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1.
Am J Psychiatry ; 176(8): 651-660, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31164008

RESUMO

OBJECTIVE: More than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium. METHODS: The samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders. RESULTS: Three genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%). CONCLUSIONS: This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.

2.
Psychiatr Genet ; 21(6): 294-306, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21876473

RESUMO

OBJECTIVES: Alcoholism and affective disorders are both strongly comorbid and heritable. We have investigated the genetic comorbidity between bipolar affective disorder and alcoholism. METHODS: A genome-wide allelic association study of 506 patients from the University College London bipolar disorder case-control sample and 510 ancestrally matched supernormal controls. One hundred forty-three of the bipolar patients fulfilled the Research Diagnostic Criteria diagnosis of alcoholism. A total of 372 193 single nucleotide polymorphisms (SNPs) were genotyped. Genes previously shown to be associated with alcoholism and addiction phenotypes were then tested for association in the bipolar alcoholic sample using gene-wise permutation tests of all SNPs genotyped within a 50-kb region flanking each gene. RESULTS: Several central nervous system genes showed significant (P<0.05) gene-wise evidence of association with bipolar alcoholism. The genes implicated, which replicated genes previously shown to be associated with alcoholism were: cadherin 11, collagen type 11 α2, neuromedin U receptor 2, exportin7, and semaphorin-associated protein 5A. The SNPs most strongly implicated in bipolar alcoholism, but, which did not meet conventional genome-wide significance criteria were the insulin-like growth factor-binding protein 7, carboxypeptidase O, cerebellin 2, and the cadherin 12 genes. CONCLUSION: We have confirmed the role of some genes previously shown to be associated with alcoholism in the comorbid bipolar alcoholism subgroup. In this subgroup, bipolar disorder may lower the threshold for the phenotypic expression of these alcoholism susceptibility genes. We also show that some genes may independently increase susceptibility to affective disorder and alcoholism.


Assuntos
Alcoolismo/epidemiologia , Alcoolismo/genética , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Caderinas/genética , Estudos de Casos e Controles , Comorbidade , Feminino , Marcadores Genéticos , Humanos , Londres/epidemiologia , Masculino , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos Testes
3.
Am J Med Genet B Neuropsychiatr Genet ; 156(2): 177-87, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21302346

RESUMO

Insulin-like growth factor 1 (IGF1) has been shown to have an important role in brain development and function. Studies of IGF1 administration in rodents have shown that it has an anxiolytic and antidepressant effect. A genome-wide association study (GWAS) of the first University College London (UCL) cohort of 506 bipolar affective disorder subjects and 510 controls was carried out. The exons and flanking regions of IGF1 were resequenced, any new polymorphisms found were genotyped in an enlarged UCL sample of 937 cases and 941 controls. GWAS data gave good evidence of allelic and haplotypic association between multiple IGF1 SNP's and bipolar disorder (BD). New polymorphisms were found by resequencing IGF1 region. Data from GWAS and the new markers showed that twelve out of 43 SNPs showed association with BD with the four most significant SNPs having values of 3.7 × 10(-5) , 8.4 × 10(-4) , 2.6 × 10(-4) , and 2.5 × 10(-4) . A 5' promoter microsatellite polymorphism previously correlated with plasma lipoprotein concentration was also associated with BD (P = 0.013). Haplotypic association confirmed association with BD with significance values similar to the single marker SNP values. The marker rs12426318 has also been found to be associated with BD in a second sample. A test of gene wide significance with permutation testing for all markers genotyped at IGF1 was also significant. These data implicate IGF1 as a candidate gene to cause genetic susceptibility to BD.


Assuntos
Transtorno Bipolar/genética , Predisposição Genética para Doença , Fator de Crescimento Insulin-Like I/genética , Polimorfismo de Nucleotídeo Único , Alelos , Estudos de Casos e Controles , Mapeamento Cromossômico/estatística & dados numéricos , Estudos de Coortes , Éxons , Marcadores Genéticos , Estudo de Associação Genômica Ampla/métodos , Genótipo , Haplótipos , Humanos , Londres , Repetições de Microssatélites
4.
Eur J Hum Genet ; 19(5): 588-92, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21206513

RESUMO

Genetic deletions and duplications known as copy number variants have been strongly implicated in genetic susceptibility to schizophrenia, autism, attention deficit hyperactivity disorder and epilepsy. The overall rate of copy number variants in the University College London (UCL) bipolar disorder sample was found to be slightly lower than the rate in controls. This finding confirms the results from other studies that have also shown no increased rate of copy number variants in bipolar disorder. However, some rare duplications and deletions were observed only in bipolar disorder cases and not in controls, these included some that had previously been detected only in rare cases of bipolar disorder. We conclude that copy-number variant analysis shows no obvious sharing of the same genetic susceptibility between schizophrenia and bipolar disorder. Copy number variants do not seem to have an important role in susceptibility to bipolar disorder, they may, however, still represent a rare cause of the disease, although the evidence for this is far from clear.


Assuntos
Transtorno Bipolar/genética , Variações do Número de Cópias de DNA , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Reino Unido
5.
Psychiatr Genet ; 21(1): 1-4, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21057379

RESUMO

OBJECTIVE: There are theoretical reasons why comparing marker allele frequencies between cases of different diseases, rather than with controls, may offer benefits. The samples may be better matched, especially for background risk factors common to both diseases. Genetic loci may also be detected which influence which of the two diseases occurs if common risk factors are present. METHOD: We used samples of UK bipolar and schizophrenic cases that had earlier been subject to genome-wide association studies and compared marker allele frequencies between the two samples. When these differed for a marker, we compared the case sample allele frequencies with those of a control sample. RESULTS: Eight markers were significant at P value of less than 10(-5). Of these, the most interesting finding was for rs17645023, which was significant at P value of less than 10(-6) and which lies 36 kb from CACNG5. Control allele frequencies for this marker were intermediate between those for bipolar and schizophrenic cases. CONCLUSION: The application of this approach suggests that it does have some merits. The finding for CACNG5, taken together with the earlier implication of CACNA1C and CACNA1B, strongly suggests a key role for voltage-dependent calcium channel genes in the susceptibility to bipolar disorder and/or schizophrenia.


Assuntos
Transtorno Bipolar/genética , Canais de Cálcio/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Esquizofrenia/genética , Estudos de Casos e Controles , Estudos de Coortes , Marcadores Genéticos , Humanos
6.
Am J Med Genet B Neuropsychiatr Genet ; 153B(2): 582-591, 2010 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-19693800

RESUMO

A recent study published by our group implicated the bromodomain containing protein 1 (BRD1) gene located at chromosome 22q13.33 with schizophrenia (SZ) and bipolar affective disorder (BPD) susceptibility and provided evidence suggesting a possible role for BRD1 in neurodevelopment. The present study reports an association analysis of BRD1 and the neighboring gene ZBED4 using a Caucasian case-control sample from Denmark and England (UK/DK sample: 490 patients with BPD, 527 patients with SZ, and 601 control individuals), and genotypes obtained from a BPD genome wide association (GWA) study of an overlapping English sample comprising 506 patients with BPD and 510 control individuals (UCL sample). In the UK/DK sample we genotyped 11 SNPs in the BRD1 region, of which six showed association with SZ (minimal single marker P-values of 0.0014), including two SNPs that previously showed association in a Scottish population [Severinsen et al. (2006); Mol Psychiatry 11(12): 1126-1138]. Haplotype analysis revealed specific risk as well as protective haplotypes with a minimal P-value of 0.0027. None of the 11 SNPs showed association with BPD. However, analyzing seven BRD1 SNPs obtained from the BPD GWA study, positive associations with BPD was observed with all markers (minimal P-value of 0.0014). The associations reported add further support for the implication of BRD1 with SZ and BPD susceptibility.


Assuntos
Transtorno Bipolar/genética , Predisposição Genética para Doença , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Alelos , Estudos de Casos e Controles , Saúde da Família , Marcadores Genéticos , Variação Genética , Genótipo , Haplótipos , Humanos , Modelos Genéticos , Análise de Sequência com Séries de Oligonucleotídeos
7.
Behav Brain Funct ; 5: 28, 2009 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-19586533

RESUMO

BACKGROUND: Previous linkage and association studies have implicated the D-amino acid oxidase activator gene (DAOA)/G30 locus or neighbouring region of chromosome 13q33.2 in the genetic susceptibility to both schizophrenia and bipolar disorder. Four single nucleotide polymorphisms (SNPs) within the D-amino acid oxidase (DAO) gene located at 12q24.11 have also been found to show allelic association with schizophrenia. METHODS: We used the case control method to test for genetic association with variants at these loci in a sample of 431 patients with schizophrenia, 303 patients with bipolar disorder and 442 ancestrally matched supernormal controls all selected from the UK population. RESULTS: Ten SNPs spanning the DAOA locus were genotyped in these samples. In addition three SNPs were genotyped at the DAO locus in the schizophrenia sample. Allelic association was detected between the marker rs3918342 (M23), 3' to the DAOA gene and both schizophrenia (chi2 = 5.824 p = 0.016) and bipolar disorder (chi2 = 4.293 p = 0.038). A trend towards association with schizophrenia was observed for two other DAOA markers rs3916967 (M14, chi2 = 3.675 p = 0.055) and rs1421292 (M24; chi2 = 3.499 p = 0.062). A test of association between a three marker haplotype comprising of the SNPs rs778293 (M22), rs3918342 (M23) and rs1421292 (M24) and schizophrenia gave a global empirical significance of p = 0.015. No evidence was found to confirm the association of genetic markers at the DAO gene with schizophrenia. CONCLUSION: Our results provide some support for a role for DAOA in susceptibility to schizophrenia and bipolar disorder.

8.
Am J Psychiatry ; 166(6): 718-25, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19448189

RESUMO

OBJECTIVE: Lithium remains a first-line treatment for bipolar disorder, but the mechanisms by which it prevents the recurrence of mood episodes are not known. The authors utilized data from a genomewide association study to examine associations between single nucleotide polymorphisms (SNPs) and the outcome of lithium treatment in two cohorts of patients with bipolar I disorder or bipolar II disorder. METHOD: The hazard for mood episode recurrence was examined among 1,177 patients with bipolar I disorder or bipolar II disorder, including 458 individuals treated with lithium carbonate or citrate, who were participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) cohort. SNPs showing the greatest evidence of association in Cox regression models were then examined for association with positive lithium response among 359 bipolar I or II disorder patients treated with lithium carbonate or citrate in a second cohort from the University College London. RESULTS: The strongest association in the STEP-BD cohort (minimum p=5.5 x 10(-7)) was identified for a region on chromosome 10p15 (rs10795189). Of the regions showing suggestive evidence (p<5 x 10(-4)) of association with lithium response, five were further associated with positive lithium response in the University College London cohort, including SNPs in a region on chromosome 4q32 spanning a gene coding for the glutamate/alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionate (AMPA) receptor GRIA2. CONCLUSIONS: Multiple novel loci merit further examination for association with lithium response in bipolar disorder patients, including one region that spans the GRIA2 gene, for which expression has been shown to be regulated by lithium treatment.


Assuntos
Antipsicóticos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/genética , Genoma , Carbonato de Lítio/uso terapêutico , Adulto , Alelos , Transtorno Bipolar/diagnóstico , Cromossomos Humanos Par 4/genética , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Receptores de AMPA/genética , Prevenção Secundária
9.
Psychiatr Genet ; 19(4): 165-70, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19451863

RESUMO

BACKGROUND: Recent studies have reported large common regions of homozygosity (ROHs) that are the result of autozygosity, that is, the cooccurrence within individuals of long haplotypes that have a high frequency in the population. A recent study reports that such regions are found more commonly in individuals with schizophrenia compared with controls, and identified nine 'risk ROHs' that were individually more common in cases. Of these, four contained or neighboured genes associated with schizophrenia (NOS1AP/UHMK1, ATF2, NSF and PIK3C3). METHODS: We have applied the same methodology to a UK sample of 506 cases with bipolar disorder and 510 controls. RESULTS: There was no overall excess of common ROHs among bipolar individuals. With one exception, the haplotypes accounting for the ROHs appeared to be distributed according to the Hardy-Weinberg equilibrium. One ROH was individually more common among cases (uncorrected P = 0.0003). This ROH spanned the chromosome 2p23.3 gene ITSN2 (the gene for intersectin 2 isoform 2). However, inspection of the homozygous haplotypes and haplotype-based tests for association failed to provide a clearer understanding of why this ROH was occurring more commonly. CONCLUSION: Overall, we conclude that, in contrast with schizophrenia, common ROHs are rarely associated with susceptibility to bipolar disorder. This supports the idea that predominantly different genes are increasing susceptibility to schizophrenia and bipolar affective disorders.


Assuntos
Transtorno Bipolar/genética , Homozigoto , Estudos de Casos e Controles , Haplótipos , Heterozigoto , Humanos
10.
Nat Genet ; 40(9): 1056-8, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18711365

RESUMO

To identify susceptibility loci for bipolar disorder, we tested 1.8 million variants in 4,387 cases and 6,209 controls and identified a region of strong association (rs10994336, P = 9.1 x 10(-9)) in ANK3 (ankyrin G). We also found further support for the previously reported CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel; combined P = 7.0 x 10(-8), rs1006737). Our results suggest that ion channelopathies may be involved in the pathogenesis of bipolar disorder.


Assuntos
Anquirinas/genética , Transtorno Bipolar/genética , Canais de Cálcio Tipo L/genética , Estudo de Associação Genômica Ampla , Cromossomos Humanos Par 10 , Cromossomos Humanos Par 12 , Cromossomos Humanos Par 15 , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Polimorfismo de Nucleotídeo Único
11.
Eur J Hum Genet ; 16(10): 1275-82, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18414510

RESUMO

UHMK1 has previously been implicated as a susceptibility gene for schizophrenia in the 1q23.3 region by significant evidence of allelic and haplotypic association between schizophrenia and several genetic markers at UHMK1 in a London-based case-control sample. Further fine mapping of the UHMK1 gene locus in the University College London schizophrenia case-control sample was carried out with tagging SNPs. Two additional SNPs were found to be associated with schizophrenia (rs6604863 P = 0.02, rs10753578 P = 0.017). Tests of allelic and haplotypic association were then carried out in a second independent sample from Aberdeen consisting of 858 individuals with schizophrenia and 591 controls. Two of these SNPs also showed association in the Aberdeen sample (rs7513662 P = 0.0087, rs10753578 P = 0.022) and several haplotypes were associated (global permutation P = 0.0004). When the UCL and Aberdeen samples were combined three SNPs (rs7513662 P = 0.0007, rs6427680 P = 0.0252, rs6694863 P = 0.015) and several haplotypes showed association (eg HAP-A, HAP-B, HAP-C permutation P = 0.00005). The finding of allelic association with markers in the UHMK1 gene might help explain why it has not been possible, despite great effort, to satisfactorily confirm previously reported associations between schizophrenia and the genes RGS4 and NOS1AP/CAPON. These genes flank UHMK1 and all three loci are within a 700 kb region showing linkage to schizophrenia. The confirmation of association between UHMK1 and schizophrenia, rather than RGS4 and NOS1AP in the London sample, points to the possibility that previous efforts to accurately fine map a gene in the 1q23.3 region have lacked accuracy or may have suffered from methodological flaws.


Assuntos
Cromossomos Humanos Par 1/genética , Predisposição Genética para Doença , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Serina-Treonina Quinases/genética , Esquizofrenia/enzimologia , Esquizofrenia/genética , Adulto , Feminino , Marcadores Genéticos , Haplótipos , Humanos , Desequilíbrio de Ligação/genética , Masculino , Polimorfismo de Nucleotídeo Único/genética
12.
Behav Brain Funct ; 3: 50, 2007 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-17888175

RESUMO

BACKGROUND: Previous linkage and association studies may have implicated the Dystrobrevin-binding protein 1 (DTNBP1) gene locus or a gene in linkage disequilibrium with DTNBP1 on chromosome 6p22.3 in genetic susceptibility to schizophrenia. METHODS: We used the case control design to test for of allelic and haplotypic association with schizophrenia in a sample of four hundred and fifty research subjects with schizophrenia and four hundred and fifty ancestrally matched supernormal controls. We genotyped the SNP markers previously found to be significantly associated with schizophrenia in the original study and also other markers found to be positive in subsequent studies. RESULTS: We could find no evidence of allelic, genotypic or haplotypic association with schizophrenia in our UK sample. CONCLUSION: The results suggest that the DTNBP1 gene contribution to schizophrenia must be rare or absent in our sample. The discrepant allelic association results in previous studies of association between DTNBP1 and schizophrenia could be due population admixture. However, even positive studies of European populations do not show any consistent DTNBP1 alleles or haplotypes associated with schizophrenia. Further research is needed to resolve these issues. The possible confounding of linkage with association in family samples already showing linkage at 6p22.3 might be revealed by testing genes closely linked to DTNBP1 for allelic association and by restricting family based tests of association to only one case per family.

13.
Am J Hum Genet ; 80(4): 664-72, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17357072

RESUMO

Previous linkage analyses of families with multiple cases of schizophrenia by us and others have confirmed the involvement of the chromosome 11q22-24 region in the etiology of schizophrenia, with LOD scores of 3.4 and 3.1. We now report fine mapping of a susceptibility gene in the 11q22-24 region, determined on the basis of a University College London (UCL) sample of 496 cases and 488 supernormal controls. Confirmation was then performed by the study of an Aberdeen sample consisting of 858 cases and 591 controls (for a total of 2,433 individuals: 1,354 with schizophrenia and 1,079 controls). Seven microsatellite or single-nucleotide polymorphism (SNP) markers localized within or near the FXYD6 gene showed empirically significant allelic associations with schizophrenia in the UCL sample (for D11S1998, P=.021; for rs3168238, P=.009; for TTTC20.2, P=.048; for rs1815774, P=.049; for rs4938445, P=.010; for rs4938446, P=.025; for rs497768, P=.023). Several haplotypes were also found to be associated with schizophrenia; for example, haplotype Hap-F21 comprising markers rs10790212-rs4938445-rs497768 was found to be associated with schizophrenia, by a global permutation test (P=.002). Positive markers in the UCL sample were then genotyped in the Aberdeen sample. Two of these SNPs were found to be associated with schizophrenia in the Scottish sample (for rs4938445, P=.044; for rs497768, P=.037). The Hap-F21 haplotype also showed significant association with schizophrenia in the Aberdeen sample, with the same alleles being associated (P=.013). The FXYD6 gene encodes a protein called "phosphohippolin" that is highly expressed in regions of the brain thought to be involved in schizophrenia. The protein functions by modulating the kinetic properties of Na,K-ATPase to the specific physiological requirements of the tissue. Etiological base-pair changes in FXYD6 or in associated promoter/control regions are likely to cause abnormal function or expression of phosphohippolin and to increase genetic susceptibility to schizophrenia.


Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 11/genética , Predisposição Genética para Doença , Canais Iônicos/genética , Esquizofrenia/genética , Feminino , Haplótipos/genética , Humanos , Desequilíbrio de Ligação , Masculino , Repetições de Microssatélites/genética , Polimorfismo de Nucleotídeo Único/genética , Reino Unido
14.
Biol Psychiatry ; 61(7): 873-9, 2007 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-16978587

RESUMO

BACKGROUND: Linkage studies by us and others have confirmed that chromosome 1q23.3 is a susceptibility locus for schizophrenia. Based on this information, several research groups have published evidence that markers within both the RGS4 and CAPON genes, which are 700 kb apart, independently showed allelic association with schizophrenia. Tests of allelic association with both of these genes in our case control sample were negative. Therefore, we carried out further fine mapping between the RGS4 and CAPON genes. METHODS: Twenty-nine SNP and microsatellite markers in the 1q23.3 region were genotyped in the United Kingdom based sample of 450 cases and 450 supernormal control subjects. RESULTS: We detected positive allelic association after the eighth marker was genotyped and found that three microsatellite markers (p = .011, p = .014, p = .049) and two SNPs (p = .004, p = .043) localized in the 700 kb region between the RGS4 and CAPON genes, within the UHMK1 gene, were associated with schizophrenia. Tests of significance for marker rs10494370 remained significant following Bonferroni correction (alpha = .006) for multiple tests. Tests of haplotypic association were also significant for UHMK1 (p = .009) using empirical permutation tests, which make it unnecessary to further correct for both multiple alleles and multiple markers. CONCLUSIONS: These results provide preliminary evidence that the UHMK1 gene increases susceptibility to schizophrenia. Further confirmation in adequately powered samples is needed. UHMK1 is a serine threonine kinase nuclear protein and is highly expressed in regions of the brain implicated in schizophrenia.


Assuntos
Cromossomos Humanos Par 1 , Predisposição Genética para Doença , Repetições de Microssatélites , Polimorfismo Genético , Proteínas Serina-Treonina Quinases/genética , Esquizofrenia/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Estudos de Casos e Controles , Mapeamento Cromossômico/métodos , Feminino , Frequência do Gene , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Proteínas RGS/genética
15.
Am J Psychiatry ; 163(10): 1767-76, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17012688

RESUMO

OBJECTIVE: Three linkage studies of bipolar disorder have implicated chromosome 12q24.3, with significant lod scores of over 3.00. Several other linkage studies have found lod scores between 2.00 and 3.00. In order to identify which gene on this chromosome is responsible, the authors carried out tests of allelic association with bipolar disorder in order to fine map an affective disorder susceptibility gene. METHOD: DNA samples from 681 bipolar disorder patients and 570 comparison subjects from Denmark and the United Kingdom were genotyped with markers close to the region at which the authors had found maximum linkage in previous studies. RESULTS: Single marker allelic association was found with four markers in the Danish cohort. Seven markers in exactly the same region were then found to show significant allelic association in the U.K. cohort. Tests of haplotypic association were also significant, confirming the single marker allelic associations. CONCLUSIONS: These positive fine mapping results validate earlier linkage studies and implicate a 278-kilobase region of chromosome 12 that contributes to the etiology of bipolar disorder. Several brain transcripts are transcribed from sequences in the region. The main candidate gene has no known function but is found in human brain cDNA and is homologous to a Macaque brain cDNA. Sequencing of expressed sequences and control regions in the area should identify etiological base pair changes that increase susceptibility to bipolar disorder.


Assuntos
Transtorno Bipolar/genética , Cromossomos Humanos Par 12/genética , Ligação Genética , Haplótipos , Alelos , Transtorno Bipolar/etnologia , Transtorno Bipolar/metabolismo , Encéfalo/metabolismo , Mapeamento Cromossômico/estatística & dados numéricos , Estudos de Coortes , DNA Complementar/genética , Dinamarca/etnologia , Grupo com Ancestrais do Continente Europeu/genética , Expressão Gênica , Marcadores Genéticos , Predisposição Genética para Doença/genética , Genótipo , Humanos , Desequilíbrio de Ligação , Escore Lod , Repetições de Microssatélites , Polimorfismo de Nucleotídeo Único , Reino Unido/etnologia
16.
Arch Gen Psychiatry ; 63(8): 844-54, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16894060

RESUMO

CONTEXT: There is evidence of linkage to a schizophrenia susceptibility locus on chromosome 8p21-22 found by several family linkage studies. OBJECTIVES: To fine map and identify a susceptibility gene for schizophrenia on chromosome 8p22 and to investigate the effect of this genetic susceptibility on an endophenotype of abnormal brain structure using magnetic resonance imaging. DESIGN: Fine mapping and identification of a chromosome 8p22 susceptibility gene was carried out by finding linkage disequilibrium between genetic markers and schizophrenia in multiply affected families, a case-control sample, and a trio sample. Variation in brain morphology associated with pericentriolar material 1 (PCM1) alleles was examined using voxel-based morphometry and statistical parametric mapping with magnetic resonance imaging. Setting and Patients A family sample of 13 large families multiply affected with schizophrenia, 2 schizophrenia case-control samples from the United Kingdom and Scotland, and a sample of schizophrenic trios from the United States containing parents and 1 affected child with schizophrenia. MAIN OUTCOME MEASURES: Tests of transmission disequilibrium between PCM1 locus polymorphisms and schizophrenia using a family sample and tests of allelic association in case-control and trio samples. Voxel-based morphometry using statistical parametric mapping. RESULTS: The family and trio samples both showed significant transmission disequilibrium between marker D85261 in the PCM1 gene locus and schizophrenia. The case-control sample from the United Kingdom also found significant allelic association between PCM1 gene markers and schizophrenia. Voxel-based morphometry of cases who had inherited a PCM1 genetic susceptibility showed a significant relative reduction in the volume of orbitofrontal cortex gray matter in comparison with patients with non-PCM1-associated schizophrenia, who, by contrast, showed gray matter volume reduction in the temporal pole, hippocampus, and inferior temporal cortex. CONCLUSIONS: The PCM1 gene is implicated in susceptibility to schizophrenia and is associated with orbitofrontal gray matter volumetric deficits.


Assuntos
Autoantígenos/genética , Encéfalo/patologia , Proteínas de Ciclo Celular/genética , Centrossomo/patologia , Cromossomos Humanos Par 8/genética , Predisposição Genética para Doença/genética , Esquizofrenia/genética , Adulto , Alelos , Atrofia/patologia , Centrossomo/metabolismo , Mapeamento Cromossômico , Feminino , Lobo Frontal/patologia , Marcadores Genéticos , Humanos , Desequilíbrio de Ligação , Imagem por Ressonância Magnética , Masculino , Linhagem , Fenótipo , Polimorfismo Genético
17.
Am J Med Genet B Neuropsychiatr Genet ; 141B(3): 296-300, 2006 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-16508931

RESUMO

The chromosome 1q23.3 region, which includes the RGS4 gene has been implicated in genetic susceptibility to schizophrenia by two linkage studies with lod scores of 6.35 and 3.20 and with positive lod between 2.00 and 3.00 scores in several other studies. Reduced post mortem RGS4 gene expression in the brain of schizophrenics was reported as well as positive allelic association between markers at the RGS4 gene locus and schizophrenia. We have attempted to replicate the finding of allelic association with schizophrenia in a UK based sample of 450 subjects with schizophrenia and 450 supernormal controls. We genotyped the same SNP marker alleles investigated in the earlier studies and also a di-nucleotide (GT)14 repeat microsatellite marker, which was 7 kb distal to RGS4. In the new UK sample there was no evidence for allelic or haplotypic association between RGS4 markers and schizophrenia. This might reflect genetic heterogeneity between the population samples, genotyping or other methodological problems. The finding weakens the evidence that mutations or variation in the RGS4 gene have an effect on schizophrenia susceptibility.


Assuntos
Cromossomos Humanos Par 1/genética , Marcadores Genéticos/genética , Proteínas RGS/genética , Esquizofrenia/genética , Alelos , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença/genética , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Reino Unido
18.
Biol Psychiatry ; 59(2): 195-7, 2006 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-16202394

RESUMO

BACKGROUND: Linkage studies have confirmed that chromosome 1q23.3 is a susceptibility locus for schizophrenia. It was then claimed that markers at the carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase (CAPON) gene showed allelic association with schizophrenia in Canadian families. A second Chinese study found a base pair polymorphism at the CAPON gene also associated with schizophrenia. METHODS: We attempted replication using eight markers from the Canadian study in a UK based sample of 450 cases and 450 supernormal controls. RESULTS: We found no evidence for allelic or haplotypic association with schizophrenia for any of the markers found to be associated in the Canadian sample. CONCLUSIONS: The negative results might reflect genetic heterogeneity between the Canadian, Chinese and UK samples or be due to methodological problems. The present finding weakens the evidence that mutations or variation in the CAPON gene are causing genetic susceptibility to schizophrenia in European populations.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Cromossomos Humanos Par 1 , Predisposição Genética para Doença/genética , Esquizofrenia/genética , Adulto , Feminino , Humanos , Desequilíbrio de Ligação , Escore Lod , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Valores de Referência , Reino Unido
19.
Am J Hum Genet ; 76(5): 902-7, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15793701

RESUMO

Chromosome 5q33 is a region that has previously shown good evidence of linkage to schizophrenia, with four LOD scores >3.00 in independent linkage studies. We studied 450 unrelated white English, Irish, Welsh, and Scottish research subjects with schizophrenia and 450 ancestrally matched supernormal controls. Four adjacent markers at the 5' end of the Epsin 4 gene showed significant evidence of linkage disequilibrium with schizophrenia. These included two microsatellite markers, D5S1403 (P=.01) and AAAT11 (P=.009), and two single-nucleotide-polymorphism markers within the Epsin 4 gene, rs10046055 (P=.007) and rs254664 (P=.01). A series of different two- and three-marker haplotypes were also significantly associated with schizophrenia, as confirmed with a permutation test (HapA, P=.004; HapB, P=.0005; HapC, P=.007; and HapD, P=.01). The Epsin 4 gene encodes the clathrin-associated protein enthoprotin, which has a role in transport and stability of neurotransmitter vesicles at the synapses and within neurons. A genetically determined abnormality in the structure, function, or expression of enthoprotin is likely to be responsible for genetic susceptibility to a subtype of schizophrenia on chromosome 5q33.3.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas de Transporte/genética , Predisposição Genética para Doença , Esquizofrenia/genética , Cromossomos Humanos Par 5 , Haplótipos , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único
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