P3718Identification of nine genes as novel susceptibility loci for early-onset ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage
Authors: Yamase Y , Horibe H , Kato K , Oguri M , Fujimaki T , Hibino T , Kondo T , Sakuma J , Takeuchi I , Murohara T , Yasukochi I , Yamada Y 
Published: October 2019

Abstract

Background
Given that substantial genetic components have been shown in ischemic stroke, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH), a heritability may be higher in early-onset than late-onset individuals with these conditions. Although genome-wide association studies have identified various genes and loci significantly associated with ischemic stroke, ICH, or intracranial aneurysm mainly in European ancestry populations, genetic variants that contribute to susceptibility to these disorders in Japanese individuals remain to be identified definitively.

Purpose
The purpose of the study was to identify genetic variants that confer susceptibility to ischemic stroke, ICH, or SAH in Japanese. We have now performed exome-wide association studies (EWASs) in early-onset subjects with these conditions and corresponding controls.

Methods
A total of 6649 individuals aged ≤65 years were examined. For the EWAS of ischemic or hemorrhagic stroke, 6224 individuals (450 subjects with ischemic stroke, 5774 controls) or 6179 individuals (261 subjects with ICH, 176 subjects with SAH, 5742 controls), respectively, were examined. EWASs were performed with the use of Illumina Human Exome-12 v1.2 DNA Analysis BeadChip or Infinium Exome-24 v1.0 BeadChip. To compensate for multiple comparisons of allele frequencies with ischemic stroke, ICH, or SAH, we applied a false discovery rate (FDR) of <0.05 for statistical significance of association.

Results
The relation of allele frequencies of 31,245 single nucleotide polymorphisms (SNPs) that passed quality control to ischemic stroke was examined with Fisher's exact test, and 31 SNPs were significantly (FDR <0.05) associated with ischemic stroke. The relation of allele frequencies of 31,253 or 30,970 SNPs to ICH or SAH, respectively, was examined with Fisher's exact test, and six or two SNPs were significantly (FDR <0.05) associated with ICH or SAH, respectively. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of hypertension and diabetes mellitus revealed that 12 SNPs were significantly [P <0.0004 (Bonferroni's correction, 0.05/124)] related to ischemic stroke. Similar analysis with adjustment for age, sex, and the prevalence of hypertension revealed that six or two SNPs were significantly [P <0.0016 (0.05/32)] related to ICH or SAH, respectively. After examination of linkage disequilibrium of identified SNPs and results of previous genome-wide association studies, we have newly identified HHIPL2, CTNNA3, LOC643770, UTP20, and TRIB3 as susceptibility loci for ischemic stroke, DNTTIP2 and FAM205A as susceptibility loci for ICH, and FAM160A1 and OR52E4 as such loci for SAH.

Conclusion
We have thus newly identified nine genes that confer susceptibility to early-onset ischemic stroke, ICH, or SAH. Determination of genotypes for the SNPs in these genes may prove informative for assessment of the genetic risk for ischemic stroke, ICH, or SAH in Japanese.