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1.
Biol Psychiatry ; 86(4): 286-293, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31200929

RESUMO

BACKGROUND: Assortative mating is a nonrandom mating system in which individuals with similar genotypes and/or phenotypes mate with one another more frequently than would be expected in a random mating system. Assortative mating has been hypothesized to play a role in autism spectrum disorder (ASD) in an attempt to explain some of the increase in the prevalence of ASD that has recently been observed. ASD is considered to be a heritable neurodevelopmental disorder, but there is limited understanding of its causes. Assortative mating can be explored through both phenotypic and genotypic data, but up until now it has never been investigated through genotypic measures in ASD. METHODS: We investigated genotypically similar mating pairs using genome-wide single nucleotide polymorphism data on trio families (Autism Genome Project data [1590 parents] and Simons Simplex Collection data [1962 parents]). To determine whether or not an excess in genetic similarity was present, we employed kinship coefficients and examined spousal correlation between the principal components in both the Autism Genome Project and Simons Simplex Collection datasets. We also examined assortative mating using phenotype data on the parents to detect any correlation between ASD traits. RESULTS: We found significant evidence of genetic similarity between the parents of ASD offspring using both methods in the Autism Genome Project dataset. In the Simons Simplex Collection, there was also significant evidence of genetic similarity between the parents when explored through spousal correlation. CONCLUSIONS: This study gives further support to the hypothesis that positive assortative mating plays a role in ASD.

2.
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.

3.
Br J Psychiatry ; : 1-7, 2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30806336

RESUMO

BACKGROUND: The past decade has seen the development of services for adults presenting with symptoms of autism spectrum disorder (ASD) in the UK. Compared with children, little is known about the phenotypic and genetic characteristics of these patients.AimsThis e-cohort study aimed to examine the phenotypic and genetic characteristics of a clinically presenting sample of adults diagnosed with ASD by specialist services. METHOD: Individuals diagnosed with ASD as adults were recruited by the National Centre for Mental Health and completed self-report questionnaires, interviews and provided DNA; 105 eligible individuals were matched to 76 healthy controls. We investigated demographics, social history and comorbid psychiatric and physical disorders. Samples were genotyped, copy number variants (CNVs) were called and polygenic risk scores were calculated. RESULTS: Of individuals with ASD, 89.5% had at least one comorbid psychiatric diagnosis, with depression (62.9%) and anxiety (55.2%) being the most common. The ASD group experienced more neurological comorbidities than controls, particularly migraine headache. They were less likely to have married or be in work, and had more alcohol-related problems. There was a significantly higher load of autism common genetic variants in the adult ASD group compared with controls, but there was no difference in the rate of rare CNVs. CONCLUSIONS: This study provides important information about psychiatric comorbidity in adult ASD, which may inform clinical practice and patient counselling. It also suggests that the polygenic load of common ASD-associated variants may be important in conferring risk within the non-intellectually disabled population of adults with ASD.Declaration of interestNone.

4.
Nat Genet ; 51(3): 431-444, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804558

RESUMO

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.


Assuntos
Transtorno do Espectro Autista/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Dinamarca , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Herança Multifatorial/genética , Fenótipo , Fatores de Risco
5.
JAMA Psychiatry ; 2018 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-30326013

RESUMO

Importance: Depression often first manifests in adolescence. Thereafter, individual trajectories vary substantially, but it is not known what shapes depression trajectories in youth. Adult studies suggest that genetic risk for schizophrenia, a psychiatric disorder with a neurodevelopmental component, may contribute to an earlier onset of depression. Objective: To test the hypothesis that there are distinct trajectories of depressive symptoms and that genetic liability for neurodevelopmental psychiatric disorders (eg, schizophrenia, attention deficit/hyperactivity disorder [ADHD]), as well as for major depressive disorder (MDD), contribute to early-onset depression. Design, Setting, and Participants: The Avon Longitudinal Study of Parents and Children is an ongoing, prospective, longitudinal, population-based cohort that has been collecting data since September 6, 1990, including data on 7543 adolescents with depressive symptoms at multiple time points. The present study was conducted between November 10, 2017, and August 14, 2018. Main Outcomes and Measures: Trajectories based on self-reported depressive symptoms dichotomized by the clinical cutpoint; MDD, schizophrenia, and ADHD polygenic risk score (PRS) were predictors. Results: In 7543 adolescents with depression data on more than 1 assessment point between a mean (SD) age of 10.64 (0.25) years and 18.65 (0.49) years (3568 [47.3%] male; 3975 [52.7%] female), 3 trajectory classes were identified: persistently low (73.7%), later-adolescence onset (17.3%), and early-adolescence onset (9.0%). The later-adolescence-onset class was associated with MDD genetic risk only (MDD PRS: odds ratio [OR], 1.27; 95% CI, 1.09-1.48; P = .003). The early-adolescence-onset class was also associated with MDD genetic risk (MDD PRS: OR, 1.24; 95% CI, 1.06-1.46; P = .007) but additionally with genetic risk for neurodevelopmental disorders (schizophrenia PRS: OR, 1.22; 95% CI, 1.04-1.43; P = .01; ADHD PRS: OR, 1.32; 95% CI, 1.13-1.54; P < .001) and childhood ADHD (χ21 = 6.837; P = .009) and neurodevelopmental traits (pragmatic language difficulties: OR, 1.31; P = .004; social communication difficulties: OR, 0.68; P < .001). Conclusions and Relevance: The findings of this study appear to demonstrate evidence of distinct depressive trajectories, primarily distinguished by age at onset. The more typical depression trajectory with onset of clinically significant symptoms at age 16 years was associated with MDD genetic risk. The less-common depression trajectory, with a very early onset, was particularly associated with ADHD and schizophrenia genetic risk and, phenotypically, with childhood ADHD and neurodevelopmental traits. Findings are consistent with emerging evidence for a neurodevelopmental component in some cases of depression and suggest that the presence of this component may be more likely when the onset of depression is very early.

6.
Am J Med Genet B Neuropsychiatr Genet ; 177(3): 369-376, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29418072

RESUMO

Multiple genome-wide association studies of schizophrenia have implicated genetic variants within the gene encoding microRNA-137. As risk variants within or regulated by MIR137 have been implicated in memory performance, we investigated the additive effects of schizophrenia-associated risk variants in genes empirically regulated by MIR137 on brain regions associated with memory function. A polygenic risk score (PRS) was calculated (at a p = 0.05 threshold), using this empirically regulated MIR137 gene set, to investigate associations between this PRS and structural brain measures. These measures included total brain volume, cortical thickness, cortical surface area, and hippocampal volume, in a sample of 216 individuals consisting of healthy participants (n = 171) and patients with psychosis (n = 45). We did not observe a significant association between MIR137 PRS and these cortical thickness, surface area or hippocampal volume measures linked to memory function; a significant association between increasing PRS and decreasing total brain volume, independent of diagnosis status (R2 = 0.008, Beta = -0.09, p = 0.029), was observed. This did not survive correction for multiple testing. In conclusion, our study yielded only suggestive evidence that risk variants interacting with MIR137 impacts on cortical structure.

7.
Nat Genet ; 49(7): 978-985, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28504703

RESUMO

Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.


Assuntos
Transtorno do Espectro Autista/genética , Variação Genética , Herança Multifatorial , Adulto , Transtorno do Espectro Autista/epidemiologia , Criança , Estudos de Coortes , Escolaridade , Grupos Étnicos/genética , Saúde da Família , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genética Comportamental , Humanos , Deficiência Intelectual/genética , Inteligência/genética , Masculino , Fenótipo , Fatores de Risco , Esquizofrenia/genética , Deleção de Sequência
8.
Nat Rev Genet ; 18(6): 362-376, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28260791

RESUMO

Genetic studies have revealed the involvement of hundreds of gene variants in autism. Their risk effects are highly variable, and they are frequently related to other conditions besides autism. However, many different variants converge on common biological pathways. These findings indicate that aetiological heterogeneity, variable penetrance and genetic pleiotropy are pervasive characteristics of autism genetics. Although this advancing insight should improve clinical care, at present there is a substantial discrepancy between research knowledge and its clinical application. In this Review, we discuss the current challenges and opportunities for the translation of autism genetics knowledge into clinical practice.


Assuntos
Transtorno Autístico/genética , Transtorno Autístico/fisiopatologia , Transtorno Autístico/terapia , Predisposição Genética para Doença , Técnicas de Genotipagem , Humanos
9.
Eur J Hum Genet ; 25(2): 234-239, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27876814

RESUMO

Autism spectrum disorder (ASD) is known to be a heritable neurodevelopmental disorder affecting more than 1% of the population but in the majority of ASD cases, the genetic cause has not been identified. Parent-of-origin effects have been highlighted as an important mechanism in the pathology of neurodevelopmental disorders such as Prader-Willi and Angelman syndrome, with individuals with these syndromes often exhibiting ASD symptoms. Consequently, systematic investigation of these effects in ASD is clearly an important line of investigation in elucidating the underlying genetic mechanisms. Using estimation of maternal, imprinting and interaction effects using multinomial modelling (EMIM), we simultaneously investigated imprinting, maternal genetic effects and associations in the Autism Genome Project and Simons Simplex Consortium genome-wide association data sets. To avoid using the overly stringent genome-wide association study significance level, we used a Bayesian threshold that takes into account the sample size, allele frequency and any available prior knowledge. Between the two data sets, we identified a total of 18 imprinting effects and 68 maternal genetic effects that met this Bayesian threshold criteria, but none met the threshold in both data sets. We identified imprinting and maternal genetic effects for regions that have previously shown evidence for parent-of-origin effects in ASD. Together with these findings, we have identified maternal genetic effects not previously identified in ASD at a locus in SHANK3 on chromosome 22 and a locus in WBSCR17 on chromosome 7 (associated with Williams syndrome). Both genes have previously been associated with ASD.


Assuntos
Transtorno do Espectro Autista/genética , Impressão Genômica , Proteínas do Tecido Nervoso/genética , Linhagem , Teorema de Bayes , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 7/genética , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Masculino , N-Acetilgalactosaminiltransferases/genética , Polimorfismo de Nucleotídeo Único
10.
Eur J Hum Genet ; 24(2): 291-7, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25920553

RESUMO

Coeliac disease (CD) is a chronic immune-mediated disease triggered by the ingestion of gluten. It has an estimated prevalence of approximately 1% in European populations. Specific HLA-DQA1 and HLA-DQB1 alleles are established coeliac susceptibility genes and are required for the presentation of gliadin to the immune system resulting in damage to the intestinal mucosa. In the largest association analysis of CD to date, 39 non-HLA risk loci were identified, 13 of which were new, in a sample of 12,014 individuals with CD and 12 228 controls using the Immunochip genotyping platform. Including the HLA, this brings the total number of known CD loci to 40. We have replicated this study in an independent Irish CD case-control population of 425 CD and 453 controls using the Immunochip platform. Using a binomial sign test, we show that the direction of the effects of previously described risk alleles were highly correlated with those reported in the Irish population, (P=2.2 × 10(-16)). Using the Polygene Risk Score (PRS) approach, we estimated that up to 35% of the genetic variance could be explained by loci present on the Immunochip (P=9 × 10(-75)). When this is limited to non-HLA loci, we explain a maximum of 4.5% of the genetic variance (P=3.6 × 10(-18)). Finally, we performed a meta-analysis of our data with the previous reports, identifying two further loci harbouring the ZNF335 and NIFA genes which now exceed genome-wide significance, taking the total number of CD susceptibility loci to 42.


Assuntos
Estudo de Associação Genômica Ampla , Sistema Imunitário , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Nucleares/genética , Alelos , Predisposição Genética para Doença , Genótipo , Gliadina/genética , Gliadina/imunologia , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/imunologia , Humanos , Mucosa Intestinal/patologia
12.
Methods Mol Biol ; 1326: 93-103, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26498616

RESUMO

Genetic variation along the length of a chromosome can influence the transcription of a gene. In a heterozygous individual, this may lead to one chromosome producing different levels of RNA, compared to its paired chromosome, for a given gene. Allelic differences in gene expression can offer insight into the role of variation in transcription, and subsequently infer a route to conferring disease risk. This phenomenon is known as allele expression imbalance or AEI, which may be assayed using a PCR-based method that includes the quantification of the relative dosage of each allele (e.g., 5' exonuclease assays, TaqMan™). Importantly, in heterozygous individuals the resolution of expression imbalance is performed within a controlled system; the comparison of the alternate allele is reported relative to the wild-type, as the experiment can be performed within a single sample, controlled for background genetic information. Alternative methods for the detection of AEI include Primer-extension MALDI-TOF (Sequenom MassARRAY(®)), Next-Generation Sequencing, and SNP genotyping arrays. Here we present the methods used for the TaqMan™ approach and include a description of the SNP identification, allele-specific PCR, and analytic methods to convert allele amplification metrics to relative allele dosage.


Assuntos
Alelos , Genótipo , Fosfodiesterase I/metabolismo , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase em Tempo Real
13.
Hum Mol Genet ; 24(18): 5126-41, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26089202

RESUMO

Sprouty proteins are regulators of cell growth and branching morphogenesis. Unlike mouse Spry3, which is X-linked, human SPRY3 maps to the pseudoautosomal region 2; however, the human Y-linked allele is not expressed due to epigenetic silencing by an unknown mechanism. SPRY3 maps adjacent to X-linked Trimethyllysine hydroxylase epsilon (TMLHE), recently identified as an autism susceptibility gene. We report that Spry3 is highly expressed in central and peripheral nervous system ganglion cells in mouse and human, including cerebellar Purkinje cells and retinal ganglion cells. Transient over-expression or knockdown of Spry3 in cultured mouse superior cervical ganglion cells inhibits and promotes, respectively, neurite growth and branching. A 0.7 kb gene fragment spanning the human SPRY3 transcriptional start site recapitulates the endogenous Spry3-expression pattern in LacZ reporter mice. In the human and mouse the SPRY3 promoter contains an AG-rich repeat and we found co-expression, and promoter binding and/or regulation of SPRY3 expression by transcription factors MAZ, EGR1, ZNF263 and PAX6. We identified eight alleles of the human SPRY3 promoter repeat in Caucasians, and similar allele frequencies in autism families. We characterized multiple SPRY3 transcripts originating at two CpG islands in the X-linked F8A3-TMLHE region, suggesting X chromosome regulation of SPRY3. These findings provide an explanation for differential regulation of X and Y-linked SPRY3 alleles. In addition, the presence of a SPRY3 transcript exon in a previously described X chromosome deletion associated with autism, and the cerebellar interlobular variation in Spry3 expression coincident with the reported pattern of Purkinje cell loss in autism, suggest SPRY3 as a candidate susceptibility locus for autism.


Assuntos
Transtorno Autístico/genética , Cromossomos Humanos X , Predisposição Genética para Doença , Peptídeos e Proteínas de Sinalização Intracelular/genética , Regiões Promotoras Genéticas , Receptor PAR-2/genética , Alelos , Animais , Composição de Bases , Sequência de Bases , Linhagem Celular , Cerebelo/metabolismo , Ilhas de CpG , Metilação de DNA , Modelos Animais de Doenças , Éxons , Gânglios/metabolismo , Expressão Gênica , Regulação da Expressão Gênica , Genes Ligados ao Cromossomo X , Loci Gênicos , Humanos , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Neuritos/metabolismo , Polimorfismo Genético , Alinhamento de Sequência , Fatores de Transcrição/metabolismo , Transcrição Genética
14.
Mol Autism ; 5: 34, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25392729

RESUMO

BACKGROUND: There is an urgent need for expanding and enhancing autism spectrum disorder (ASD) samples, in order to better understand causes of ASD. METHODS: In a unique public-private partnership, 13 sites with extensive experience in both the assessment and diagnosis of ASD embarked on an ambitious, 2-year program to collect samples for genetic and phenotypic research and begin analyses on these samples. The program was called The Autism Simplex Collection (TASC). TASC sample collection began in 2008 and was completed in 2010, and included nine sites from North America and four sites from Western Europe, as well as a centralized Data Coordinating Center. RESULTS: Over 1,700 trios are part of this collection, with DNA from transformed cells now available through the National Institute of Mental Health (NIMH). Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule-Generic (ADOS-G) measures are available for all probands, as are standardized IQ measures, Vineland Adaptive Behavioral Scales (VABS), the Social Responsiveness Scale (SRS), Peabody Picture Vocabulary Test (PPVT), and physical measures (height, weight, and head circumference). At almost every site, additional phenotypic measures were collected, including the Broad Autism Phenotype Questionnaire (BAPQ) and Repetitive Behavior Scale-Revised (RBS-R), as well as the non-word repetition scale, Communication Checklist (Children's or Adult), and Aberrant Behavior Checklist (ABC). Moreover, for nearly 1,000 trios, the Autism Genome Project Consortium (AGP) has carried out Illumina 1 M SNP genotyping and called copy number variation (CNV) in the samples, with data being made available through the National Institutes of Health (NIH). Whole exome sequencing (WES) has been carried out in over 500 probands, together with ancestry matched controls, and this data is also available through the NIH. Additional WES is being carried out by the Autism Sequencing Consortium (ASC), where the focus is on sequencing complete trios. ASC sequencing for the first 1,000 samples (all from whole-blood DNA) is complete and data will be released in 2014. Data is being made available through NIH databases (database of Genotypes and Phenotypes (dbGaP) and National Database for Autism Research (NDAR)) with DNA released in Dist 11.0. Primary funding for the collection, genotyping, sequencing and distribution of TASC samples was provided by Autism Speaks and the NIH, including the National Institute of Mental Health (NIMH) and the National Human Genetics Research Institute (NHGRI). CONCLUSIONS: TASC represents an important sample set that leverages expert sites. Similar approaches, leveraging expert sites and ongoing studies, represent an important path towards further enhancing available ASD samples.

15.
Schizophr Res ; 158(1-3): 255-60, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24999052

RESUMO

There is compelling evidence for the role of copy number variants (CNVs) in schizophrenia susceptibility, and it has been estimated that up to 2-3% of schizophrenia cases may carry rare CNVs. Despite evidence that these events are associated with an increased risk across categorical neurodevelopmental disorders, there is limited understanding of the impact of CNVs on the core features of disorders like schizophrenia. Our objective was to evaluate associations between rare CNVs in differentially brain expressed (BE) genes and the core features and clinical correlates of schizophrenia. The sample included 386 cases of Irish ancestry with a diagnosis of schizophrenia, at least one rare CNV impacting any gene, and a core set of phenotypic measures. Statistically significant associations between deletions in differentially BE genes were found for family history of mental illness (decreased prevalence of all CNVs and deletions, unadjusted and adjusted) and for paternal age (increase in deletions only, unadjusted, among those with later ages at birth of patient). The strong effect of a lack of a family history on BE genes suggests that CNVs may comprise one pathway to schizophrenia, whereas a positive family history could index other genetic mechanisms that increase schizophrenia vulnerability. To our knowledge, this is the first investigation of the association between genome-wide CNVs and risk factors and sub-phenotypic features of schizophrenia beyond cognitive function.


Assuntos
Encéfalo/metabolismo , Variações do Número de Cópias de DNA , Esquizofrenia/genética , Esquizofrenia/metabolismo , Grupo com Ancestrais do Continente Europeu/genética , Família , Feminino , Predisposição Genética para Doença , Humanos , Irlanda , Modelos Logísticos , Masculino , Idade Paterna , Fenótipo , Esquizofrenia/epidemiologia
16.
JAMA Psychiatry ; 71(7): 778-785, 2014 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-24828433

RESUMO

IMPORTANCE: We investigated the variation in neuropsychological function explained by risk alleles at the psychosis susceptibility gene ZNF804A and its interacting partners using single nucleotide polymorphisms (SNPs), polygenic scores, and epistatic analyses. Of particular importance was the relative contribution of the polygenic score vs epistasis in variation explained. OBJECTIVES: To (1) assess the association between SNPs in ZNF804A and the ZNF804A polygenic score with measures of cognition in cases with psychosis and (2) assess whether epistasis within the ZNF804A pathway could explain additional variation above and beyond that explained by the polygenic score. DESIGN, SETTING, AND PARTICIPANTS: Patients with psychosis (n = 424) were assessed in areas of cognitive ability impaired in schizophrenia including IQ, memory, attention, and social cognition. We used the Psychiatric GWAS Consortium 1 schizophrenia genome-wide association study to calculate a polygenic score based on identified risk variants within this genetic pathway. Cognitive measures significantly associated with the polygenic score were tested for an epistatic component using a training set (n = 170), which was used to develop linear regression models containing the polygenic score and 2-SNP interactions. The best-fitting models were tested for replication in 2 independent test sets of cases: (1) 170 individuals with schizophrenia or schizoaffective disorder and (2) 84 patients with broad psychosis (including bipolar disorder, major depressive disorder, and other psychosis). MAIN OUTCOMES AND MEASURES: Participants completed a neuropsychological assessment battery designed to target the cognitive deficits of schizophrenia including general cognitive function, episodic memory, working memory, attentional control, and social cognition. RESULTS: Higher polygenic scores were associated with poorer performance among patients on IQ, memory, and social cognition, explaining 1% to 3% of variation on these scores (range, P = .01 to .03). Using a narrow psychosis training set and independent test sets of narrow phenotype psychosis (schizophrenia and schizoaffective disorder), broad psychosis, and control participants (n = 89), the addition of 2 interaction terms containing 2 SNPs each increased the R2 for spatial working memory strategy in the independent psychosis test sets from 1.2% using the polygenic score only to 4.8% (P = .11 and .001, respectively) but did not explain additional variation in control participants. CONCLUSIONS AND RELEVANCE: These data support a role for the ZNF804A pathway in IQ, memory, and social cognition in cases. Furthermore, we showed that epistasis increases the variation explained above the contribution of the polygenic score.


Assuntos
Epistasia Genética/genética , Variação Genética/genética , Memória de Curto Prazo/fisiologia , Transtornos Psicóticos/genética , Esquizofrenia/genética , Dedos de Zinco/genética , Adulto , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/genética , Transtornos Cognitivos/psicologia , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial/genética , Vias Neurais/fisiopatologia , Testes Neuropsicológicos , Polimorfismo de Nucleotídeo Único/genética , Transtornos Psicóticos/complicações , Transtornos Psicóticos/psicologia , Esquizofrenia/complicações , Esquizofrenia/fisiopatologia
17.
Am J Hum Genet ; 94(5): 677-94, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24768552

RESUMO

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Variações do Número de Cópias de DNA , Redes e Vias Metabólicas/genética , Criança , Feminino , Redes Reguladoras de Genes , Humanos , Masculino , Família Multigênica , Linhagem , Deleção de Sequência
18.
Hum Genet ; 133(6): 781-92, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24442360

RESUMO

Autism spectrum disorders (ASD) are heterogeneous disorders with a high heritability and complex genetic architecture. Due to the central role of the fragile X mental retardation gene 1 protein (FMRP) pathway in ASD we investigated common functional variants of ASD risk genes regulating FMRP. We genotyped ten SNPs in two German patient sets (N = 192 and N = 254 families, respectively) and report association for rs7170637 (CYFIP1; set 1 and combined sets), rs6923492 (GRM1; combined sets), and rs25925 (CAMK4; combined sets). An additional risk score based on variants with an odds ratio (OR) >1.25 in set 1 and weighted by their respective log transmitted/untransmitted ratio revealed a significant effect (OR 1.30, 95 % CI 1.11-1.53; P = 0.0013) in the combined German sample. A subsequent meta-analysis including the two German samples, the "Strict/European" ASD subsample of the Autism Genome Project (1,466 families) and a French case/control (541/366) cohort showed again association of rs7170637-A (OR 0.85, 95 % CI 0.75-0.96; P = 0.007) and rs25925-G (OR 1.31, 95 % CI 1.04-1.64; P = 0.021) with ASD. Functional analyses revealed that these minor alleles predicted to alter splicing factor binding sites significantly increase levels of an alternative mRNA isoform of the respective gene while keeping the overall expression of the gene constant. These findings underpin the role of ASD candidate genes in postsynaptic FMRP regulation suggesting that an imbalance of specific isoforms of CYFIP1, an FMRP interaction partner, and CAMK4, a transcriptional regulator of the FMRP gene, modulates ASD risk. Both gene products are related to neuronal regulation of synaptic plasticity, a pathomechanism underlying ASD and may thus present future targets for pharmacological therapies in ASD.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/genética , Transtornos Globais do Desenvolvimento Infantil/genética , Proteína do X Frágil de Retardo Mental/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adolescente , Alelos , Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/metabolismo , Criança , Transtornos Globais do Desenvolvimento Infantil/etnologia , Transtornos Globais do Desenvolvimento Infantil/metabolismo , Transtornos Globais do Desenvolvimento Infantil/patologia , Pré-Escolar , Grupo com Ancestrais do Continente Europeu , Feminino , Proteína do X Frágil de Retardo Mental/metabolismo , Regulação da Expressão Gênica , Técnicas de Genotipagem , Humanos , Masculino , Plasticidade Neuronal/genética , Ligação Proteica , Fatores de Risco , Transdução de Sinais
19.
Nat Genet ; 45(9): 984-94, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23933821

RESUMO

Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Transtornos Mentais/genética , Polimorfismo de Nucleotídeo Único , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno Bipolar/genética , Criança , Transtornos Globais do Desenvolvimento Infantil/genética , Doença de Crohn/genética , Transtorno Depressivo Maior/genética , Heterogeneidade Genética , Genoma Humano , Humanos , Padrões de Herança , Esquizofrenia/genética
20.
Am J Psychiatry ; 170(8): 909-16, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23599091

RESUMO

OBJECTIVE Although attention deficit hyperactivity disorder (ADHD) is highly heritable, genome-wide association studies (GWAS) have not yet identified any common genetic variants that contribute to risk. There is evidence that aggression or conduct disorder in children with ADHD indexes higher genetic loading and clinical severity. The authors examine whether common genetic variants considered en masse as polygenic scores for ADHD are especially enriched in children with comorbid conduct disorder. METHOD Polygenic scores derived from an ADHD GWAS meta-analysis were calculated in an independent ADHD sample (452 case subjects, 5,081 comparison subjects). Multivariate logistic regression analyses were employed to compare polygenic scores in the ADHD and comparison groups and test for higher scores in ADHD case subjects with comorbid conduct disorder relative to comparison subjects and relative to those without comorbid conduct disorder. Association with symptom scores was tested using linear regression. RESULTS Polygenic risk for ADHD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group. Polygenic score was significantly higher in ADHD case subjects with conduct disorder relative to ADHD case subjects without conduct disorder. ADHD polygenic score showed significant association with comorbid conduct disorder symptoms. This relationship was explained by the aggression items. CONCLUSIONS Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression. The findings suggest that the previously published ADHD GWAS meta-analysis contains weak but true associations with common variants, support for which falls below genome-wide significance levels. The findings also highlight the fact that aggression in ADHD indexes genetic as well as clinical severity.


Assuntos
Agressão/psicologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno da Conduta/genética , Predisposição Genética para Doença/genética , Herança Multifatorial/genética , Transtornos de Ansiedade/diagnóstico , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/psicologia , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Criança , Pré-Escolar , Comorbidade , Transtorno da Conduta/diagnóstico , Transtorno da Conduta/psicologia , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/genética , Transtorno Depressivo/psicologia , Feminino , Variação Genética/genética , Humanos , Masculino , Reino Unido
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