Genetic variation at 16q24.2 is associated with small vessel stroke
Matthew Traylor1, Rainer Malik2, Mike A Nalls3
1Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.
Annals of Neurology
|December 21, 2016
Summary
A novel genetic locus on chromosome 16q24.2 is associated with small vessel stroke (SVS). This finding advances understanding of SVS genetics and its link to cerebral small vessel disease.
Area of Science:
- Genetics
- Neurology
- Stroke Research
Background:
- Small vessel stroke (SVS) is a significant component of ischemic stroke and a primary driver of vascular cognitive impairment.
- Previous genome-wide association studies (GWAS) have identified stroke associations but not specifically for SVS.
- Younger-onset cases often exhibit a greater genetic burden, suggesting potential for novel discoveries through age-informed analyses.
Purpose of the Study:
- To identify novel genetic associations with small vessel stroke (SVS) by conducting an age-at-onset informed GWAS meta-analysis.
- To leverage a large cohort of younger-onset SVS cases to maximize the detection of genetic associations.
- To investigate the functional impact of identified genetic loci on related small vessel disease phenotypes and gene regulation.
Main Methods:
- A three-stage, age-at-onset informed GWAS meta-analysis was employed to identify novel genetic variants associated with stroke.
- Upon identifying a novel locus for SVS, its influence was assessed on other small vessel disease phenotypes.
- Messenger RNA (mRNA) expression and DNA methylation of nearby genes were analyzed in relation to the identified genetic locus.
Main Results:
- A significant association with SVS was identified on chromosome 16q24.2 (rs12445022) in 4,203 cases and 50,728 controls.
- The lead single-nucleotide polymorphism (rs12445022) also correlated with cerebral white matter hyperintensities but not intracerebral hemorrhage.
- Rs12445022 demonstrated associations with ZCCHC14 mRNA expression in arterial tissues and DNA methylation in whole blood.
Conclusions:
- The 16q24.2 locus is significantly associated with small vessel stroke (SVS).
- The observed associations with gene expression and DNA methylation suggest a regulatory role for this genetic locus in SVS.
- This discovery provides new insights into the genetic underpinnings of SVS and its relationship with cerebral small vessel disease.
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