents the 95% CI. Unadjusted P values obtained by two-sided Wald test for genetic correlations are indicated. Asterisks indicate significance after Bonferroni…

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  Fig. 4. Mendelian randomization associations between main cardiovascular risk factors and SCAD or CAD. a,b, Forest plots representing Mendelian randomization associations between cardiovascular risk factors and SCAD (ncases = 1,917; ncontrols = 9,292) (a) or CAD (ncases = 181,522; ncontrols = 984,168) (b). Association estimates (β; center of the error bars) obtained from Mendelian randomization analyses using the IVW method are represented on the x axis. The range of each bar represents the 95% CI. Unadjusted P values from the associations obtained by two-sided Wald test are indicated. n = 340,159 (SBP), 340,162 (DBP), 359,983 (BMI), 315,133 (HDL), 343,621 (LDL), 343,992 (triglycerides (TG)), 164,638 cases and 195,068 controls (smoking (SMK)) and 74,124 cases and 824,006 controls (type 2 diabetes (T2D)). The asterisks indicate significance after Bonferroni correction for testing nine traits (P < 5.6 × 10−3) (Supplementary Table 13).