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1.
Biol Psychiatry ; 86(4): 265-273, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31230729

RESUMO

BACKGROUND: A recent genome-wide association study (GWAS) of autism spectrum disorder (ASD) (ncases = 18,381, ncontrols = 27,969) has provided novel opportunities for investigating the etiology of ASD. Here, we integrate the ASD GWAS summary statistics with summary-level gene expression data to infer differential gene expression in ASD, an approach called transcriptome-wide association study (TWAS). METHODS: Using FUSION software, ASD GWAS summary statistics were integrated with predictors of gene expression from 16 human datasets, including adult and fetal brains. A novel adaptation of established statistical methods was then used to test for enrichment within candidate pathways and specific tissues and at different stages of brain development. The proportion of ASD heritability explained by predicted expression of genes in the TWAS was estimated using stratified linkage disequilibrium score regression. RESULTS: This study identified 14 genes as significantly differentially expressed in ASD, 13 of which were outside of known genome-wide significant loci (±500 kb). XRN2, a gene proximal to an ASD GWAS locus, was inferred to be significantly upregulated in ASD, providing insight into the functional consequence of this associated locus. One novel transcriptome-wide significant association from this study is the downregulation of PDIA6, which showed minimal evidence of association in the GWAS, and in gene-based analysis using MAGMA. Predicted gene expression in this study accounted for 13.0% of the total ASD single nucleotide polymorphism heritability. CONCLUSIONS: This study has implicated several genes as significantly up/downregulated in ASD, providing novel and useful information for subsequent functional studies. This study also explores the utility of TWAS-based enrichment analysis and compares TWAS results with a functionally agnostic approach.

2.
Nat Genet ; 51(5): 793-803, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31043756

RESUMO

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.


Assuntos
Transtorno Bipolar/genética , Loci Gênicos , Transtorno Bipolar/classificação , Estudos de Casos e Controles , Transtorno Depressivo Maior/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Transtornos Psicóticos/genética , Esquizofrenia/genética , Biologia de Sistemas
3.
Transl Psychiatry ; 9(1): 74, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718481

RESUMO

Common genetic variation contributes a substantial proportion of risk for both schizophrenia and bipolar disorder. Furthermore, there is evidence of significant, but not complete, overlap in genetic risk between the two disorders. It has been hypothesised that genetic variants conferring risk for these disorders do so by influencing brain development, leading to the later emergence of symptoms. The comparative profile of risk gene expression for schizophrenia and bipolar disorder across development over different brain regions however remains unclear. Using genotypes derived from genome-wide associations studies of the largest available cohorts of patients and control subjects, we investigated whether genes enriched for schizophrenia and bipolar disorder association show a bias for expression across any of 13 developmental stages in prefrontal cortical and subcortical brain regions. We show that genetic association with schizophrenia is positively correlated with expression in the prefrontal cortex during early midfetal development and early infancy, and negatively correlated with expression during late childhood, which stabilises in adolescence. In contrast, risk-associated genes for bipolar disorder did not exhibit a bias towards expression at any prenatal stage, although the pattern of postnatal expression was similar to that of schizophrenia. These results highlight the dynamic expression of genes harbouring risk for schizophrenia and bipolar disorder across prefrontal cortex development and support the hypothesis that prenatal neurodevelopmental events are more strongly associated with schizophrenia than bipolar disorder.


Assuntos
Desenvolvimento do Adolescente/fisiologia , Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , Desenvolvimento Infantil/fisiologia , Desenvolvimento Fetal/fisiologia , Perfilação da Expressão Gênica , Expressão Gênica/genética , Predisposição Genética para Doença , Córtex Pré-Frontal/crescimento & desenvolvimento , Córtex Pré-Frontal/metabolismo , Esquizofrenia/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudo de Associação Genômica Ampla , Humanos , Lactente , Adulto Jovem
4.
Hum Mol Genet ; 26(R2): R83-R90, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28977442

RESUMO

In the decades since the genes and mutations associated with the commoner Mendelian disorders were first discovered, technological advances in genetic analysis have made finding genomic variation a much less onerous task. Recently, the global efforts to collect subjects with Mendelian disorders, to better define the disorders and to empower appropriate clinical trials, along with improved genetic technologies, have allowed the identification of genetic variation that does not cause disease, but substantially modifies disease presentation. The advantage of this is it identifies biological pathways and molecules, that, if modified in people, might alter disease presentation. In Huntington's disease (HD), caused by an expanded CAG repeat tract in HTT, genetic variation has been uncovered that is associated with change in the onset or progression of disease. Some of this variation lies in genes that are part of the DNA damage response, previously suggested to be important in modulating expansion of the repeat tract in germline and somatic cells. The genetic evidence implicates a DNA damage response-related pathway in modulating the pathogenicity of the repeat tracts in HD, and possibly, in other trinucleotide repeat disorders. These findings offer new targets for drug development in these currently intractable disorders.


Assuntos
Proteína Huntingtina/genética , Doença de Huntington/genética , Genes Modificadores , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Proteína Huntingtina/metabolismo , Mutação/genética , Expansão das Repetições de Trinucleotídeos/genética , Repetições de Trinucleotídeos/genética
5.
Sci Rep ; 7(1): 9079, 2017 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-28831049

RESUMO

Some neuropsychiatric disease, including schizophrenia, may originate during prenatal development, following periods of gestational hypoxia and placental oxidative stress. Here we investigated if gestational hypoxia promotes damaging secretions from the placenta that affect fetal development and whether a mitochondria-targeted antioxidant MitoQ might prevent this. Gestational hypoxia caused low birth-weight and changes in young adult offspring brain, mimicking those in human neuropsychiatric disease. Exposure of cultured neurons to fetal plasma or to secretions from the placenta or from model trophoblast barriers that had been exposed to altered oxygenation caused similar morphological changes. The secretions and plasma contained altered microRNAs whose targets were linked with changes in gene expression in the fetal brain and with human schizophrenia loci. Molecular and morphological changes in vivo and in vitro were prevented by a single dose of MitoQ bound to nanoparticles, which were shown to localise and prevent oxidative stress in the placenta but not in the fetus. We suggest the possibility of developing preventative treatments that target the placenta and not the fetus to reduce risk of psychiatric disease in later life.

6.
Am J Med Genet B Neuropsychiatr Genet ; 174(7): 724-731, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28719003

RESUMO

Risk of schizophrenia is conferred by alleles occurring across the full spectrum of frequencies from common SNPs of weak effect through to ultra rare alleles, some of which may be moderately to highly penetrant. Previous studies have suggested that some of the risk of schizophrenia is attributable to uncommon alleles represented on Illumina exome arrays. Here, we present the largest study of exomic variation in schizophrenia to date, using samples from the United Kingdom and Sweden (10,011 schizophrenia cases and 13,791 controls). Single variants, genes, and gene sets were analyzed for association with schizophrenia. No single variant or gene reached genome-wide significance. Among candidate gene sets, we found significant enrichment for rare alleles (minor allele frequency [MAF] < 0.001) in genes intolerant of loss-of-function (LoF) variation and in genes whose messenger RNAs bind to fragile X mental retardation protein (FMRP). We further delineate the genetic architecture of schizophrenia by excluding a role for uncommon exomic variants (0.01 ≤ MAF ≥ 0.001) that confer a relatively large effect (odds ratio [OR] > 4). We also show risk alleles within this frequency range exist, but confer smaller effects and should be identified by larger studies.


Assuntos
Exoma , Proteína do X Frágil de Retardo Mental/genética , Mutação , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Estudos de Casos e Controles , Estudos de Coortes , Seguimentos , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Prognóstico
7.
Nat Genet ; 49(1): 27-35, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27869829

RESUMO

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10-15), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10-6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10-5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.


Assuntos
Variações do Número de Cópias de DNA/genética , Loci Gênicos/genética , Marcadores Genéticos/genética , Estudo de Associação Genômica Ampla , Esquizofrenia/genética , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Fatores de Risco
8.
BMC Genomics ; 16: 1079, 2015 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-26691352

RESUMO

BACKGROUND: The YAC128 model of Huntington's disease (HD) shows substantial deficits in motor, learning and memory tasks and alterations in its transcriptional profile. We examined the changes in the transcriptional profile in the YAC128 mouse model of HD at 6, 12 and 18 months and compared these with those seen in other models and human HD caudate. RESULTS: Differential gene expression by genotype showed that genes related to neuronal function, projection outgrowth and cell adhesion were altered in expression. A Time-course ANOVA revealed that genes downregulated with increased age in wild-type striata were likely to be downregulated in the YAC128 striata. There was a substantial overlap of concordant gene expression changes in the YAC128 striata compared with those in human HD brain. Changes in gene expression over time showed fewer striatal YAC128 RNAs altered in abundance than in the HdhQ150 striata but there was a very marked overlap in transcriptional changes at all time points. Despite the similarities in striatal expression changes at 18 months the HdhQ150 mice showed widespread mHTT and ubiquitin positive inclusion staining in the striatum whereas this was absent in the YAC128 striatum. CONCLUSIONS: The gene expression changes in YAC128 striata show a very closely matched profile to that of HdhQ150 striata and are already significantly different between genotypes by six months of age, implying that the temporal molecular gene expression profiles of these models match very closely, despite differences in the prevalence of brain inclusion formation between the models. The YAC128 gene expression changes appear to correlate well with gene expression differences caused by ageing. A relatively small number of genes showed significant differences in expression between the striata of the two models and these could explain some of the phenotypic differences between the models.


Assuntos
Encéfalo/crescimento & desenvolvimento , Doença de Huntington/epidemiologia , Doença de Huntington/genética , Transcriptoma , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Doença de Huntington/patologia , Masculino , Camundongos , Prevalência
9.
PLoS One ; 9(2): e89441, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24586781

RESUMO

BACKGROUND: The quest to understand the neurobiology of schizophrenia and bipolar disorder is ongoing with multiple lines of evidence indicating abnormalities of glia, mitochondria, and glutamate in both disorders. Despite high heritability estimates of 81% for schizophrenia and 75% for bipolar disorder, compelling links between findings from neurobiological studies, and findings from large-scale genetic analyses, are only beginning to emerge. METHOD: Ten publically available gene sets (pathways) related to glia, mitochondria, and glutamate were tested for association to schizophrenia and bipolar disorder using MAGENTA as the primary analysis method. To determine the robustness of associations, secondary analyses were performed with: ALIGATOR, INRICH, and Set Screen. Data from the Psychiatric Genomics Consortium (PGC) were used for all analyses. There were 1,068,286 SNP-level p-values for schizophrenia (9,394 cases/12,462 controls), and 2,088,878 SNP-level p-values for bipolar disorder (7,481 cases/9,250 controls). RESULTS: The Glia-Oligodendrocyte pathway was associated with schizophrenia, after correction for multiple tests, according to primary analysis (MAGENTA p = 0.0005, 75% requirement for individual gene significance) and also achieved nominal levels of significance with INRICH (p = 0.0057) and ALIGATOR (p = 0.022). For bipolar disorder, Set Screen yielded nominally and method-wide significant associations to all three glial pathways, with strongest association to the Glia-Astrocyte pathway (p = 0.002). CONCLUSIONS: Consistent with findings of white matter abnormalities in schizophrenia by other methods of study, the Glia-Oligodendrocyte pathway was associated with schizophrenia in our genomic study. These findings suggest that the abnormalities of myelination observed in schizophrenia are at least in part due to inherited factors, contrasted with the alternative of purely environmental causes (e.g. medication effects or lifestyle). While not the primary purpose of our study, our results also highlight the consequential nature of alternative choices regarding pathway analysis, in that results varied somewhat across methods, despite application to identical datasets and pathways.


Assuntos
Neuroglia/metabolismo , Esquizofrenia/genética , Transdução de Sinais/genética , Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , Estudos de Casos e Controles , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Ácido Glutâmico/genética , Ácido Glutâmico/metabolismo , Humanos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/metabolismo
10.
Am J Psychiatry ; 169(12): 1309-17, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23212062

RESUMO

OBJECTIVE: Multiple sources of evidence suggest that genetic factors influence variation in clinical features of schizophrenia. The authors present the first genome-wide association study (GWAS) of dimensional symptom scores among individuals with schizophrenia. METHOD: Based on the Lifetime Dimensions of Psychosis Scale ratings of 2,454 case subjects of European ancestry from the Molecular Genetics of Schizophrenia (MGS) sample, three symptom factors (positive, negative/disorganized, and mood) were identified with exploratory factor analysis. Quantitative scores for each factor from a confirmatory factor analysis were analyzed for association with 696,491 single-nucleotide polymorphisms (SNPs) using linear regression, with correction for age, sex, clinical site, and ancestry. Polygenic score analysis was carried out to determine whether case and comparison subjects in 16 Psychiatric GWAS Consortium (PGC) schizophrenia samples (excluding MGS samples) differed in scores computed by weighting their genotypes by MGS association test results for each symptom factor. RESULTS: No genome-wide significant associations were observed between SNPs and factor scores. Most of the SNPs producing the strongest evidence for association were in or near genes involved in neurodevelopment, neuroprotection, or neurotransmission, including genes playing a role in Mendelian CNS diseases, but no statistically significant effect was observed for any defined gene pathway. Finally, polygenic scores based on MGS GWAS results for the negative/disorganized factor were significantly different between case and comparison subjects in the PGC data set; for MGS subjects, negative/disorganized factor scores were correlated with polygenic scores generated using case-control GWAS results from the other PGC samples. CONCLUSIONS: The polygenic signal that has been observed in cross-sample analyses of schizophrenia GWAS data sets could be in part related to genetic effects on negative and disorganized symptoms (i.e., core features of chronic schizophrenia).


Assuntos
Estudo de Associação Genômica Ampla , Herança Multifatorial/genética , Esquizofrenia/genética , Psicologia do Esquizofrênico , Estudos de Casos e Controles , Análise Fatorial , Feminino , Humanos , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único/genética , Escalas de Graduação Psiquiátrica
11.
Am J Psychiatry ; 169(9): 963-73, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22885689

RESUMO

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.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Esquizofrenia/genética , Grupo com Ancestrais do Continente Africano/genética , Estudos de Casos e Controles , Variações do Número de Cópias de DNA/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único/genética
12.
Am J Med Genet B Neuropsychiatr Genet ; 156B(8): 929-40, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21960518

RESUMO

Genetic factors are likely to influence clinical variation in schizophrenia, but it is unclear which variables are most suitable as phenotypes and which molecular genetic loci are involved. We evaluated clinical variable phenotypes and applied suitable phenotypes in genome-wide covariate linkage analysis. We ascertained 170 affected relative pairs (168 sibling-pairs and two avuncular pairs) with DSM-IV schizophrenia or schizoaffective disorder from the United Kingdom. We defined psychotic symptom dimensions, age at onset (AAO), and illness course using the OPCRIT checklist. We evaluated phenotypes using within sibling-pair correlations and applied suitable phenotypes in multipoint covariate linkage analysis based on 372 microsatellite markers at ∼10 cM intervals. The statistical significance of linkage results was assessed by simulation. The positive and disorganized symptom dimensions, AAO, and illness course qualified as suitable phenotypes. There were no genome-wide significant linkage results. There was suggestive evidence of linkage for the positive dimension on chromosomes 2q32, 10q26, and 20q12; the disorganized dimension on 8p21 and 17q21; and illness course on 2q33 and 22q11. The linkage peak for disorganization on 17q21 remained suggestive after correction for multiple testing. To our knowledge, this is the first study to integrate phenotype evaluation and genome-wide covariate linkage analysis for symptom dimensions and illness history variables in sibling-pairs with schizophrenia. The significant within-pair correlations strengthen the evidence that some clinical variables within schizophrenia are suitable phenotypes for molecular genetic investigations. At present there are no genome-wide significant linkage results for these phenotypes, but a number of suggestive findings warrant further investigation.


Assuntos
Ligação Genética , Estudo de Associação Genômica Ampla , Transtornos Psicóticos/genética , Esquizofrenia/genética , Adulto , Idade de Início , Alelos , Mapeamento Cromossômico , Feminino , Predisposição Genética para Doença , Genoma Humano , Genótipo , Humanos , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Fenótipo , Esquizofrenia/diagnóstico , Irmãos
13.
Am J Med Genet B Neuropsychiatr Genet ; 156B(7): 764-71, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21812096

RESUMO

We sought to investigate the contribution of extended runs of homozygosity in a genome-wide association dataset of 1,955 Alzheimer's disease cases and 955 elderly screened controls genotyped for 529,205 autosomal single nucleotide polymorphisms. Tracts of homozygosity may mark regions inherited from a common ancestor and could reflect disease loci if observed more frequently in cases than controls. We found no excess of homozygous tracts in Alzheimer's disease cases compared to controls and no individual run of homozygosity showed association to Alzheimer's disease.


Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença , Homozigoto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Cromossomos Humanos Par 8/genética , Feminino , Genes/genética , Estudo de Associação Genômica Ampla , Humanos , Masculino
14.
Am J Psychiatry ; 168(3): 302-16, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21285140

RESUMO

OBJECTIVE: To evaluate previously reported associations of copy number variants (CNVs) with schizophrenia and to identify additional associations, the authors analyzed CNVs in the Molecular Genetics of Schizophrenia study (MGS) and additional available data. METHOD: After quality control, MGS data for 3,945 subjects with schizophrenia or schizoaffective disorder and 3,611 screened comparison subjects were available for analysis of rare CNVs (<1% frequency). CNV detection thresholds were chosen that maximized concordance in 151 duplicate assays. Pointwise and genewise analyses were carried out, as well as analyses of previously reported regions. Selected regions were visually inspected and confirmed with quantitative polymerase chain reaction. RESULTS: In analyses of MGS data combined with other available data sets, odds ratios of 7.5 or greater were observed for previously reported deletions in chromosomes 1q21.1, 15q13.3, and 22q11.21, duplications in 16p11.2, and exon-disrupting deletions in NRXN1. The most consistently supported candidate associations across data sets included a 1.6-Mb deletion in chromosome 3q29 (21 genes, TFRC to BDH1) that was previously described in a mild-moderate mental retardation syndrome, exonic duplications in the gene for vasoactive intestinal peptide receptor 2 (VIPR2), and exonic duplications in C16orf72. The case subjects had a modestly higher genome-wide number of gene-containing deletions (>100 kb and >1 Mb) but not duplications. CONCLUSIONS: The data strongly confirm the association of schizophrenia with 1q21.1, 15q13.3, and 22q11.21 deletions, 16p11.2 duplications, and exonic NRXN1 deletions. These CNVs, as well as 3q29 deletions, are also associated with mental retardation, autism spectrum disorders, and epilepsy. Additional candidate genes and regions, including VIPR2, were identified. Study of the mechanisms underlying these associations should shed light on the pathophysiology of schizophrenia.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 3/genética , Variações do Número de Cópias de DNA/genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Esquizofrenia/genética , Grupos Étnicos/genética , Predisposição Genética para Doença , Humanos
15.
Alcohol Clin Exp Res ; 35(5): 963-75, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21314694

RESUMO

BACKGROUND: While genetic influences on alcohol dependence (AD) are substantial, progress in the identification of individual genetic variants that impact on risk has been difficult. METHODS: We performed a genome-wide association study on 3,169 alcohol consuming subjects from the population-based Molecular Genetics of Schizophrenia (MGS2) control sample. Subjects were asked 7 questions about symptoms of AD which were analyzed by confirmatory factor analysis. Genotyping was performed using the Affymetrix 6.0 array. Three sets of analyses were conducted separately for European American (EA, n = 2,357) and African-American (AA, n = 812) subjects: individual single nucleotide polymorphisms (SNPs), candidate genes and enriched pathways using gene ontology (GO) categories. RESULTS: The symptoms of AD formed a highly coherent single factor. No SNP approached genome-wide significance. In the EA sample, the most significant intragenic SNP was in KCNMA1, the human homolog of the slo-1 gene in C. Elegans. Genes with clusters of significant SNPs included AKAP9, phosphatidylinositol glycan anchor biosynthesis, class G (PIGG), and KCNMA1. In the AA sample, the most significant intragenic SNP was CEACAM6 and genes showing empirically significant SNPs included KCNQ5, SLC35B4, and MGLL. In the candidate gene based analyses, the most significant findings were with ADH1C, nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1) and ankyrin repeat and kinase domain containing 1 (ANKK1) in the EA sample, and ADH5, POMC, and CHRM2 in the AA sample. The ALIGATOR program identified a significant excess of associated SNPs within and near genes in a substantial number of GO categories over a range of statistical stringencies in both the EA and AA sample. CONCLUSIONS: While we cannot be highly confident about any single result from these analyses, a number of findings were suggestive and worthy of follow-up. Although quite large samples will be needed to obtain requisite power, the study of AD symptoms in general population samples is a viable complement to case-control studies in identifying genetic risk variants for AD.


Assuntos
Alcoolismo/epidemiologia , Alcoolismo/genética , Estudo de Associação Genômica Ampla/métodos , Vigilância da População/métodos , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Feminino , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Distribuição Aleatória
16.
Ann Hum Genet ; 75(3): 428-38, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21241274

RESUMO

A common design in family-based association studies consists of siblings without parents. Several methods have been proposed for analysis of sibship data, but they mostly do not allow for missing data, such as haplotype phase or untyped markers. On the other hand, general methods for nuclear families with missing data are computationally intensive when applied to sibships, since every family has missing parents that could have many possible genotypes. We propose a computationally efficient model for sibships by conditioning on the sets of alleles transmitted into the sibship by each parent. This means that the likelihood can be written only in terms of transmitted alleles and we do not have to sum over all possible untransmitted alleles when they cannot be deduced from the siblings. The model naturally accommodates missing data and admits standard theory of estimation, testing, and inclusion of covariates. Our model is quite robust to population stratification and can test for association in the presence of linkage. We show that our model has similar power to FBAT for single marker analysis and improved power for haplotype analysis. Compared to summing over all possible untransmitted alleles, we achieve similar power with considerable reductions in computation time.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Genótipo , Modelos Genéticos , Feminino , Frequência do Gene , Humanos , Masculino , Modelos Estatísticos , Irmãos
17.
PLoS One ; 5(11): e13950, 2010 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-21085570

RESUMO

BACKGROUND: Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes. METHODOLOGY: We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset. PRINCIPAL FINDINGS: We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD. SIGNIFICANCE: Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.


Assuntos
Doença de Alzheimer/genética , Colesterol/metabolismo , Estudo de Associação Genômica Ampla , Sistema Imunitário/metabolismo , Doença de Alzheimer/imunologia , Doença de Alzheimer/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Mapeamento Cromossômico , Predisposição Genética para Doença/genética , Genoma Humano , Humanos , Polimorfismo de Nucleotídeo Único
18.
Am J Med Genet B Neuropsychiatr Genet ; 153B(7): 1347-9, 2010 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-20583128

RESUMO

We have previously reported evidence that variation at GABA(A) receptor genes is associated with susceptibility to bipolar disorder with schizophrenia-like psychotic features (Research Diagnostic Criteria (RDC) schizoaffective disorder, bipolar type) with gene-wide significance at GABRB1, GABRA4, GABRB3, GABRA5, and GABRR3. Here we provide suggestive evidence implicating a sixth member of the gene family, GABRR1 (gene-wide P = 0.0058; experiment-wide corrected significance P = 0.052).


Assuntos
Transtorno Bipolar/genética , Predisposição Genética para Doença/genética , Polimorfismo Genético , Receptores de GABA-A/genética , Esquizofrenia/genética , Estudos de Casos e Controles , Frequência do Gene , Humanos
19.
Arch Gen Psychiatry ; 67(4): 318-27, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20368508

RESUMO

CONTEXT: Recent studies suggest that copy number variation in the human genome is extensive and may play an important role in susceptibility to disease, including neuropsychiatric disorders such as schizophrenia and autism. The possible involvement of copy number variants (CNVs) in bipolar disorder has received little attention to date. OBJECTIVES: To determine whether large (>100,000 base pairs) and rare (found in <1% of the population) CNVs are associated with susceptibility to bipolar disorder and to compare with findings in schizophrenia. DESIGN: A genome-wide survey of large, rare CNVs in a case-control sample using a high-density microarray. SETTING: The Wellcome Trust Case Control Consortium. PARTICIPANTS: There were 1697 cases of bipolar disorder and 2806 nonpsychiatric controls. All participants were white UK residents. MAIN OUTCOME MEASURES: Overall load of CNVs and presence of rare CNVs. RESULTS: The burden of CNVs in bipolar disorder was not increased compared with controls and was significantly less than in schizophrenia cases. The CNVs previously implicated in the etiology of schizophrenia were not more common in cases with bipolar disorder. CONCLUSIONS: Schizophrenia and bipolar disorder differ with respect to CNV burden in general and association with specific CNVs in particular. Our data are consistent with the possibility that possession of large, rare deletions may modify the phenotype in those at risk of psychosis: those possessing such events are more likely to be diagnosed as having schizophrenia, and those without them are more likely to be diagnosed as having bipolar disorder.


Assuntos
Transtorno Bipolar/genética , Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Esquizofrenia/genética , Genótipo , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Fatores de Risco
20.
Am J Psychiatry ; 166(11): 1229-37, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19755578

RESUMO

OBJECTIVE: Family studies have suggested that postpartum mood symptoms might have a partly genetic etiology. The authors used a genome-wide linkage analysis to search for chromosomal regions that harbor genetic variants conferring susceptibility for such symptoms. The authors then fine-mapped their best linkage regions, assessing single nucleotide polymorphisms (SNPs) for genetic association with postpartum symptoms. METHOD: Subjects were ascertained from two studies: the NIMH Genetics Initiative Bipolar Disorder project and the Genetics of Recurrent Early-Onset Depression. Subjects included women with a history of pregnancy, any mood disorder, and information about postpartum symptoms. In the linkage study, 1,210 women met criteria (23% with postpartum symptoms), and 417 microsatellite markers were analyzed in multipoint allele sharing analyses. For the association study, 759 women met criteria (25% with postpartum symptoms), and 16,916 SNPs in the regions of the best linkage peaks were assessed for association with postpartum symptoms. RESULTS: The maximum linkage peak for postpartum symptoms occurred on chromosome 1q21.3-q32.1, with a chromosome-wide significant likelihood ratio Z score (Z(LR)) of 2.93 (permutation p=0.02). This was a significant increase over the baseline Z(LR) of 0.32 observed at this locus among all women with a mood disorder (permutation p=0.004). Suggestive linkage was also found on 9p24.3-p22.3 (Z(LR)=2.91). In the fine-mapping study, the strongest implicated gene was HMCN1 (nominal p=0.00017), containing four estrogen receptor binding sites, although this was not region-wide significant. CONCLUSIONS: This is the first study to examine the genetic etiology of postpartum mood symptoms using genome-wide data. The results suggest that genetic variations on chromosomes 1q21.3-q32.1 and 9p24.3-p22.3 may increase susceptibility to postpartum mood symptoms.


Assuntos
Transtorno Bipolar/genética , Depressão Pós-Parto/diagnóstico , Depressão Pós-Parto/genética , Transtorno Depressivo Maior/genética , Ligação Genética , Estudo de Associação Genômica Ampla , Adulto , Transtorno Bipolar/diagnóstico , Mapeamento Cromossômico , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 9/genética , Transtorno Depressivo Maior/diagnóstico , Feminino , Seguimentos , Predisposição Genética para Doença , Variação Genética , Genótipo , Humanos , Repetições de Microssatélites , Pessoa de Meia-Idade , Modelos Genéticos , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Gravidez
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