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Identification of PTCSC3 as a Novel Locus for Large-Vessel Ischemic Stroke: A Genome-Wide Association Study.

ABSTRACT: BACKGROUND:Ischemic stroke is a major cause of death and disability in the world. A major ischemic stroke subtype, large-vessel ischemic stroke (large artery atherosclerosis; LAA), has been shown to have some genetic components in individuals of European ancestry. However, it is not clear whether the genetic predisposition to LAA stroke varies among ethnicities. We sought to identify genetic factors that contribute to LAA stroke in 2 independent samples of Han Chinese individuals. METHODS AND RESULTS:Novel genetic variants that predispose individuals to LAA stroke were identified using a genome-wide association study (GWAS) of 444 individuals with LAA stroke and 1727 controls in a Han Chinese population residing in Taiwan. The study was replicated in an independent Han Chinese population comprising an additional 319 cases and 1802 controls. We identified 5 single-nucleotide polymorphisms, including rs2415317 (P=3.10×10(-8)), rs934075 (P=4.00×10(-9)), rs944289 (P=3.57×10(-8)), rs2787417 (P=1.76×10(-8)), and rs1952706 (P=2.92×10(-8)), at one novel locus on chromosome 14q13.3 within PTCSC3 (encoding papillary thyroid carcinoma susceptibility candidate 3) that were associated with LAA stroke at genome-wide significance (P<5×10(-8)). CONCLUSIONS:Our data provide strong support for future studies on the role of PTCSC3 in the pathogenesis of LAA stroke and the association between LAA stroke development and thyroid function. In addition, these findings provide insights into the genetic basis of LAA stroke and identify a novel pathway that might be applicable for future therapeutic intervention.

SUBMITTER: Lee TH

PROVIDER: S-EPMC4943273 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Identification of PTCSC3 as a Novel Locus for Large-Vessel Ischemic Stroke: A Genome-Wide Association Study.

Lee Tsong-Hai TH Ko Tai-Ming TM Chen Chien-Hsiun CH Lee Ming-Ta Michael MT Chang Yeu-Jhy YJ Chang Chien-Hung CH Huang Kuo-Lun KL Chang Ting-Yu TY Lee Jiann-Der JD Chang Ku-Chou KC Yang Jen-Tsung JT Wen Ming-Shien MS Wang Chao-Yung CY Chen Ying-Ting YT Hsieh Chia-San CS Chou Shu-Yu SY Liu Yi-Min YM Chen Hui-Wen HW Liao Hung-Ting HT Wang Chia-Wen CW Chen Shih-Ping SP Lu Liang-Suei LS Chen Yuan-Tsong YT Wu Jer-Yuarn JY

Journal of the American Heart Association 20160329 3

<h4>Background</h4>Ischemic stroke is a major cause of death and disability in the world. A major ischemic stroke subtype, large-vessel ischemic stroke (large artery atherosclerosis; LAA), has been shown to have some genetic components in individuals of European ancestry. However, it is not clear whether the genetic predisposition to LAA stroke varies among ethnicities. We sought to identify genetic factors that contribute to LAA stroke in 2 independent samples of Han Chinese individuals.<h4>Met ...[more]

PMID: 27025970

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Project description:BackgroundGenetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies.MethodsFor the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84 961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45·8 years to 76·4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at p<5 × 10(-6)) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70 804 participants, of whom 19 816 had stroke). Summary-level results of discovery and follow-up stages were combined using inverse-variance weighted fixed-effects meta-analysis, and in-silico lookups were done in stroke subtypes. For genome-wide significant findings (at p<5 × 10(-8)), we explored associations with additional cerebrovascular phenotypes and did functional experiments using conditional (inducible) deletion of the probable causal gene in mice. We also studied the expression of orthologs of this probable causal gene and its effects on cerebral vasculature in zebrafish mutants.FindingsWe replicated seven of eight known loci associated with risk for ischaemic stroke, and identified a novel locus at chromosome 6p25 (rs12204590, near FOXF2) associated with risk of all-stroke (odds ratio [OR] 1·08, 95% CI 1·05-1·12, p=1·48 × 10(-8); minor allele frequency 21%). The rs12204590 stroke risk allele was also associated with increased MRI-defined burden of white matter hyperintensity-a marker of cerebral small vessel disease-in stroke-free adults (n=21 079; p=0·0025). Consistently, young patients (aged 2-32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter hyperintensity. Deletion of Foxf2 in adult mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The orthologs of FOXF2 in zebrafish (foxf2b and foxf2a) are expressed in brain pericytes and mutant foxf2b(-/-) cerebral vessels show decreased smooth muscle cell and pericyte coverage.InterpretationWe identified common variants near FOXF2 that are associated with increased stroke susceptibility. Epidemiological and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells. Further expression studies in appropriate human tissues, and further functional experiments with long follow-up periods are needed to fully understand the underlying mechanisms.FundingNIH, NINDS, NHMRC, CIHR, European national research institutions, Fondation Leducq.

Dataset Information

Identification of PTCSC3 as a Novel Locus for Large-Vessel Ischemic Stroke: A Genome-Wide Association Study.

Publications

Identification of PTCSC3 as a Novel Locus for Large-Vessel Ischemic Stroke: A Genome-Wide Association Study.

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