Integrate Molecular Phenome and Polygenic Interaction to Detect the Genetic Risk of Ischemic Stroke

Abstract

Ischemic stroke (IS) is one of the leading causes of death, and the genetic risk of which are continuously calculated and detected by association study of single nucleotide polymorphism (SNP) and the phenotype relations. However, the systematic assessment of IS risk still needs the accumulation of molecular phenotype and function from the level of omics. In this study, we integrated IS phenome, polygenic interaction gene expression and molecular function to screen the risk gene and molecular function. Then, we performed a case-control study including 507 cases and 503 controls to verify the genetic associated relationship among the candidate functional genes and the IS phenotype in a northern Chinese Han population. Mediation analysis revealed that the blood pressure, high density lipoprotein (HDL) and glucose mediated the potential effect of SOCS1, CD137, ALOX5AP, RNLS, and KALRN in IS, both for the functional analysis and genetic association. And the SNP-SNP interactions analysis by multifactor dimensionality reduction (MDR) approach also presented a combination effect of IS risk. The further interaction network and gene ontology (GO) enrichment analysis suggested that CD137 and KALRN functioning in inflammatory could play an expanded role during the pathogenesis and progression of IS. The present study opens a new avenue to evaluate the underlying mechanisms and biomarkers of IS through integrating multiple omics information.

Keywords: Interaction network analysis; ischemic stroke; molecular function; molecular phenome; polygenic interaction.

FIGURE 1

Circos plot showing the mediation model of the SNP, risk factors and IS (A); SNP, risk factors and atherothrombosis subtype of IS (B); SNP, risk factors and lacunar subtype of IS (C); SNP, risk factors and combination subtype of IS (D). Purple in the upper left corner showing Prop Mediated (pm). The outer layer to the inner of ring were BMI, systolic BP, diastolic BP, blood glucose, TC, TG, HDL, LDL, respectively. Green indicate mediated effect p-value; orange indicate direct effect p-value; blue indicate total p-value. ***p < 0.05.

FIGURE 2

IS (A), atherothrombosis subtype of IS (B), lacunar subtype of IS (C), combination subtype of IS (D) results from MDR analysis. (a) interaction graph, for each SNP is reported in per cent the value of Information Gain (IG), while numbers in the connections indicate the entropy-based IG for the SNP pairs. Red bar and orange bar indicate the high-level synergies on the phenotype, while the brown indicate a medium-level interaction, green and blue connections with negative IG values indicate redundancy or lack of synergistic interactions between the markers. (b) shows the interaction dendrogram. Histograms in (c) reports the distributions of controls (left bars) and cases (right bars) genotype combinations of SNP. Dark-shaded cells are considered “high-risk” while light-shaded cells are considered “low risk.” White cells indicate no subjects with those genotype combinations that were observed in the data set.

FIGURE 3

The layout of mRNA-mRNA network. The view of the mRNA-mRNA network (A). The GO enrichment analysis of the network (B).