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Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci.
Mol Psychiatry. 2014 Mar;19(3):325-33
Publication Type
A D Børglum
D. Demontis
J. Grove
J. Pallesen
M V Hollegaard
C B Pedersen
A. Hedemand
M. Mattheisen
A. Uitterlinden
M. Nyegaard
T. Ørntoft
C. Wiuf
M. Didriksen
M. Nordentoft
M M Nöthen
M. Rietschel
R A Ophoff
S. Cichon
R H Yolken
D M Hougaard
P B Mortensen
O. Mors
Mol Psychiatry. 2014 Mar;19(3):325-33
Publication Type
ARNTL Transcription Factors - genetics
Cadherins - genetics
Case-Control Studies
Cytomegalovirus Infections - complications - genetics
European Continental Ancestry Group - genetics
Gene-Environment Interaction
Genetic Predisposition to Disease - genetics
Genome-Wide Association Study
Homeodomain Proteins - genetics
Maternal Exposure
Polymorphism, Single Nucleotide - genetics
Schizophrenia - complications - genetics
Sorting Nexins - genetics
Transcription Factors - genetics
alpha Catenin - genetics
Genetic and environmental components as well as their interaction contribute to the risk of schizophrenia, making it highly relevant to include environmental factors in genetic studies of schizophrenia. This study comprises genome-wide association (GWA) and follow-up analyses of all individuals born in Denmark since 1981 and diagnosed with schizophrenia as well as controls from the same birth cohort. Furthermore, we present the first genome-wide interaction survey of single nucleotide polymorphisms (SNPs) and maternal cytomegalovirus (CMV) infection. The GWA analysis included 888 cases and 882 controls, and the follow-up investigation of the top GWA results was performed in independent Danish (1396 cases and 1803 controls) and German-Dutch (1169 cases, 3714 controls) samples. The SNPs most strongly associated in the single-marker analysis of the combined Danish samples were rs4757144 in ARNTL (P=3.78 ? 10(-6)) and rs8057927 in CDH13 (P=1.39 ? 10(-5)). Both genes have previously been linked to schizophrenia or other psychiatric disorders. The strongest associated SNP in the combined analysis, including Danish and German-Dutch samples, was rs12922317 in RUNDC2A (P=9.04 ? 10(-7)). A region-based analysis summarizing independent signals in segments of 100?kb identified a new region-based genome-wide significant locus overlapping the gene ZEB1 (P=7.0 ? 10(-7)). This signal was replicated in the follow-up analysis (P=2.3 ? 10(-2)). Significant interaction with maternal CMV infection was found for rs7902091 (P(SNP ? CMV)=7.3 ? 10(-7)) in CTNNA3, a gene not previously implicated in schizophrenia, stressing the importance of including environmental factors in genetic studies.
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PubMed ID
23358160 View in PubMed
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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.
Mol Psychiatry. 2010 May;15(5):463-72
Publication Type
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.
Mol Psychiatry. 2010 May;15(5):463-72
Publication Type
Antipsychotic Agents - therapeutic use
Case-Control Studies
Chromosomes, Human, Pair 17 - genetics
Chromosomes, Human, Pair 22 - genetics
Genetic Predisposition to Disease
Genome-Wide Association Study
Lipogenesis - drug effects - genetics
Middle Aged
Odds Ratio
Polymorphism, Single Nucleotide - genetics
Schizophrenia - drug therapy - genetics
Sterol Regulatory Element Binding Protein 1 - genetics
Sterol Regulatory Element Binding Protein 2 - genetics
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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