Document Detail

Heritability of MRI lesion volume in CADASIL: evidence for genetic modifiers.
MedLine Citation:
PMID:  17008614     Owner:  NLM     Status:  MEDLINE    
BACKGROUND AND PURPOSE: The phenotypic expressivity shows striking variability among individuals with CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), a small vessel disease caused by mutations in NOTCH3. However, little is known about the factors that underlie this variability. We sought to quantify the contribution of modifying genetic effects to individual differences in the volume of cerebral ischemic lesions. METHODS: One hundred and fifty-one affected individuals (mean age+/-SD=45.7+/-10.4) from 95 unrelated families with CADASIL underwent MRI. The volume of lesions visible on T2-weighted images and the intracranial volume (ICV) were quantified and vascular risk factors were assessed. Because of a skewed distribution, lesion volume measures were square-root transformed. Variance component methods were used to estimate the heritability of lesion volumes (ie, the proportion of variation caused by additive genetic factors) after adjusting for covariates. RESULTS: In multivariate analyses, higher age, a larger ICV, and a higher diastolic blood pressure were independently associated with a larger volume of T2-visible lesions (all P<0.05). After adjustment for age the point estimate for the heritability of the square-root-transformed measure of T2 lesion volume was 0.634 (SE=+/-0.286). Adjustment for age, sex, ICV, and diastolic blood pressure increased the estimated heritability to 0.738 (SE+/-0.255). CONCLUSIONS: Heritability estimates in CADASIL suggest a strong modifying influence of genetic factors distinct from the causative NOTCH3 mutation on the amount of ischemic brain lesions. These findings justify a systematic search for genetic variants that modify disease progression.
Christian Opherk; Nils Peters; Markus Holtmannspötter; Andreas Gschwendtner; Bertram Müller-Myhsok; Martin Dichgans
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-09-28
Journal Detail:
Title:  Stroke; a journal of cerebral circulation     Volume:  37     ISSN:  1524-4628     ISO Abbreviation:  Stroke     Publication Date:  2006 Nov 
Date Detail:
Created Date:  2006-10-31     Completed Date:  2006-11-14     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0235266     Medline TA:  Stroke     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2684-9     Citation Subset:  IM    
Neurologische Klinik, Klinikum Grosshadern, Ludwig-Maximilians-University, Marchioninistrasse 15, D 81377 München, Germany.
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MeSH Terms
Brain / pathology
CADASIL / epidemiology,  genetics*,  pathology*
Magnetic Resonance Imaging*
Middle Aged
Quantitative Trait, Heritable*
Receptors, Notch / genetics
Reg. No./Substance:
0/NOTCH3 protein, human; 0/Receptors, Notch

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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