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Psychiatry research. 02/2013;
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Tilo Kircher,
Renate Thienel,
Michael Wagner,
Martina Reske,
Ute Habel,
Thilo Kellermann,
Ingo Frommann, Sibylle Schwab,
Wolfgang Wölwer,
Martina von Wilmsdorf,
Dieter F. Braus,
Andrea Schmitt,
Alexander Rapp,
Tony Stöcker,
N. Jon Shah,
Fritz A. Henn,
Heinrich Sauer,
Wolfgang Gaebel,
Wolfgang Maier,
Frank Schneider
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ABSTRACT: The Neuregulin (NRG1) gene has been associated with schizophrenia, but its functional implications are largely unknown. Our
aim was to assess differential brain activation between patients carrying an at-risk allele on the Neuregulin 1 gene and patients
without this genetic risk. Neural signal changes between 14 first episode schizophrenia patients with the at risk allele (SNP8NRG221533)
from the Icelandic core haplotype and 14 without were measured with fMRI during a working memory task. Patients without the
at risk allele showed greater activations (P<0.05; corrected) in the left hippocampus, precuneus and cerebellum, as well as the right anterior cingulate. Brain regions
previously associated with the pathology of Schizophrenia are differentially affected in those with a genetic at risk status
in the NRG1 gene. Heterogeneity of structural and functional measures within patients characterized by clinical phenotypes
may be in part due to this genetic variation.
European Archives of Psychiatry and Clinical Neuroscience 04/2012; 259(2):72-79. · 3.49 Impact Factor
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Rainald Mössner,
Anna Schuhmacher,
Michael Wagner,
Boris B Quednow,
Ingo Frommann,
Kai-Uwe Kühn, Sibylle G Schwab,
Marcella Rietschel,
Peter Falkai,
Wolfgang Wölwer,
Stephan Ruhrmann,
Andreas Bechdolf,
Wolfgang Gaebel,
Joachim Klosterkötter,
Wolfgang Maier
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ABSTRACT: The genetic factors determining the progression of prodromal syndromes to first episode schizophrenia have remained enigmatic to date. In a unique prospective multicentre trial, we assessed whether variants at the D-amino acid oxidase activator (DAOA)/G72 locus influence progression to psychosis. Young subjects with a prodromal syndrome were observed prospectively for up to 2 years to assess the incidence of progression to schizophrenia or first episode psychosis. Of the 82 probands with a prodromal syndrome, 21 probands experienced progression to psychosis within the observation period. Assessment of nine common variants in the DAOA/G72 locus yielded two variants with the predictive value for symptom progression: all four probands with the rs1341402 CC genotype developed psychosis compared with 17 out of 78 probands with the TT or CT genotypes (chi(2) = 12.348; df = 2; p = 0.002). The relative risk for progression to psychosis was significantly increased in the CC genotype: RR = 4.588 (95% CI = 2.175-4.588). Similarly, for rs778294, 50% of probands with the AA genotype, but only 22% of probands with a GG or GA genotype progressed to psychosis (chi(2) = 7.027; df = 2; p = 0.030). Moreover, haplotype analysis revealed a susceptibility haplotype for progression to psychosis. This is one of the first studies to identify a specific genetic factor for the progression of prodromal syndromes to schizophrenia, and further underscores the importance of the DAOA/G72 gene for schizophrenia.
Archiv f ur Psychiatrie und Nervenkrankheiten 09/2009; 260(3):209-15. · 2.75 Impact Factor
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ABSTRACT: Two polymorphic regions of serotonin transporter (5-HTT) gene: a 44 base pair (bp) insertion/deletion in the promoter region (5-HTTLPR) and a 17 bp variable number of tandem repeats in second intron (VNTR-2), seem to modulate the gene's transcription in allele-dependent manner.
We have earlier demonstrated association with 5-HTT gene in families multiply affected by schizophrenia. Here, we investigated separate and combined effects of VNTR-2 and 5-HTTLPR on the rate of peripheral 5-HTT transcription in a sample of offspring from those families. Relative 5-HTT mRNA levels were determined in 53 permanent lymphoblast cell lines by semiquantitative real-time polymerase chain reaction using beta-actin as reference.
Since the low-expressing alleles (short [S], 10) appeared to act dominantly, genotypes were grouped as "high-expressing" (long [L]/L, 12/12) versus "low-expressing" (S, 10). At both loci, nonsignificant differences in 5-HTT mRNA levels ( approximately 30%) were observed between "high"- and "low-expressing" genotypes. In order to search for the potential combined effect of 5-HTTLPR and VNTR-2, levels of 5-HTT mRNA were compared among three groups of samples having "low-expressing" genotype at none, one, or both loci. Increase in number of "low-expressing" genotypes significantly reduced relative 5-HTT gene expression (p <.02).
Our results indicate weak individual influence, but possible combined effect, of 5-HTTLPR and VNTR-2 polymorphisms on 5-HTT gene expression.
Biological Psychiatry 07/2004; 55(11):1090-4. · 8.28 Impact Factor
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Thomas Rohrmeier,
Albert Putzhammer,
Heino Sartor,
Michael Knapp,
Margot Albus,
Margitta Borrmann-Hassenbach,
Dirk Lichtermann,
Dieter Wildenauer, Sibylle Schwab,
Wolfgang Maier,
Helmfried E Klein,
Peter Eichhammer
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ABSTRACT: Recently, a putative functional polymorphism (-141C Ins/Del) in the 5'-flanking region of the dopamine D2 receptor was found. An association of the Ins allele with schizophrenia has been described in a Japanese sample. In the present study this association was examined in a German schizophrenia patient population. In a family based approach 190 German family trios were analyzed for the -141C Ins/Del genotype. Using the transmission disequilibrium test (TDT) we found no evidence for an association of the Ins allele with schizophrenia (TDT = 0.152, P = 0.696). In parallel, we performed an independent case control study with 268 schizophrenic patients and 244 controls. Again, we did not detect an overrepresentation of the Ins allele in patients (P = 0.124). Thus, our data do not support the hypothesis that the -141C Ins variant plays a major role in predisposition to schizophrenia. To confirm our conclusion further preferentially family based studies are needed.
Psychiatrische Praxis 06/2003; 30 Suppl 2:S212-5. · 1.64 Impact Factor
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Thomas Rohrmeier,
Albert Putzhammer,
Heino Sartor,
Michael Knapp,
Margot Albus,
Margitta Borrmann-Hassenbach,
Dirk Lichtermann,
Dieter Wildenauer, Sibylle Schwab,
Wolfgang Maier,
Helmfried E. Klein,
Peter Eichhammer
[show abstract]
[hide abstract]
ABSTRACT: Recently, a putative functional polymorphism (- 141C Ins/Del) in the 5'-flanking region of the dopamine D (2) receptor was found. An association of the Ins allele with schizophrenia has been described in a Japanese sample. In the present study this association was examined in a German schizophrenia patient population. In a family based approach 190 German family trios were analyzed for the - 141C Ins/Del genotype. Using the transmission disequilibrium test (TDT) we found no evidence for an association of the Ins allele with schizophrenia (TDT = 0.152, P = 0.696). In parallel, we performed an independent case control study with 268 schizophrenic patients and 244 controls. Again, we did not detect an overrepresentation of the Ins allele in patients (P = 0.124). Thus, our data do not support the hypothesis that the - 141C Ins variant plays a major role in predisposition to schizophrenia. To confirm our conclusion further preferentially family based studies are needed.
Psychiatrische Praxis 06/2003; 30(Suppl 2):212-215. · 1.64 Impact Factor
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Nicole Herbon,
Monika Werner,
Christine Braig,
Henning Gohlke,
Gaby Dütsch,
Thomas Illig,
Janine Altmüller,
Jochen Hampe,
Annette Lantermann,
Stefan Schreiber,
Ezio Bonifacio,
Annette Ziegler, Sibylle Schwab,
Dieter Wildenauer,
Dirk van den Boom,
Andreas Braun,
Michael Knapp,
Peter Reitmeir,
Matthias Wjst
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ABSTRACT: We apply a high-throughput protocol of chip-based mass spectrometry (matrix-assisted laser desorption/ionization time-of-flight; MALDI-TOF) as a method of screening for differences in single-nucleotide polymorphism (SNP) allele frequencies. Using pooled DNA from individuals with asthma, Crohn's disease (CD), schizophrenia, type 1 diabetes (T1D), and controls, we selected 534 SNPs from an initial set of 1435 SNPs spanning a 25-Mb region on chromosome 6p21. The standard deviations of measurements of time of flight at different dots, from different PCRs, and from different pools indicate reliable results on each analysis step. In 90% of the disease-control comparisons we found allelic differences of <10%. Of the T1D samples, which served as a positive control, 10 SNPs with significant differences were observed after taking into account multiple testing. Of these 10 SNPs, 5 are located between DQB1 and DRB1, confirming the known association with the DR3 and DR4 haplotypes whereas two additional SNPs also reproduced known associations of T1D with DOB and LTA. In the CD pool also, two earlier described associations were found with SNPs close to DRB1 and MICA. Additional associations were found in the schizophrenia and asthma pools. They should be confirmed in individual samples or can be used to develop further quality criteria for accepting true differences between pools. The determination of SNP allele frequencies in pooled DNA appears to be of value in assigning further genotyping priorities also in large linkage regions.
Genomics 05/2003; 81(5):510-8. · 3.02 Impact Factor
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ABSTRACT: The genetic analysis of schizophrenia has increasingly focused on localizing susceptibility genes. Converging evidence from linkage studies proposes some areas on the genome (5q, 6p, 6q, 8p, 10p, 13q, 18p and 22q) that may contain contributing genes. Replicated linkage signals are weak, however, as is the strength of the replicated associations with markers of candidate genes. Progress in the Human Genome Project, from improved clinical strategies to reduce complexity, and extension of informative family samples will aid future search for susceptibility genes.
Current Opinion in Psychiatry 12/1999; 13(1):3-9. · 3.05 Impact Factor
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ABSTRACT: Schizophrenia is aggregated in families because of underlying genetic factors.The application of efficient molecular-genetic techniques have produced findings of several linkages on the genome, with independent replications on chromosomes 5q, 6p, 8p, 13q and 22q. Susceptibility genes are probably localized in these regions and have to be identified. The multiplicity of suggestive regions showing linkage to schizophrenia argues against a single causal or major operating gene for schizophrenia. Despite replications, the observed strength of linkages is modest, as is the strength of associations. These observations suggest that the effect sizes of the single susceptibility genes are small, that complex interactions with environmental factors are operating, or both.
Current Opinion in Psychiatry 12/1997; 11(1):19-25. · 3.05 Impact Factor
