Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.719147
Title: Investigating the genetics of white matter hyperintensities in ischaemic stroke
Author: Adib-Samii, Poneh
Awarding Body: St George's, University of London
Current Institution: St George's, University of London
Date of Award: 2016
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Abstract:
White matter hyperintensities (WMH) are highly prevalent radiological findings and predictors of morbidity and mortality. Despite their importance there is limited pathophysiological understanding and therapy. WMH are influenced by genetics, environment and their interactions. This research applied genome-wide association (GWA) methods to dissect these contributions, aiming to identify novel WMH genetic risk factors. WMH GWA-studies have thus far been limited to stroke-free populations but WMH are more severe in ischaemic stroke (IS) and likely due to small vessel disease (SVD). Here >2500 IS subjects from nine GWA-studies across Europe, America and Australia were included in a collaborative study. WMH volume in the stroke-free hemisphere was quantified on MRI and adjusted for age, sex and intracranial volume. WMH variance explained by common single nucleotide polymorphisms (SNP) was doubled in hypertensives-only (45% versus 23%) and gene-by­hypertension interactions accounted for a significant proportion of trait variance. WMH GWA in IS did not find significant associations. Moderately associated loci were tested for gene-by-hypertension interactions identifying three significant associations (5q23, 10q23, 12q21). Meta-analysis with WMH GWA in stroke-free populations revealed three novel associations (5q23, 2q33,14q32). The 17q25 WMH risk locus was replicated but did not associate with another manifestation of SVD, lacunar stroke. Conversely, the COL4A1 locus was associated with both WMH and lacunar stroke. Genetic risk score analyses revealed that WMH-variants contribute to Alzheimer’s Disease (AD) independent of age, but the converse was not true. The results suggest that 1) WMH genetic architecture differs between non­hypertensives and hypertensives, 2) WMH genetic risk factors overlap and are distinct from those of lacunar stroke, and 3) WMH risk factors contribute to AD rather than shared disease mechanisms. I discuss what these findings reveal about WMH pathophysiology. I conclude that environmental risk stratification may identify more homogeneous disease subgroups and gene-environment interactions, important in complex trait dissection.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.719147  DOI: Not available
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