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Douglas F Levinson,
Jianxin Shi,
Kai Wang,
Sang Oh,
Brien Riley,
Ann E Pulver,
Dieter B Wildenauer,
Claudine Laurent,
Bryan J Mowry,
Pablo V Gejman, [......],
Jeremy M Silverman,
Nadine Norton,
Nancy Zhang,
Hakon Hakonarson,
Cynthia Gao,
Ami Citri,
Mark Hansen,
Stephan Ripke,
Frank Dudbridge,
Peter A Holmans
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ABSTRACT: OBJECTIVE The authors used a genome-wide association study (GWAS) of multiply affected families to investigate the association of schizophrenia to common single-nucleotide polymorphisms (SNPs) and rare copy number variants (CNVs). METHOD The family sample included 2,461 individuals from 631 pedigrees (581 in the primary European-ancestry analyses). Association was tested for single SNPs and genetic pathways. Polygenic scores based on family study results were used to predict case-control status in the Schizophrenia Psychiatric GWAS Consortium (PGC) data set, and consistency of direction of effect with the family study was determined for top SNPs in the PGC GWAS analysis. Within-family segregation was examined for schizophrenia-associated rare CNVs. RESULTS No genome-wide significant associations were observed for single SNPs or for pathways. PGC case and control subjects had significantly different genome-wide polygenic scores (computed by weighting their genotypes by log-odds ratios from the family study) (best p=10-17, explaining 0.4% of the variance). Family study and PGC analyses had consistent directions for 37 of the 58 independent best PGC SNPs (p=0.024). The overall frequency of CNVs in regions with reported associations with schizophrenia (chromosomes 1q21.1, 15q13.3, 16p11.2, and 22q11.2 and the neurexin-1 gene [NRXN1]) was similar to previous case-control studies. NRXN1 deletions and 16p11.2 duplications (both of which were transmitted from parents) and 22q11.2 deletions (de novo in four cases) did not segregate with schizophrenia in families. CONCLUSIONS Many common SNPs are likely to contribute to schizophrenia risk, with substantial overlap in genetic risk factors between multiply affected families and cases in large case-control studies. Our findings are consistent with a role for specific CNVs in disease pathogenesis, but the partial segregation of some CNVs with schizophrenia suggests that researchers should exercise caution in using them for predictive genetic testing until their effects in diverse populations have been fully studied.
American Journal of Psychiatry 08/2012; 169(9):963-973. · 12.54 Impact Factor
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Stephan Ripke,
Alan R Sanders,
Kenneth S Kendler,
Douglas F Levinson,
Pamela Sklar,
Peter A Holmans,
Dan-Yu Lin,
Jubao Duan,
Roel A Ophoff,
Ole A Andreassen, [......],
Durk Wiersma,
Dieter B Wildenauer,
Hywel J Williams,
Nigel M Williams,
Brandon Wormley,
Stan Zammit,
Patrick F Sullivan,
Michael C O'Donovan,
Mark J Daly,
Pablo V Gejman
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ABSTRACT: We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 × 10(-11)) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 × 10(-9)), ANK3 (rs10994359, P = 2.5 × 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 × 10(-9)).
Nature Genetics 09/2011; 43(10):969-76. · 35.53 Impact Factor
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Flavie Mathieu,
Marie-Hélène Dizier,
Bruno Etain,
Stéphane Jamain,
Marcella Rietschel,
Wolfgang Maier, Margot Albus,
Patrick McKeon,
Siobhan Roche,
Douglas Blackwood, [......],
Thomas G Schulze,
Diana Zelenica,
Céline Charon,
Andrej Marusic,
Mojca C Dernovsek,
Hugh Gurling,
Markus Nöthen,
Mark Lathrop,
Marion Leboyer,
Frank Bellivier
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ABSTRACT: Bipolar disorder has a genetic component, but the mode of inheritance remains unclear. A previous genome scan conducted in 70 European families led to detect eight regions linked to bipolar disease. Here, we present an investigation of whether the phenotypic heterogeneity of the disorder corresponds to genetic heterogeneity in these regions using additional markers and an extended sample of families. The MLS statistic was used for linkage analyses. The predivided sample test and the maximum likelihood binomial methods were used to test genetic homogeneity between early-onset bipolar type I (cut-off of 22 years) and other types of the disorder (later onset of bipolar type I and early-onset bipolar type II), using a total of 138 independent bipolar-affected sib-pairs. Analysis of the extended sample of families supports linkage in four regions (2q14, 3p14, 16p23, and 20p12) of the eight regions of linkage suggested by our previous genome scan. Heterogeneity testing revealed genetic heterogeneity between early and late-onset bipolar type I in the 2q14 region (P = 0.0001). Only the early form of the bipolar disorder but not the late form appeared to be linked to this region. This region may therefore include a genetic factor either specifically involved in the early-onset bipolar type I or only influencing the age at onset (AAO). Our findings illustrate that stratification according to AAO may be valuable for the identification of genetic vulnerability polymorphisms. © 2010 Wiley-Liss, Inc.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 09/2010; 153B(8):1425-33. · 3.70 Impact Factor
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ABSTRACT: Single nucleotide polymorphisms (SNPs) in the trace amine associated receptor trace amine associated receptor 6 gene and 3' flanking region have been shown to be associated with schizophrenia. To replicate these findings, we conducted a family-based association study with the five most significant SNPs in our sample of 79 sib-pair families (56/79 sib-pair families showed linkage to 6q23) and 125 triads. No evidence for association was obtained between these SNPs and schizophrenia in our sample, even when limited to the 56 linked families (P>0.2). We conclude that trace amine associated receptor 6 is not important for the development of schizophrenia in our family samples.
Psychiatric genetics 08/2008; 18(4):208-10. · 2.33 Impact Factor
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ABSTRACT: Recent studies investigating the association of DNA variants in the metabotropic glutamate receptor gene (GRM3) with schizophrenia susceptibility revealed conflicting results. In this study, we focused on DNA sequence variants, for which association was reported and attempted to replicate association with schizophrenia or with cognitive deficits known to be present in patients with schizophrenia.
A sample of 242 families with affected offspring and five single nucleotide markers located in the genomic region of GRM3 has been used to replicate association with schizophrenia. In addition, results of neuropsychological tests, trail making test B and the Stroop color-naming task were available for a subgroup of these families (N=88) and an independent sample of 148 patients with schizophrenia. Correlation of these measurements with genotypic data was performed using analysis of variance.
No statistical evidence for association with schizophrenia or correlation with cognitive deficits as measured by the trail making test B or the Stroop color-naming task and the five DNA sequence variants could be detected. A trend towards association with schizophrenia was revealed for a single marker (rs2237562, P=0.056) and for 2-marker and 3-marker haplotypes containing this variant.
Our study of DNA sequence variants in the GRM3 gene did not provide further support for genetic association with schizophrenia or for correlation with cognitive deficits.
Psychiatric Genetics 03/2008; 18(1):25-30. · 2.58 Impact Factor
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Alexandra Schosser,
Harald N Aschauer,
Dieter B Wildenauer,
Sibylle G Schwab, Margot Albus,
Wolfgang Maier,
Monika Schloegelhofer,
Friedrich Leisch,
Kurt Hornik,
Sarah S Murray,
Christoph Gasche
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ABSTRACT: Infections of unknown origin and an altered immune response have been hypothesized to play a role in the pathogenesis of schizophrenia. We have previously identified two single nucleotide polymorphisms (SNPs) of the IL-10 receptor 1 (IL-10R1) causing a substitution of glycine 330 to arginine (G330R) and of serine 138 to glycine (S138G). A possible association between these IL-10R1 variants and schizophrenia has been investigated in the present study. DNA of 101 unrelated Austrian patients with a DSM-III-R (Diagnostic and Statistical Manual of Mental Disorders) consensus diagnosis of schizophrenia (n = 70) or schizoaffective disorder (n = 31) and DNA of 121 German schizophrenic patients (DSM-III-R) was analyzed for the presence of S138G and G330R by allele-specific multiplex PCRs. Data from patients were compared with 250 unrelated, psychiatric healthy controls. No difference in allele frequency was detected between patients and controls (G330R: 34.0% vs. 30.0%, P = 0.208; S138G: 19.7% vs. 16.6%, P = 0.235; by Fisher's exact test). However, there was a significant difference in genotype distribution (wt/wt, wt/mut, mut/mut) for G330R between patients (46.8%, 38.3%, 14.9%) and controls (47.6%, 44.8%, 7.6%; Fisher's test P = 0.032). No such difference was seen for S138G. Our results suggest that homozygosity of the IL-10R1 G330R allele is associated with schizophrenia and may contribute to the expression of disease phenotype in susceptible individuals.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 05/2007; 144B(3):347-50. · 3.70 Impact Factor
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Matthew B McQueen,
B Devlin,
Stephen V Faraone,
Vishwajit L Nimgaonkar,
Pamela Sklar,
Jordan W Smoller,
Rami Abou Jamra, Margot Albus,
Silviu-Alin Bacanu,
Miron Baron, [......],
Ann E Pulver,
John P Rice,
Marcella Rietschel,
William Scheftner,
Johannes Schumacher,
Ricardo Segurado,
Kristel Van Steen,
Weiting Xie,
Peter P Zandi,
Nan M Laird
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ABSTRACT: Several independent studies and meta-analyses aimed at identifying genomic regions linked to bipolar disorder (BP) have failed to find clear and consistent evidence of linkage regions. Our hypothesis is that combining the original genotype data provides benefits of increased power and control over sources of heterogeneity that outweigh the difficulty and potential pitfalls of the implementation. We conducted a combined analysis using the original genotype data from 11 BP genomewide linkage scans comprising 5,179 individuals from 1,067 families. Heterogeneity among studies was minimized in our analyses by using uniform methods of analysis and a common, standardized marker map and was assessed using novel methods developed for meta-analysis of genome scans. To date, this collaboration is the largest and most comprehensive analysis of linkage samples involving a psychiatric disorder. We demonstrate that combining original genome-scan data is a powerful approach for the elucidation of linkage regions underlying complex disease. Our results establish genomewide significant linkage to BP on chromosomes 6q and 8q, which provides solid information to guide future gene-finding efforts that rely on fine-mapping and association approaches.
The American Journal of Human Genetics 11/2005; 77(4):582-95. · 10.60 Impact Factor
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ABSTRACT: Involvement of AKT signaling pathways in schizophrenia has been recently suggested, on the basis of several lines of evidence. In addition to impairment of protein-levels and phosphorylation levels in the pathway, association of DNA sequence variants in the AKT1 gene with schizophrenia has been detected in a family sample.
We investigated the reported association of DNA sequence variants in the AKT1 gene in a sample of 79 sib-pair families with schizophrenia using the five single nucleotide polymorphisms (SNPs) of the original study and two additional SNPs in the neighborhood of the SNP for which association had been reported.
We obtained statistical significance for single markers (p = .002) and multilocus haplotypes (p = .0013) located in the same region as has been reported in the previous study.
The replication of association of variants in the AKT1 gene in a family sample with similar ethnical background as in the original study adds further evidence for involvement of AKT1 in development of schizophrenic disorders.
Biological Psychiatry 10/2005; 58(6):446-50. · 8.28 Impact Factor
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ABSTRACT: The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) mediates a multitude of central nervous functions by activating 5-HT receptor subtypes. A dysfunction of serotonergic neurotransmission is considered to play a major role in the pathophysiology of complex neuropsychiatric disorders. In our study, a mutation screen of the serotonin receptor gene HTR3B was carried out to explore a putative contribution to the etiology of bipolar affective disorder (BPAD) and schizophrenia (SZ). Screening of 49 patients suffering from BPAD, 78 patients with SZ and 62 control individuals revealed eleven sequence variations including a 3 bp deletion within the 5'UTR (5' untranslated region), four exonic and five intronic SNPs as well as a point mutation in the 3'UTR of HTR3B. Four of these sequence variations have not been described previously. Statistical computation rated most variants as probably non-disease related polymorphisms. However, IVS6 + 31C > T, IVS6 + 40C > A, and 1386T > C were solely detected in bipolar affective patients and in none of the controls. Interestingly, we observed a significant underrepresentation of the 3 bp deletion -100_-102delAAG in an extended sample of 162 bipolar affected patients compared to controls (allele-wise: 8% vs. 15%, P = 0.006, OR = 0.49, 95% CI: 0.3-0.82; genotype-wise: 15,5% vs. 29,0%, P = 0.005, OR = 0.45, 95% CI: 0.26-0.77). We suggest that this deletion may influence translational efficiency, thereby possibly affecting the development of bipolar affective disease.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 11/2004; 131B(1):1-5. · 3.70 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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Sibylle G Schwab,
Stephanie Mondabon,
Michael Knapp, Margot Albus,
Joachim Hallmayer,
Margitta Borrmann-Hassenbach,
Matyas Trixler,
Magdalena Gross,
Thomas G Schulze,
Marcella Rietschel,
Bernard Lerer,
Wolfgang Maier,
Dieter B Wildenauer
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ABSTRACT: Tumor necrosis factor alpha (TNFalpha), a cytokine involved in inflammatory processes, has been implicated in the pathophysiology of schizophrenia. The chromosomal location in the major histocompatibility complex (MHC) region on 6p21.1-21.3, a region with evidence for linkage, suggests a role in susceptibility to schizophrenia. Association of the minor (A) allele of the -G308A TNFalpha gene polymorphism with schizophrenia has been reported [Mol. Psychiatry 6 (2001) 79].
Association of the -G308A TNFalpha gene and the lymphotoxin alpha (LTalpha)+A252G gene polymorphisms with schizophrenia was studied in 79 sib pair families with linkage in the MHC region and in 128 trio families using the transmission disequilibrium test (TDT).
Weak association of the common G allele was detected for TNFalpha -G308A in both samples independently with borderline significance in the sib pair families (0.064) and with a nominally significant value of P=0.022 in the trio families. Combining both samples produced P=0.003, while LTalpha+A252G, located approximately 2-3 kb distally, revealed P=0.03 and the two locus haplotype yielded a P value of 0.001.
Our data suggests association of the common G allele of the -G308A TNFalpha gene polymorphism with schizophrenia in a sample of 207 families. However, linkage disequilibrium with a different allele of the TNFalpha gene or another gene in the MHC region cannot be excluded.
Schizophrenia Research 01/2004; 65(1):19-25. · 4.75 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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Sibylle G Schwab,
Michael Knapp,
Stephanie Mondabon,
Joachim Hallmayer,
Margitta Borrmann-Hassenbach, Margot Albus,
Bernard Lerer,
Marcella Rietschel,
Matyas Trixler,
Wolfgang Maier,
Dieter B Wildenauer
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ABSTRACT: Genetic variants in a gene on 6p22.3, dysbindin, have been shown recently to be associated with schizophrenia (Straub et al. 2002a). There is no doubt that replication in other independent samples would enhance the significance of this finding considerably. Since the gene is located in the center of the linkage peak on chromosome 6p that we reported earlier, we decided to test six of the most positive DNA polymorphisms in a sib-pair sample and in an independently ascertained sample of triads comprising 203 families, including the families for which we detected linkage on chromosome 6p. Evidence for association was observed in the two samples separately as well as in the combined sample (P=.00068 for SNP rs760761). Multilocus haplotype analysis increased the significance further to .00002 for a two-locus haplotype and to .00001 for a three-locus haplotype. Estimation of frequencies for six-locus haplotypes revealed one common haplotype with a frequency of 73.4% in transmitted, and only 57.6% in nontransmitted, parental haplotypes. All other six-locus haplotypes occurring at a frequency of >1% were less often transmitted than nontransmitted. Our results represent a first successful replication of linkage disequilibrium in psychiatric genetics detected in a region with previous evidence of linkage and will encourage the search for causes of schizophrenia by the genetic approach.
The American Journal of Human Genetics 01/2003; 72(1):185-90. · 10.60 Impact Factor
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Sibylle G Schwab,
Joachim Hallmayer,
Julia Freimann,
Bernard Lerer, Margot Albus,
Margitta Borrmann-Hassenbach,
Ronnen H Segman,
Matyas Trixler,
Marcella Rietschel,
Wolfgang Maier,
Dieter B Wildenauer
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ABSTRACT: The hypothesis that HLA antigens confer susceptibility to schizophrenic disorders has been tested by studying linkage and association in a family sample with 69 sib-pair families. Suggestive evidence for linkage was obtained by nonparametric multipoint LOD score analysis with a maximum around DQB CAR (P = 0.0004), a microsatellite marker that is in linkage disequilibrium with the HLA antigen DQB1. Spurious evidence for negative association as calculated by the transmission disequilibrium test was found for HLA- DRB1*11 (chi-square = 11.72, corrected P value = 0.03) and for the haplotype DQB1*301-DQA1*501-DRB1*11 (chi-square = 11.3, corrected P value = 0.043). No evidence of association with these alleles was obtained in a sample of 89 trios with schizophrenic offspring and parents. Our results are not in favor of a direct involvement of the HLA system in development of schizophrenia, but are compatible with the possible existence of a susceptibility gene in the MHC region at chromosome 6p 21.31.
American Journal of Medical Genetics 05/2002; 114(3):315-20.
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Douglas F Levinson,
Peter A Holmans,
Claudine Laurent,
Brien Riley,
Ann E Pulver,
Pablo V Gejman,
Sibylle G Schwab,
Nigel M Williams,
Michael J Owen,
Dieter B Wildenauer, [......],
George Papadimitriou,
Ann Weilbaecher,
Bernard Lerer,
Michael C O'Donovan,
Dimitris Dikeos,
Jeremy M Silverman,
Kenneth S Kendler,
Jacques Mallet,
Raymond R Crowe,
Marilyn Walters
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ABSTRACT: Reports of substantial evidence for genetic linkage of schizophrenia to chromosome 1q were evaluated by genotyping 16 DNA markers across 107 centimorgans of this chromosome in a multicenter sample of 779 informative schizophrenia pedigrees. No significant evidence was observed for such linkage, nor for heterogeneity in allele sharing among the eight individual samples. Separate analyses of European-origin families, recessive models of inheritance, and families with larger numbers of affected cases also failed to produce significant evidence for linkage. If schizophrenia susceptibility genes are present on chromosome 1q, their population-wide genetic effects are likely to be small.
Science 05/2002; 296(5568):739-41. · 31.20 Impact Factor
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Sven Cichon,
Johannes Schumacher,
Daniel J Müller,
Martina Hürter,
Christine Windemuth,
Konstantin Strauch,
Susanne Hemmer,
Thomas G Schulze,
Gabriele Schmidt-Wolf, Margot Albus, [......],
Jürgen Minges,
Dirk Lichtermann,
Bernhard Lerer,
Kyra Kanyas,
Max P Baur,
Thomas F Wienker,
Wolfgang Maier,
Marcella Rietschel,
Peter Propping,
Markus M Nöthen
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ABSTRACT: Bipolar affective disorder (BPAD), also known as manic depressive illness, is a severe psychiatric disorder characterized by episodes of mania and depression. It has a lifetime prevalence of ∼1% in all human populations. In order to identify chromosomal regions containing genes that play a role in determining susceptibility to this psychiatric condition, we have conducted a complete genome screen with 382 markers (average marker spacing of 9.3 cM) in a sample of 75 BPAD families which were recruited through an explicit ascertainment scheme. Pedigrees were of German, Israeli and Italian origin, respectively. Parametric and non-parametric linkage analysis was performed. The highest two-point LOD score was obtained on 8q24 (D8S514; LOD score = 3.62), in a region that has not attracted much attention in previous linkage studies of BPAD. The second best finding was seen on 10q25–q26 (D10S217; LOD score = 2.86) and has been reported in independent studies of BPAD. Other regions showing ‘suggestive’ evidence for linkage localized to 1p33–p36, 2q21–q33, 3p14, 3q26–q27, 6q21–q22, 8p21, 13q11 and 14q12–q13. In addition, we aimed at detecting possible susceptibility loci underlying genomic imprinting by analyzing the autosomal genotype data with the recently developed extension of the GENEHUNTER program, GENEHUNTER-IMPRINTING. Putative paternally imprinted loci were identified in chromosomal regions 2p24–p21 and 2q31–q32. Maternally imprinted susceptibility genes may be located on 14q32 and 16q21–q23.
Human Molecular Genetics 01/2002; · 7.64 Impact Factor
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ABSTRACT: Serotonin receptor type 3 is a ligand-gated ion channel implicated in behavioural disorders. Our objective was to identify nucleotide variants in a specific portion of the 5′ region of the serotonin receptor gene (HTR3A) containing upstream open reading frames (uORFs) and to investigate their effect on bipolar disease. Mutations in uORFs have been recently shown to cause disease by changing expression on the translational level. We identified one polymorphism, C195T, and one missense mutation, C178T (Pro16Ser) within an upstream open reading frame. No significant association was found between the C195T polymorphism and bipolar affective disorder. A significant association was, however, found between the variant C178T in 156 patients with bipolar disorder compared to 156 healthy controls (P = 0.00016). To investigate the relevance of this variant on gene expression, luciferase reporter constructs containing the C178T (Pro16Ser) allele were established and compared to the C178T plus C195T and wild-type alleles. Reporter constructs containing the C178T (Pro16Ser) allele drove 245% and 138% expression compared to the wild-type allele. These findings show that the C178T(Pro16Ser) variant in HTR3A may represent a functional variant and affect the susceptibility to bipolar disorder.
Pharmacogenetics and Genomics 07/2001; 11(6):471-475. · 3.48 Impact Factor
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Pamela Sklar,
Sibylle G. Schwab,
Nigel M. Williams,
Mark Daly,
Stephen Schaffner,
Wolfgang Maier, Margot Albus,
Matyas Trixler,
Peter Eichhammer,
Bernard Lerer, [......],
Stan Zammit,
Alastair G. Cardno,
Sue Jones,
Geraldine McCarthy,
Vihra Milanova,
George Kirov,
Michael C. O'Donovan,
Eric S. Lander,
Michael J. Owen,
Dieter B. Wildenauer
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ABSTRACT: A genetic association between NOTCH4 and schizophrenia has previously been proposed1. Unsing all markers previously shown to be associated, we found no evidence for such in three independent family-based samples (n=519 parent-offspring trios), and a case-control sample derived from the same ethnic background as the original observaton. These data strongly suggest that NOTCH4 is not a significant susceptibility allele for schizophrenia.
Nature Genetics. 05/2001; 28(2):126-128.
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Beate Niesler,
Birgit Weiss,
Christine Fischer,
Markus M. Nöthen,
Peter Propping,
Brigitta Bondy,
Marcella Rietschel,
Wolfgang Maier, Margot Albus,
Ernst Franzek,
Gudrun A. Rappold
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ABSTRACT: Serotonin receptor genes have always been considered excellent candidate genes in the aetiology of neurogenetic diseases. In this study, we assessed sequence variations of the HTR3A gene. For this purpose, we established exon-specific primers and analysed DNA samples from 165 unrelated individuals including 70 schizophrenic patients, 48 patients with bipolar affective disorder and 47 healthy control persons using polymerase chain reaction/single-strand conformational polymorphism analysis. We discovered six sequence variants, five of which represent polymorphisms. These polymorphisms could not be associated with schizophrenia and bipolar affective disorder (P = 0.055-1). We also detected a missense mutation in exon 9 in a schizophrenic patient at a conserved position (Pro391Arg). To determine the incidence of this substitution an extended set of 358 schizophrenic patients and 155 control individuals was investigated. The Pro391Arg mutation was not detected in these schizophrenic patients and controls screened. However, a second missense mutation (Arg344His) was detected in one schizophrenic patient, but not in any of the controls. These results suggest that the observed mutations in HTR3A are rare and therefore do not play a major role in the aetiology of the disorder. Further studies are needed to support the hypothesis that HTR3A may contribute to the schizophrenia in these patients.
Pharmacogenetics and Genomics 01/2001; 11(1):21-27. · 3.48 Impact Factor
