RESUMO
Inherited alleles account for most of the genetic risk for schizophrenia. However, new (de novo) mutations, in the form of large chromosomal copy number changes, occur in a small fraction of cases and disproportionally disrupt genes encoding postsynaptic proteins. Here we show that small de novo mutations, affecting one or a few nucleotides, are overrepresented among glutamatergic postsynaptic proteins comprising activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-d-aspartate receptor (NMDAR) complexes. Mutations are additionally enriched in proteins that interact with these complexes to modulate synaptic strength, namely proteins regulating actin filament dynamics and those whose messenger RNAs are targets of fragile X mental retardation protein (FMRP). Genes affected by mutations in schizophrenia overlap those mutated in autism and intellectual disability, as do mutation-enriched synaptic pathways. Aligning our findings with a parallel case-control study, we demonstrate reproducible insights into aetiological mechanisms for schizophrenia and reveal pathophysiology shared with other neurodevelopmental disorders.
Assuntos
Modelos Neurológicos , Mutação/genética , Rede Nervosa/metabolismo , Vias Neurais/metabolismo , Esquizofrenia/genética , Esquizofrenia/fisiopatologia , Sinapses/metabolismo , Transtornos Globais do Desenvolvimento Infantil/genética , Proteínas do Citoesqueleto/metabolismo , Exoma/genética , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Humanos , Deficiência Intelectual/genética , Taxa de Mutação , Rede Nervosa/fisiopatologia , Proteínas do Tecido Nervoso/metabolismo , Vias Neurais/fisiopatologia , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/metabolismo , Especificidade por SubstratoRESUMO
Duplications at 15q11.2-q13.3 overlapping the Prader-Willi/Angelman syndrome (PWS/AS) region have been associated with developmental delay (DD), autism spectrum disorder (ASD) and schizophrenia (SZ). Due to presence of imprinted genes within the region, the parental origin of these duplications may be key to the pathogenicity. Duplications of maternal origin are associated with disease, whereas the pathogenicity of paternal ones is unclear. To clarify the role of maternal and paternal duplications, we conducted the largest and most detailed study to date of parental origin of 15q11.2-q13.3 interstitial duplications in DD, ASD and SZ cohorts. We show, for the first time, that paternal duplications lead to an increased risk of developing DD/ASD/multiple congenital anomalies (MCA), but do not appear to increase risk for SZ. The importance of the epigenetic status of 15q11.2-q13.3 duplications was further underlined by analysis of a number of families, in which the duplication was paternally derived in the mother, who was unaffected, whereas her offspring, who inherited a maternally derived duplication, suffered from psychotic illness. Interestingly, the most consistent clinical characteristics of SZ patients with 15q11.2-q13.3 duplications were learning or developmental problems, found in 76% of carriers. Despite their lower pathogenicity, paternal duplications are less frequent in the general population with a general population prevalence of 0.0033% compared to 0.0069% for maternal duplications. This may be due to lower fecundity of male carriers and differential survival of embryos, something echoed in the findings that both types of duplications are de novo in just over 50% of cases. Isodicentric chromosome 15 (idic15) or interstitial triplications were not observed in SZ patients or in controls. Overall, this study refines the distinct roles of maternal and paternal interstitial duplications at 15q11.2-q13.3, underlining the critical importance of maternally expressed imprinted genes in the contribution of Copy Number Variants (CNVs) at this interval to the incidence of psychotic illness. This work will have tangible benefits for patients with 15q11.2-q13.3 duplications by aiding genetic counseling.
Assuntos
Síndrome de Angelman/genética , Transtorno do Espectro Autista/genética , Herança Paterna/genética , Síndrome de Prader-Willi/genética , Esquizofrenia/genética , Síndrome de Angelman/patologia , Transtorno do Espectro Autista/patologia , Duplicação Cromossômica/genética , Cromossomos Humanos Par 15/genética , Variações do Número de Cópias de DNA/genética , Feminino , Impressão Genômica/genética , Humanos , Masculino , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Fenótipo , Síndrome de Prader-Willi/patologia , Esquizofrenia/patologiaRESUMO
We carried out a genome-wide association study of schizophrenia (479 cases, 2,937 controls) and tested loci with P < 10(-5) in up to 16,726 additional subjects. Of 12 loci followed up, 3 had strong independent support (P < 5 x 10(-4)), and the overall pattern of replication was unlikely to occur by chance (P = 9 x 10(-8)). Meta-analysis provided strongest evidence for association around ZNF804A (P = 1.61 x 10(-7)) and this strengthened when the affected phenotype included bipolar disorder (P = 9.96 x 10(-9)).
Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Fatores de Transcrição Kruppel-Like/genética , Esquizofrenia/genética , Transtorno Bipolar/genética , Estudos de Casos e Controles , Mapeamento Cromossômico , Seguimentos , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
An increased rate of de novo copy number variants (CNVs) has been found in schizophrenia (SZ), autism and developmental delay. An increased rate has also been reported in bipolar affective disorder (BD). Here, in a larger BD sample, we aimed to replicate these findings and compare de novo CNVs between SZ and BD. We used Illumina microarrays to genotype 368 BD probands, 76 SZ probands and all their parents. Copy number variants were called by PennCNV and filtered for frequency (<1%) and size (>10 kb). Putative de novo CNVs were validated with the z-score algorithm, manual inspection of log R ratios (LRR) and qPCR probes. We found 15 de novo CNVs in BD (4.1% rate) and 6 in SZ (7.9% rate). Combining results with previous studies and using a cut-off of >100 kb, the rate of de novo CNVs in BD was intermediate between controls and SZ: 1.5% in controls, 2.2% in BD and 4.3% in SZ. Only the differences between SZ and BD and SZ and controls were significant. The median size of de novo CNVs in BD (448 kb) was also intermediate between SZ (613 kb) and controls (338 kb), but only the comparison between SZ and controls was significant. Only one de novo CNV in BD was in a confirmed SZ locus (16p11.2). Sporadic or early onset cases were not more likely to have de novo CNVs. We conclude that de novo CNVs play a smaller role in BD compared with SZ. Patients with a positive family history can also harbour de novo mutations.
Assuntos
Transtorno Bipolar/genética , Variações do Número de Cópias de DNA , Loci Gênicos , Esquizofrenia/genética , Adolescente , Adulto , Algoritmos , Transtorno Bipolar/fisiopatologia , Estudos de Casos e Controles , Criança , Cromossomos Humanos Par 16 , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , Esquizofrenia/fisiopatologiaRESUMO
Large and rare copy number variants (CNVs) at several loci have been shown to increase risk for schizophrenia. Aiming to discover novel susceptibility CNV loci, we analyzed 6882 cases and 11 255 controls genotyped on Illumina arrays, most of which have not been used for this purpose before. We identified genes enriched for rare exonic CNVs among cases, and then attempted to replicate the findings in additional 14 568 cases and 15 274 controls. In a combined analysis of all samples, 12 distinct loci were enriched among cases with nominal levels of significance (P < 0.05); however, none would survive correction for multiple testing. These loci include recurrent deletions at 16p12.1, a locus previously associated with neurodevelopmental disorders (P = 0.0084 in the discovery sample and P = 0.023 in the replication sample). Other plausible candidates include non-recurrent deletions at the glutamate transporter gene SLC1A1, a CNV locus recently suggested to be involved in schizophrenia through linkage analysis, and duplications at 1p36.33 and CGNL1. A burden analysis of large (>500 kb), rare CNVs showed a 1.2% excess in cases after excluding known schizophrenia-associated loci, suggesting that additional susceptibility loci exist. However, even larger samples are required for their discovery.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 16 , Cromossomos Humanos Par 1 , Proteínas do Citoesqueleto/genética , Transportador 3 de Aminoácido Excitatório/genética , Duplicação Gênica , Esquizofrenia/genética , Variações do Número de Cópias de DNA , Feminino , Deleção de Genes , Dosagem de Genes , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Humanos , MasculinoRESUMO
The GPHN gene codes for gephyrin, a key scaffolding protein in the neuronal postsynaptic membrane, responsible for the clustering and localization of glycine and GABA receptors at inhibitory synapses. Gephyrin has well-established functional links with several synaptic proteins that have been implicated in genetic risk for neurodevelopmental disorders such as autism spectrum disorder (ASD), schizophrenia and epilepsy including the neuroligins (NLGN2, NLGN4), the neurexins (NRXN1, NRXN2, NRXN3) and collybistin (ARHGEF9). Moreover, temporal lobe epilepsy has been linked to abnormally spliced GPHN mRNA lacking exons encoding the G-domain of the gephyrin protein, potentially arising due to cellular stress associated with epileptogenesis such as temperature and alkalosis. Here, we present clinical and genomic characterization of six unrelated subjects, with a range of neurodevelopmental diagnoses including ASD, schizophrenia or seizures, who possess rare de novo or inherited hemizygous microdeletions overlapping exons of GPHN at chromosome 14q23.3. The region of common overlap across the deletions encompasses exons 3-5, corresponding to the G-domain of the gephyrin protein. These findings, together with previous reports of homozygous GPHN mutations in connection with autosomal recessive molybdenum cofactor deficiency, will aid in clinical genetic interpretation of the GPHN mutation spectrum. Our data also add to the accumulating evidence implicating neuronal synaptic gene products as key molecular factors underlying the etiologies of a diverse range of neurodevelopmental conditions.
Assuntos
Sequência de Bases , Proteínas de Transporte/genética , Cromossomos Humanos Par 14/genética , Éxons , Proteínas de Membrana/genética , Esquizofrenia/genética , Convulsões/genética , Deleção de Sequência , Transtorno Autístico , Proteínas de Ligação ao Cálcio , Proteínas de Transporte/metabolismo , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Cromossomos Humanos Par 14/metabolismo , Feminino , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Masculino , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Moléculas de Adesão de Célula Nervosa , Splicing de RNA/genética , Receptores de GABA/genética , Receptores de GABA/metabolismo , Receptores de Glicina/genética , Receptores de Glicina/metabolismo , Fatores de Troca de Nucleotídeo Guanina Rho , Esquizofrenia/metabolismo , Convulsões/metabolismo , Membranas Sinápticas/genética , Membranas Sinápticas/metabolismoRESUMO
BACKGROUND: A number of copy number variants (CNVs) have been suggested as susceptibility factors for schizophrenia. For some of these the data remain equivocal, and the frequency in individuals with schizophrenia is uncertain. AIMS: To determine the contribution of CNVs at 15 schizophrenia-associated loci (a) using a large new data-set of patients with schizophrenia (n = 6882) and controls (n = 6316), and (b) combining our results with those from previous studies. METHOD: We used Illumina microarrays to analyse our data. Analyses were restricted to 520 766 probes common to all arrays used in the different data-sets. RESULTS: We found higher rates in participants with schizophrenia than in controls for 13 of the 15 previously implicated CNVs. Six were nominally significantly associated (P<0.05) in this new data-set: deletions at 1q21.1, NRXN1, 15q11.2 and 22q11.2 and duplications at 16p11.2 and the Angelman/Prader-Willi Syndrome (AS/PWS) region. All eight AS/PWS duplications in patients were of maternal origin. When combined with published data, 11 of the 15 loci showed highly significant evidence for association with schizophrenia (P<4.1×10(-4)). CONCLUSIONS: We strengthen the support for the majority of the previously implicated CNVs in schizophrenia. About 2.5% of patients with schizophrenia and 0.9% of controls carry a large, detectable CNV at one of these loci. Routine CNV screening may be clinically appropriate given the high rate of known deleterious mutations in the disorder and the comorbidity associated with these heritable mutations.
Assuntos
Deleção Cromossômica , Variações do Número de Cópias de DNA/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Esquizofrenia/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Síndrome de Angelman/genética , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença/epidemiologia , Impressão Genômica , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome de Prader-Willi/genética , Adulto JovemRESUMO
The oligodendrocyte lineage transcription factor 2 (OLIG2) regulates the genesis of oligodendrocytes, the brain cells responsible for axonal myelination. Although it has been associated with psychiatric and neurological disorders, the impact of this gene on white matter integrity has never been investigated in humans. Using diffusion tensor imaging, we examined the effect of a single nucleotide polymorphism (rs1059004) in OLIG2 previously associated with reduced gene expression, and with psychiatric disorders on fractional anisotropy in 78 healthy subjects. We found that the risk allele (A) was associated with reduced white matter integrity in the corona radiata bilaterally. This is consistent with evidence that it is a schizophrenia susceptibility gene, and suggests that it may confer increased risk through an effect on neuroanatomical connectivity.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Encéfalo/citologia , Fibras Nervosas Mielinizadas/ultraestrutura , Proteínas do Tecido Nervoso/genética , Adolescente , Adulto , Imagem de Tensor de Difusão , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Fator de Transcrição 2 de Oligodendrócitos , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Esquizofrenia/genética , Adulto JovemRESUMO
Copy number variations (CNVs) account for a substantial proportion of human genomic variation, and have been shown to cause neurodevelopmental disorders. We sought to determine the relevance of CNVs to the aetiology of schizophrenia (SZ). Whole-genome, high-resolution, tiling path BAC array comparative genomic hybridization (array CGH) was employed to test DNA from 93 individuals with DSM-IV SZ. Common DNA copy number changes that are unlikely to be directly pathogenic in SZ were filtered out by comparison to a reference dataset of 372 control individuals analyzed in our laboratory, and a screen against the Database of Genomic Variants. The remaining aberrations were validated with Affymetrix 250K SNP arrays or 244K Agilent oligo-arrays and tested for inheritance from the parents. A total of 13 aberrations satisfied our criteria. Two of them are very likely to be pathogenic. The first one is a deletion at 2p16.3 that was present in an affected sibling and disrupts NRXN1. The second one is a de novo duplication at 15q13.1 spanning APBA2. The proteins of these two genes interact directly and play a role in synaptic development and function. Both genes have been affected by CNVs in patients with autism and mental retardation, but neither has been previously implicated in SZ.
Assuntos
Caderinas/genética , Proteínas de Transporte/genética , Glicoproteínas/genética , Proteínas do Tecido Nervoso/genética , Neuropeptídeos/genética , Esquizofrenia/genética , Adolescente , Adulto , Transtorno Autístico/genética , Estudos de Casos e Controles , Cromossomos Humanos Par 15/genética , Feminino , Dosagem de Genes , Variação Genética , Humanos , Deficiência Intelectual/genética , Masculino , Pessoa de Meia-Idade , Hibridização de Ácido Nucleico , Esquizofrenia/etiologiaRESUMO
We evaluated the hypothesis that dopaminergic polymorphisms are risk factors for schizophrenia (SZ). In stage I, we screened 18 dopamine-related genes in two independent US Caucasian samples: 150 trios and 328 cases/501 controls. The most promising associations were detected with SLC6A3 (alias DAT), DRD3, COMT and SLC18A2 (alias VMAT2). In stage II, we comprehensively evaluated these four genes by genotyping 68 SNPs in all 478 cases and 501 controls from stage I. Fifteen (23.1%) significant associations were found (p < or = 0.05). We sought epistasis between pairs of SNPs providing evidence of a main effect and observed 17 significant interactions (169 tests); 41.2% of significant interactions involved rs3756450 (5' near promoter) or rs464049 (intron 4) at SLC6A3. In stage III, we confirmed our findings by genotyping 65 SNPs among 659 Bulgarian trios. Both SLC6A3 variants implicated in the US interactions were overtransmitted in this cohort (rs3756450, p = 0.035; rs464049, p = 0.011). Joint analyses from stages II and III identified associations at all four genes (p(joint) < 0.05). We tested 29 putative interactions from stage II and detected replication between seven locus pairs (p < or = 0.05). Simulations suggested our stage II and stage III interaction results were unlikely to have occurred by chance (p = 0.008 and 0.001, respectively). In stage IV we evaluated rs464049 and rs3756450 for functional effects and found significant allele-specific differences at rs3756450 using electrophoretic mobility shift assays and dual-luciferase promoter assays. Our data suggest that a network of dopaminergic polymorphisms increase risk for SZ.
Assuntos
Catecol O-Metiltransferase/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Variação Genética , Receptores de Dopamina D3/genética , Esquizofrenia/genética , Proteínas Vesiculares de Transporte de Monoamina/genética , Alelos , Bulgária , Estudos de Casos e Controles , Estudos de Coortes , Interpretação Estatística de Dados , Feminino , Frequência do Gene , Genes Reporter , Humanos , Desequilíbrio de Ligação , Modelos Logísticos , Luciferases de Renilla/metabolismo , Razão de Chances , Linhagem , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Fatores Sexuais , Estados UnidosRESUMO
Recessive mutations in the phenylalanine hydroxylase (PAH) gene predispose to phenylketonuria (PKU) in conjunction with dietary exposure to phenylalanine. Previous studies have suggested PAH variations could confer risk for schizophrenia, but comprehensive follow-up has not been reported. We analyzed 15 common PAH "tag" SNPs and three exonic variations that are rare in Caucasians but common in African-Americans among four independent samples (total n = 5,414). The samples included two US Caucasian cohorts (260 trios, 230 independent cases, 474 controls), Bulgarian families (659 trios), and an African-American sample (464 families, 401 controls). Analyses of both US Caucasian samples revealed associations with five SNPs; most notably the common allele (G) of rs1522305 from case-control analyses (z = 2.99, P = 0.006). This SNP was independently replicated in the Bulgarian cohort (z = 2.39, P = 0.015). A non-significant trend was also observed among African-American families (z = 1.39, P = 0.165), and combined analyses of all four samples were significant (rs1522305: chi(2) = 23.28, 8 d.f., P = 0.003). Results for rs1522305 met our a priori criteria for statistical significance, namely an association that was robust to multiple testing correction in one sample, a replicated risk allele in multiple samples, and combined analyses that were nominally significant. Case-control results in African-Americans detected an association with L321L (P = 0.047, OR = 1.46). Our analyses suggest several associations at PAH, with consistent evidence for rs1522305. Further analyses, including additional variations and environmental influences such as phenylalanine exposure are warranted.
Assuntos
Predisposição Genética para Doença , Desequilíbrio de Ligação/genética , Fenilalanina Hidroxilase/genética , Esquizofrenia/genética , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Genótipo , Humanos , Masculino , Mutação/genética , Fenilcetonúrias/genética , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
THE AIM: of the present study was to reveal the characteristics of an. MATERIALS AND METHODS: Susceptibility testing, conjugation experiments, isoelectric focusing, PCR and sequencing were carrying out. RESULTS: Of 176. CONCLUSIONS: To the best of our knowledge this is the first report of DHA-1 producing isolate in Bulgaria. The emergence of DHA-1 producing.
Assuntos
Cefalosporinase/biossíntese , Enterobacter cloacae/isolamento & purificação , Enterobacter cloacae/efeitos dos fármacos , Enterobacter cloacae/metabolismo , Humanos , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Several linkage studies suggest that chromosome 5q31-32 might contain risk loci for schizophrenia (SZ). We wanted to identify susceptibility genes for schizophrenia within this region. METHODS: We saturated the interval between markers D5S666 and D5S436 with 90 polymorphic microsatellite markers and genotyped two sets of DNA pools consisting of 300 SZ patients of Bulgarian origin and their 600 parents. Positive associations were followed-up with SNP genotyping. RESULTS: Nominally significant evidence for association (p < 0.05) was found for seven markers (D5S0023i, IL9, RH60252, 5Q3133_33, D5S2017, D5S1481, D5S0711i) which were then individually genotyped in the trios. The predicted associations were confirmed for two of the markers: D5S2017, localised in the SPRY4-FGF1 locus (p = 0.004) and IL9, localized within the IL9 gene (p = 0.014). Fine mapping was performed using single nucleotide polymorphisms (SNPs) around D5S2017 and IL9. In each region four SNPs were chosen and individually genotyped in our full sample of 615 SZ trios. Two SNPs showed significant evidence for association: rs7715300 (p = 0.001) and rs6897690 (p = 0.032). Rs7715300 is localised between the TGFBI and SMAD5 genes and rs6897690 is within the SPRY4 gene. CONCLUSION: Our screening of 5q31-32 implicates three potential candidate genes for SZ: SMAD5, TGFBI and SPRY4.
Assuntos
Cromossomos Humanos Par 5/genética , Pool Gênico , Ligação Genética , Genótipo , Esquizofrenia/genética , Adulto , Criança , Proteínas da Matriz Extracelular/genética , Fator 1 de Crescimento de Fibroblastos/genética , Predisposição Genética para Doença , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Repetições de Microssatélites/genética , Proteínas do Tecido Nervoso/genética , Mutação Puntual/genética , Polimorfismo de Nucleotídeo Único/genética , Prevalência , Esquizofrenia/epidemiologia , Proteína Smad5/genética , Fator de Crescimento Transformador beta/genéticaRESUMO
BACKGROUND: Genotyping technology has advanced such that genome-wide association studies of complex diseases based upon dense marker maps are now technically feasible. However, the cost of such projects remains high. Pooled DNA genotyping offers the possibility of applying the same technologies at a fraction of the cost, and there is some evidence that certain ultra-high throughput platforms also perform with an acceptable accuracy. However, thus far, this conclusion is based upon published data concerning only a small number of SNPs. RESULTS: In the current study we prepared DNA pools from the parents and from the offspring of 30 parent-child trios that have been extensively genotyped by the HapMap project. We analysed the two pools with Affymetrix 10 K Xba 142 2.0 Arrays. The availability of the HapMap data allowed us to validate the performance of 6843 SNPs for which we had both complete individual and pooled genotyping data. Pooled analyses averaged over 5-6 microarrays resulted in highly reproducible results. Moreover, the accuracy of estimating differences in allele frequency between pools using this ultra-high throughput system was comparable with previous reports of pooling based upon lower throughput platforms, with an average error for the predicted allelic frequencies differences between the two pools of 1.37% and with 95% of SNPs showing an error of < 3.2%. CONCLUSION: Genotyping thousands of SNPs with DNA pooling using Affymetrix microarrays produces highly accurate results and can be used for genome-wide association studies.
Assuntos
DNA/genética , DNA/isolamento & purificação , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Polimorfismo de Nucleotídeo Único , Alelos , Biologia Computacional , Feminino , Frequência do Gene , Genoma Humano , Genótipo , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos/estatística & dados numéricos , Reprodutibilidade dos TestesRESUMO
IMPORTANCE: A recently published study of national data by McGrath et al in 2014 showed increased risk of schizophrenia (SCZ) in offspring associated with both early and delayed parental age, consistent with a U-shaped relationship. However, it remains unclear if the risk to the child is due to psychosocial factors associated with parental age or if those at higher risk for SCZ tend to have children at an earlier or later age. OBJECTIVE: To determine if there is a genetic association between SCZ and age at first birth (AFB) using genetically informative but independently ascertained data sets. DESIGN, SETTING, AND PARTICIPANTS: This investigation used multiple independent genome-wide association study data sets. The SCZ sample comprised 18â¯957 SCZ cases and 22â¯673 controls in a genome-wide association study from the second phase of the Psychiatric Genomics Consortium, and the AFB sample comprised 12â¯247 genotyped women measured for AFB from the following 4 community cohorts: Estonia (Estonian Genome Center Biobank, University of Tartu), the Netherlands (LifeLines Cohort Study), Sweden (Swedish Twin Registry), and the United Kingdom (TwinsUK). Schizophrenia genetic risk for each woman in the AFB community sample was estimated using genetic effects inferred from the SCZ genome-wide association study. MAIN OUTCOMES AND MEASURES: We tested if SCZ genetic risk was a significant predictor of response variables based on published polynomial functions that described the relationship between maternal age and SCZ risk in offspring in Denmark. We substituted AFB for maternal age in these functions, one of which was corrected for the age of the father, and found that the fit was superior for the model without adjustment for the father's age. RESULTS: We observed a U-shaped relationship between SCZ risk and AFB in the community cohorts, consistent with the previously reported relationship between SCZ risk in offspring and maternal age when not adjusted for the age of the father. We confirmed that SCZ risk profile scores significantly predicted the response variables (coefficient of determination R2 = 1.1E-03, P = 4.1E-04), reflecting the published relationship between maternal age and SCZ risk in offspring by McGrath et al in 2014. CONCLUSIONS AND RELEVANCE: This study provides evidence for a significant overlap between genetic factors associated with risk of SCZ and genetic factors associated with AFB. It has been reported that SCZ risk associated with increased maternal age is explained by the age of the father and that de novo mutations that occur more frequently in the germline of older men are the underlying causal mechanism. This explanation may need to be revised if, as suggested herein and if replicated in future studies, there is also increased genetic risk of SCZ in older mothers.
Assuntos
Ordem de Nascimento , Estudo de Associação Genômica Ampla , Idade Materna , Esquizofrenia/genética , Adulto , Alelos , Estudos de Coortes , Dinamarca , Feminino , Predisposição Genética para Doença/genética , Humanos , Fenótipo , Gravidez , RiscoRESUMO
BACKGROUND: A long-standing epidemiological puzzle is the reduced rate of rheumatoid arthritis (RA) in those with schizophrenia (SZ) and vice versa. Traditional epidemiological approaches to determine if this negative association is underpinned by genetic factors would test for reduced rates of one disorder in relatives of the other, but sufficiently powered data sets are difficult to achieve. The genomics era presents an alternative paradigm for investigating the genetic relationship between two uncommon disorders. METHODS: We use genome-wide common single nucleotide polymorphism (SNP) data from independently collected SZ and RA case-control cohorts to estimate the SNP correlation between the disorders. We test a genotype X environment (GxE) hypothesis for SZ with environment defined as winter- vs summer-born. RESULTS: We estimate a small but significant negative SNP-genetic correlation between SZ and RA (-0.046, s.e. 0.026, P = 0.036). The negative correlation was stronger for the SNP set attributed to coding or regulatory regions (-0.174, s.e. 0.071, P = 0.0075). Our analyses led us to hypothesize a gene-environment interaction for SZ in the form of immune challenge. We used month of birth as a proxy for environmental immune challenge and estimated the genetic correlation between winter-born and non-winter born SZ to be significantly less than 1 for coding/regulatory region SNPs (0.56, s.e. 0.14, P = 0.00090). CONCLUSIONS: Our results are consistent with epidemiological observations of a negative relationship between SZ and RA reflecting, at least in part, genetic factors. Results of the month of birth analysis are consistent with pleiotropic effects of genetic variants dependent on environmental context.
Assuntos
Artrite Reumatoide/genética , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Adolescente , Adulto , Estudos de Coortes , Estudos Transversais , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
OBJECTIVES: Cadherins play a critical role in morphogenesis and maintenance of neuronal connections in the adult brain. We examined the gene encoding a member of the non-classic seven-pass transmembrane cadherins, CELSR1 for association with schizophrenia. It maps to chromosome 22q13.31, a region in which evidence for linkage to schizophrenia has been reported. The gene has an unusually large first exon of 3544 nucleotides, which encodes the signal peptide and all nine ectodomains in the protein. METHODS: We screened this exon in 24 schizophrenic patients using denaturing high-performance liquid chromatography followed by sequencing. Genotyping of amino-acid changes was performed with primer extension on a sample of 244 Bulgarian schizophrenic patients from 233 families and all their parents, as well as 180 schizophrenic patients from the UK and 157 controls. RESULTS: Three amino-acid changes were identified and shown to be in complete linkage disequilibrium: L556 V, S664W and R1126C. There was no preferential transmission of alleles from heterozygous parents to affected offspring. In the UK population the rare alleles were even more common in controls, and this difference almost reached statistical significance for R1126C (chi2=3.63, P=0.057). CONCLUSIONS: We conclude that variations in the nine ectodomains of CELSR1 do not increase susceptibility to schizophrenia.
Assuntos
Caderinas/genética , Variação Genética , Esquizofrenia/genética , Substituição de Aminoácidos , Sequência de Bases , Bulgária , Primers do DNA , Feminino , Predisposição Genética para Doença/genética , Humanos , Desequilíbrio de Ligação , Masculino , Núcleo Familiar , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Valores de Referência , Reino Unido , População Branca/genéticaRESUMO
The serotonin transporter (5-HTT) is a suitable candidate gene to test for involvement in the pathogenesis of major psychiatric disorders. We used the method of family-based controls to test for association between disease and a variable number tandem repeat (VNTR) in intron 2 of the gene, which has received support for involvement in the pathogenesis of several psychiatric disorders. We analysed 413 proband-parent trios of Bulgarian origin: 266 had a schizophrenic proband, 103 had a bipolar proband and 44 had a schizoaffective proband. The results were analysed using the extended transmission disequilibrium test. Possible effects of different alleles on certain clinical variables were examined by correlation analysis. Three alleles were detected: STin2.9, STin2.10 and STin2.12. None of the three diagnostic samples showed preferential transmission of alleles that reached conventional levels of statistical significance. We could not confirm previous results that STin2.12 allele increases susceptibility to bipolar disorder type I. The rare STin2.9 showed a non-significant trend for preferential transmission in the sample as a whole: 18 transmitted versus 11 non-transmitted (P = 0.2). The VNTR polymorphism in the 5-HTT gene does not appear to be a major risk factor for increasing susceptibility to major psychiatric disorders.
Assuntos
Proteínas de Transporte/genética , Glicoproteínas de Membrana/genética , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Transtornos Psicóticos/genética , Adulto , Alelos , Transtorno Bipolar/genética , Bulgária/etnologia , Família , Feminino , Triagem de Portadores Genéticos , Humanos , Íntrons , Masculino , Repetições Minissatélites , Esquizofrenia/genética , Proteínas da Membrana Plasmática de Transporte de SerotoninaRESUMO
BACKGROUND: Several recurrent copy number variants (CNVs) have been shown to increase the risk of developing schizophrenia (SCZ), developmental delay (DD), autism spectrum disorders (ASD), and various congenital malformations (CM). Their penetrance for SCZ has been estimated to be modest. However, comparisons between their penetrance for SCZ or DD/ASD/CM, or estimates of the total penetrance for any of these disorders have not yet been made. METHODS: We use data from the largest available studies on SCZ and DD/ASD/CM, including a new sample of 6882 cases and 6316 controls, to estimate the frequencies of 70 implicated CNVs in carriers with these disorders, healthy control subjects, and the general population. On the basis of these frequencies, we estimate their penetrance. We also estimate the strength of the selection pressure against CNVs and correlate this against their overall penetrance. RESULTS: The rates of nearly all CNVs are higher in DD/ASD/CM compared with SCZ. The penetrance of CNVs is at least several times higher for the development of a disorder from the group of DD/ASD/CM. The overall penetrance of SCZ-associated CNVs for developing any disorder is high, ranging between 10.6% and 100%. CONCLUSIONS: CNVs associated with SCZ have high pathogenicity. The majority of the increased risk conferred by CNVs is toward the development of an earlier-onset disorder, such as DD/ASD/CM, rather than SCZ. The penetrance of CNVs correlates strongly with their selection coefficients. The improved estimates of penetrance will provide crucial information for genetic counselling.
Assuntos
Aberrações Cromossômicas , Variações do Número de Cópias de DNA/genética , Deficiências do Desenvolvimento/genética , Predisposição Genética para Doença , Penetrância , Esquizofrenia/genética , Feminino , Humanos , MasculinoRESUMO
BACKGROUND: There is support that Neuregulin 1 (NRG1) plays a role in susceptibility to schizophrenia but limited evidence for its involvement in bipolar disorder. We wished to investigate further the involvement of NRG1 in schizophrenia and bipolar disorder. METHODS: We used hierarchical association analysis in parent-offspring trios, 634 with schizophrenia/schizoaffective disorder (SZ/SA) and 243 with bipolar 1 disorder (BP1). The primary analysis was the markers defining the "core Icelandic haplotype" (HAP(ICE)). We undertook polymorphism discovery, additional genotyping, and also explored phenotypic associations, as a secondary analysis aimed at refining the signal. RESULTS: The initial global haplotype test yielded significant evidence for association (p = .01) with SZ/SA and BP1 (p = .004), although HAP(ICE) was not overtransmitted. The marker showing strongest evidence for association in the deCODE studies, SNP8NRG221533, was associated with SZ/SA (p(corrected) = .039) and with BP1 (p(corrected) = .039), with BP1 showing association to the opposite allele as SZ/SA. The pattern of transmission at SNP8NRG221533 was significantly different in SZ/SA than in BP1 (p = .0004). Secondary analyses of markers and phenotypes provided no additional evidence for association to SZ/SA. However, a new marker, rs7014762, was associated with an a priori defined "typical" bipolar phenotype characterized by excellent recovery between episodes and no mood incongruent features (p(corrected) = .003). CONCLUSIONS: Our data provide significant levels of support for NRG1 as a susceptibility gene for both major forms of psychosis, and this cannot be interpreted as being due to population stratification. More tentatively, they also might indicate the presence of multiple alleles that influence the psychosis phenotype.