Genetic link between metabolic syndrome and coronary artery disease: Insights from genome-wide cross-trait analysis

Fig. 1. Overview of this study. Cis-eQTL and GWAS summary statistics data were used to conduct SMR analysis and identify the genes related to diseases. eQTL colocalization focused on genes that have passed SMR test (FDR < 0.05, HEIDI > 0.05). Intersecting SMR and phenotype-phenotype colocalization included the genes that have passed FDR but failed HEIDI. g-p,eQTL. p-p, phenotype-phenotype.

Fig. 2. The SMR results of MeS and CAD. The Manhattan plot show the genes of SMR analysis of MeS and CAD in blood (a), brain (b) and liver (c). The genes of diseases were color-coded. The dash line indicates the significant threshold FDR = 0.05. d-f. The Upset plot show the connection of MeS and CAD in blood (d), brain (e) and liver (f). The mode of how to calculate the size of combination set is distinct.

Fig. 3. The correlation between diseases and genes in the eQTL colocalization. a-c. The Upset plot shows genes shared by six diseases in blood (a), brain (b) and liver (c). Genes were identified by Bayesian colocalization analysis. The significant level was PPH4 > 0.8. The chord plot shows the connection between six diseases and genes. Each gene in the chord plot is linked with more than two diseases.

Fig. 4. The role of eQTL colocalization genes in different knockout mice. Hectd4 (a-b), Mras (c-d), Rbm6 (e) and Aldh2 (f-i) knockout mice exhibited phenotype changes in metabolism/ adipose tissue. Life stage is early adult. HOM, homozygous. ns, P value > 0.05. *, P value < 0.05. **, P value < 0.01. ***, P value < 0.001.

Fig. 5. Loci and genes of phenotype-phenotype colocalization. a. The distribution of loci which shared causal variant with MeS and CAD in chromosome. b. Phenotype enrichment analysis for phenotype-phenotype colocalization genes (P value < 1e-4). c. The intersection genes of the SMR analysis and phenotype-phenotype colocalization for MeS and CAD. The genes of SMR and phenotype-phenotype colocalization column are the intersect results of MeS and CAD. phe-phe, phenotype-phenotype. d. The plot showing the relative position of genes and SNPs. The dash line indicates significant threshold P value = 1e-5.

Fig. 6. The role of phenotype-phenotype colocalization genes in different knockout mice. The phenotype changes of Camk1d (a-c) and Agpat1 (d-f) knockout mice included cardiovascular system and metabolism/adipose tissue. Ilrun (g-h), Tmem116 (i-j) and Npepps (k-l) knockout mice exhibited phenotype changes in metabolism/adipose tissue. d. The interval between electrocardiograms was prolonged. Life stage is early adult. Glucose tolerance, Intraperitoneal glucose tolerance test (IPGTT), the charts show the results of measuring Area under glucose response curve. HOM, homozygous.