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

Xiaoying Li,Wenying Hou,Rui Lu,Ruyou Zhang,Yingnan Wu,Jiawei Tian,Shuang Zhang,Litao Sun,Weilin Shi,Yanan Feng

doi:10.3389/fcell.2020.00453

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.

Highlights

Stroke is one of the three most common causes of death, and a major cause of adult disability in developed and developing countries, accounting for almost 6.5 million stroke deaths each year, and its global burden continues to grow (Endres et al, 2011; Bejot et al, 2016)
All single nucleotide polymorphism (SNP) were found to be in Hardy-Weinberg equilibrium in all subjects
The associations between each SNP and risk factors of Ischemic stroke (IS) were analyzed in correlation method

Summary

Introduction

Stroke is one of the three most common causes of death, and a major cause of adult disability in developed and developing countries, accounting for almost 6.5 million stroke deaths each year, and its global burden continues to grow (Endres et al, 2011; Bejot et al, 2016). Genetic Risk of Ischemic Stroke injury (Benjamin et al, 2019). There is a need to develop an effective prevention approach for stroke, which necessitates a better understanding of the underlying risk factors. The genetic factor operates through a mechanism involving multiple genes, and is affected by environmental factors (Dichgans and Markus, 2005), besides, the risk attributable to any individual variant has been modest. Fully understand the genetic factors in a multi-omics perspective helps to clarify the underlying molecular mechanisms contributing to IS. This study aimed to explore the combined effect of SNP from multiple genes and their interaction with risk factors in the development of IS. We performed functional analyses of the selected genes at the transcriptome

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