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Polymorphisms in SREBF1 and SREBF2, two antipsychotic-activated transcription factors controlling cellular lipogenesis, are associated with schizophrenia in German and Scandinavian samples.

https://arctichealth.org/en/permalink/ahliterature154634
Source
Mol Psychiatry. 2010 May;15(5):463-72
Publication Type
Article
Date
May-2010
Author
S. Le Hellard
T W Mühleisen
S. Djurovic
J. Fernø
Z. Ouriaghi
M. Mattheisen
C. Vasilescu
M B Raeder
T. Hansen
J. Strohmaier
A. Georgi
F F Brockschmidt
I. Melle
I. Nenadic
H. Sauer
M. Rietschel
M M Nöthen
T. Werge
O A Andreassen
S. Cichon
V M Steen
Author Affiliation
Department of Clinical Medicine, Bergen Mental Health Research Center, University of Bergen, Bergen, Norway. stephanie.le.hellard@helse-bergen.no
Source
Mol Psychiatry. 2010 May;15(5):463-72
Date
May-2010
Language
English
Publication Type
Article
Keywords
Adult
Antipsychotic Agents - therapeutic use
Case-Control Studies
Chromosomes, Human, Pair 17 - genetics
Chromosomes, Human, Pair 22 - genetics
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Germany
Humans
Lipogenesis - drug effects - genetics
Male
Middle Aged
Odds Ratio
Polymorphism, Single Nucleotide - genetics
Scandinavia
Schizophrenia - drug therapy - genetics
Sterol Regulatory Element Binding Protein 1 - genetics
Sterol Regulatory Element Binding Protein 2 - genetics
Abstract
Several studies have reported structural brain abnormalities, decreased myelination and oligodendrocyte dysfunction in schizophrenia. In the central nervous system, glia-derived de novo synthesized cholesterol is essential for both myelination and synaptogenesis. Previously, we demonstrated in glial cell lines that antipsychotic drugs induce the expression of genes involved in cholesterol and fatty acids biosynthesis through activation of the sterol regulatory element binding protein (SREBP) transcription factors, encoded by the sterol regulatory element binding transcription factor 1 (SREBF1) and sterol regulatory element binding transcription factor 2 (SREBF2) genes. Considering the importance of these factors in the lipid biosynthesis and their possible involvement in antipsychotic drug effects, we hypothesized that genetic variants of SREBF1 and/or SREBF2 could affect schizophrenia susceptibility. We therefore conducted a HapMap-based association study in a large German sample, and identified association between schizophrenia and five markers in SREBF1 and five markers in SREBF2. Follow-up studies in two independent samples of Danish and Norwegian origin (part of the Scandinavian collaboration of psychiatric etiology study, SCOPE) replicated the association for the five SREBF1 markers and for two markers in SREBF2. A combined analysis of all samples resulted in highly significant genotypic P-values of 9 x 10(-4) for SREBF1 (rs11868035, odd ration (OR)=1.26, 95% confidence interval (CI) (1.09-1.45)) and 4 x 10(-5) for SREBF2 (rs1057217, OR=1.39, 95% CI (1.19-1.63)). This finding strengthens the hypothesis that SREBP-controlled cholesterol biosynthesis is involved in the etiology of schizophrenia.
PubMed ID
18936756 View in PubMed
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