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SHR Neuro Cancer Cardio Metab Microb Lipid

Genetic determinants of cerebral small vessel disease

Abstract: Cerebral small vessel disease is the second most common endemic entity of the ageing brain following Alzheimer pathology. Its hallmark lesions are leuko-araiosis and lacunar infarctions, which can be non-invasively depicted with brain magnetic resonance imaging. Up to 90% of persons above the age of 65 years present with leuko-araiosis. Lacunes occur less common with a frequency of 6% to 20%. Decreased mobility of the elderly due to disequilibrium and gait abnormalities, and progressive cognitive impairment up to dementia are frequent clinical sequelae of cerebral microangiopathy. Established risk factors are arterial hypertension and advancing age. There does not exist any established treatment yet which allows to modify the evolution of small vessel disease-related brain damage.
The heritability of leukoaraiosis volume ranges between 55% and 73%. There are no heritability estimates of other characteristics of white matter lesions such as type and progression are available. Similarly, the heritability of other components of small vessel disease such as lacunes, brain atrophy and microbleeds have not yet been investigated yet. Association studies indicated that the APOE, ACE, eNOS, MTHFR genes might be related to these pathologies. We found positive associations with APOE, PON1 as well as the AGT, with considerable evidence for a causal relationship for the latter. Very recently, the results of the first genome wide scan on white matter lesion volume have been reported by the Framingham Heart Study describing a significant LOD score on chromosome 4 and a suggestive LOD score for linkage on chromosome 17.
The aim of our study is to genetically dissect the complexity of cerebral small vessel disease in order to better understand the pathomechanisms leading to these lesions. First we will apply genome wide association as well as fine map the linkage regions on Chr 4 and 17 in the the Austrian Stroke Prevention Study cohort, which is one of the largest community-dwelling studies on cerebral small vessel disease and the study with the longest MRI follow up so far. Second, we will recruit families ascertained through participants of the Austrian Stroke Prevention Study. Family members will undergo the same study protocol including brain MRI as the probands in the population based cohort. In the family based cohort we will estimate heritability of and genetic correlation between different lesion characteristics of cerebral small vessel disease and its major risk factors. We aim to develop a spectrum of possible endophenotypes for cerebral small vessel disease. In the family based cohort we also aim to verify genes associated with cerebral small vessel disease in previous studies.
The co-existence of a family and a population based cohort characterized with identical study protocol will offer a unique and outstanding resource to identify genes by allowing for the combined use of linkage and association. Knowledge of genes involved in cerebral small vessel disease will improve our understanding of the pathogenesis of these lesions and will possibly facilitate the development of novel therapeutic targets.

Keywords: human genetics; medical molecular biology; magnetic resonance tomography; neurology; DNA analysis (also: genetic fingerprinting); Alterung; genomweite Assoziationsstudie; Schlaganfall

Project Leader:: Schmidt Helena

Duration:: 01.05.2008-31.12.2012

Programme:: Einzelprojekt

Type of Research: basic research

Staff: Schmidt H., Project Leader; Tscherner M., Co-worker; Schmidt R., Co-worker; Fazekas F., Co-worker

MUG Research Units: Department of Neurology; Division of General Neurology; Division of Molecular Biology and Biochemistry

Funded by: FWF, Fonds zur Förderung der Wissenschaftlichen Forschung, Wien, Austria

Project results published: > Circulating miRNAs as possible biomarkers for cogn... BI-IMBA-IMP meeting on microRNAs in human disease; 15-17 January 2014; Gumpoldskirchen, Austria. 2014.; > Heritability Estimates Identify a Substantial Gene... Stroke. 2013; 44(6):1578-1583; > The molecular genetic architecture of self-employm... PLoS One. 2013; 8(4):e60542-e60542; > Common variants at 12q14 and 12q24 are associated ... Nat Genet. 2012; 44(5):545-551; > Burden of Risk Alleles for Hypertension Increases ... Stroke. 2012; 43(11):2877-2883; > Genetics of age-related white matter lesions from ... J Neurol Sci. 2012; 322(1-2):82-86; > Genome-wide association and functional follow-up r... PLoS Genet. 2012; 8(3):e1002584-e1002584; > Common variants at 6q22 and 17q21 are associated w... Nat Genet. 2012; 44(5):539-544; > Genetics of subcortical vascular dementia.... Exp Gerontol. 2012; 47(11):873-877; > Meta-analysis of genome-wide association studies f... Nat Genet. 2011; 43(10):940-947; > Genetic variants of the NOTCH3 gene in the elderly... Brain. 2011; 134(Pt 11): 3384-3397.; > Genome-wide association studies of MRI-defined bra... Stroke. 2010; 41(2): 210-217.