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2.
J Psychiatry Neurosci ; 43(4): 245-253, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29947606

RESUMO

BACKGROUND: Cognitive impairments are well-established features of schizophrenia, but there is ongoing debate about the nature and degree of cognitive impairment in patients with schizoaffective disorder and bipolar disorder. We hypothesized that there is a spectrum of increasing impairment from bipolar disorder to schizoaffective disorder bipolar type, to schizoaffective disorder depressive type and schizophrenia. METHODS: We compared performance on the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery between participants with schizophrenia (n = 558), schizoaffective disorder depressive type (n = 112), schizoaffective disorder type (n = 76), bipolar disorder (n = 78) and healthy participants (n = 103) using analysis of covariance with post hoc comparisons. We conducted an ordinal logistic regression to examine whether cognitive impairments followed the hypothesized spectrum from bipolar disorder (least severe) to schizophrenia (most severe). In addition to categorical diagnoses, we addressed the influence of symptom domains, examining the association between cognition and mania, depression and psychosis. RESULTS: Cognitive impairments increased in severity from bipolar disorder to schizoaffective disorder bipolar type, to schizophrenia and schizoaffective disorder depressive type. Participants with schizophrenia and schizoaffective disorder depressive type showed equivalent performance (d = 0.07, p = 0.90). The results of the ordinal logistic regression were consistent with a spectrum of deficits from bipolar disorder to schizoaffective disorder bipolar type, to schizophrenia/schizoaffective disorder depressive type (odds ratio = 1.98, p < 0.001). In analyses of the associations between symptom dimensions and cognition, higher scores on the psychosis dimension were associated with poorer performance (B = 0.015, standard error = 0.002, p < 0.001). LIMITATIONS: There were fewer participants with schizoaffective disorder and bipolar disorder than schizophrenia. Despite this, our analyses were robust to differences in group sizes, and we were able to detect differences between groups. CONCLUSION: Cognitive impairments represent a symptom dimension that cuts across traditional diagnostic boundaries.

3.
Thyroid ; 28(7): 891-901, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29897006

RESUMO

BACKGROUND: Euthyroid multinodular goiter (MNG) is common, but little is known about the genetic variations conferring predisposition. Previously, a family with MNG of adolescent onset was reported in which some family members developed papillary thyroid carcinomas (PTC). METHODS: Genome-wide linkage analysis and next-generation sequencing were conducted to identify genetic variants that may confer disease predisposition. A multipoint nonparametric LOD score of 3.01 was obtained, covering 19 cM on chromosome 20p. Haplotype analysis reduced the region of interest to 10 cM. RESULTS: Analysis of copy number variation identified an intronic InDel (∼1000 bp) in the PLCB1 gene in all eight affected family members and carriers (an unaffected person who has inherited the genetic trait). This InDel is present in approximately 1% of "healthy" Caucasians. Next-generation sequencing of the region identified no additional disease-associated variant, suggesting a possible role of the InDel. Since PLCB1 contributes to thyrocyte growth regulation, the InDel was investigated in relevant Caucasian cohorts. It was detected in 0/70 PTC but 4/81 unrelated subjects with MNG (three females; age at thyroidectomy 27-59 years; no family history of MNG/PTC). The InDel frequency is significantly higher in MNG subjects compared to controls (χ2 = 5.076; p = 0.024. PLCB1 transcript levels were significantly higher in thyroids with the InDel than without (p < 0.02). CONCLUSIONS: The intronic PLCB1 InDel is the first variant found in familial multiple papilloid adenomata-type MNG and in a subset of patients with sporadic MNG. It may function through overexpression, and increased PLC activity has been reported in thyroid neoplasms. The potential role of the deletion as a biomarker to identify MNG patients more likely to progress to PTC merits exploration.

4.
J Psychiatry Neurosci ; 43(3): 170076, 2018 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-29620518

RESUMO

BACKGROUND: Cognitive impairments are well-established features of schizophrenia, but there is ongoing debate about the nature and degree of cognitive impairment in patients with schizoaffective disorder and bipolar disorder. We hypothesized that there is a spectrum of increasing impairment from bipolar disorder to schizoaffective disorder bipolar type, to schizoaffective disorder depressive type and schizophrenia. METHODS: We compared performance on the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery between participants with schizophrenia (n = 558), schizoaffective disorder depressive type (n = 112), schizoaffective disorder type (n = 76), bipolar disorder (n = 78) and healthy participants (n = 103) using analysis of covariance with post hoc comparisons. We conducted an ordinal logistic regression to examine whether cognitive impairments followed the hypothesized spectrum from bipolar disorder (least severe) to schizophrenia (most severe). In addition to categorical diagnoses, we addressed the influence of symptom domains, examining the association between cognition and mania, depression and psychosis. RESULTS: Cognitive impairments increased in severity from bipolar disorder to schizoaffective disorder bipolar type, to schizophrenia and schizoaffective disorder depressive type. Participants with schizophrenia and schizoaffective disorder depressive type showed equivalent performance (d = 0.07, p = 0.90). The results of the ordinal logistic regression were consistent with a spectrum of deficits from bipolar disorder to schizoaffective disorder bipolar type, to schizophrenia/schizoaffective disorder depressive type (odds ratio = 1.98, p < 0.001). In analyses of the associations between symptom dimensions and cognition, higher scores on the psychosis dimension were associated with poorer performance (B = 0.015, standard error = 0.002, p < 0.001). LIMITATIONS: There were fewer participants with schizoaffective disorder and bipolar disorder than schizophrenia. Despite this, our analyses were robust to differences in group sizes, and we were able to detect differences between groups. CONCLUSION: Cognitive impairments represent a symptom dimension that cuts across traditional diagnostic boundaries.

5.
Nat Genet ; 50(3): 381-389, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29483656

RESUMO

Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population.

6.
Int J Epidemiol ; 46(2): 421-428, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-27694570

RESUMO

Background: Children with a diagnosis of attention-deficit hyperactivity disorder ADHD) have lower cognitive ability and are at risk of adverse educational outcomes; ADHD genetic risks have been found to predict childhood cognitive ability and other neurodevelopmental traits in the general population; thus genetic risks might plausibly also contribute to cognitive ability later in development and to educational underachievement. Methods: We generated ADHD polygenic risk scores in the Avon Longitudinal Study of Parents and Children participants (maximum N : 6928 children and 7280 mothers) based on the results of a discovery clinical sample, a genome-wide association study of 727 cases with ADHD diagnosis and 5081 controls. We tested if ADHD polygenic risk scores were associated with educational outcomes and IQ in adolescents and their mothers. Results: High ADHD polygenic scores in adolescents were associated with worse educational outcomes at Key Stage 3 [national tests conducted at age 13-14 years; ß = -1.4 (-2.0 to -0.8), P = 2.3 × 10 -6 ), at General Certificate of Secondary Education exams at age 15-16 years (ß = -4.0 (-6.1 to -1.9), P = 1.8 × 10 -4 ], reduced odds of sitting Key Stage 5 examinations at age 16-18 years [odds ratio (OR) = 0.90 (0.88 to 0.97), P = 0.001] and lower IQ scores at age 15.5 [ß = -0.8 (-1.2 to -0.4), P = 2.4 × 10 -4 ]. Moreover, maternal ADHD polygenic scores were associated with lower maternal educational achievement [ß = -0.09 (-0.10 to -0.06), P = 0.005] and lower maternal IQ [ß = -0.6 (-1.2 to -0.1), P = 0.03]. Conclusions: ADHD diagnosis risk alleles impact on functional outcomes in two generations (mother and child) and likely have intergenerational environmental effects.


Assuntos
Sucesso Acadêmico , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Mães , Herança Multifatorial , Adolescente , Cognição , Feminino , Estudo de Associação Genômica Ampla , Humanos , Testes de Inteligência , Relação entre Gerações , Modelos Lineares , Estudos Longitudinais , Masculino , Análise Multivariada , Países Baixos/epidemiologia , Fenótipo , Fatores de Risco , Índice de Gravidade de Doença
7.
J Psychopharmacol ; 30(5): 436-43, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26905920

RESUMO

RATIONALE: Antipsychotic polypharmacy (APP) is commonly used in schizophrenia despite a lack of robust evidence for efficacy, as well as evidence of increased rates of adverse drug reactions and mortality. OBJECTIVES: We sought to examine APP and the use of other adjunctive medications in patients with treatment-resistant schizophrenic disorders (ICD-10 diagnoses F20-F29) immediately prior to clozapine initiation, and to investigate clinical and sociodemographic factors associated with APP use in this setting. METHODS: Analysis of case notes from 310 patients receiving their first course of clozapine at the South London and Maudsley NHS Trust (SLaM) was undertaken using the Clinical Record Interactive Search (CRIS) case register. Medication taken immediately prior to clozapine initiation was recorded, and global clinical severity was assessed at time points throughout the year prior to medication assessment using the Clinical Global Impression - Severity scale (CGI-S). Logistic regression was used to investigate factors associated with APP. RESULTS: The point prevalence of APP prior to clozapine initiation was 13.6% (n=42), with 32.6% of subjects prescribed adjuvant psychotropic medications. APP was associated with increasing number of adjuvant medications (odds ratio (OR) 1.97, 95% confidence interval (CI) 1.27-3.06), concurrent depot antipsychotic prescription (OR 2.64, CI 1.24-5.62), concurrent antidepressant prescription (OR 4.40, CI 1.82-10.63) and a CGI-S over the previous year within the two middle quartiles (Quartile 2 vs 1 OR 6.19, CI 1.81-21.10; Quartile 3 vs 1 OR 4.45, CI 1.29-15.37; Quartile 4 vs 1 OR 1.88, CI 0.45-7.13). CONCLUSIONS: APP and augmentation of antipsychotics with antidepressants, mood stabilizers and benzodiazepines are being employed in treatment-resistant schizophrenia prior to clozapine. The conservative APP rate observed may have been influenced by an initiative within SLaM that reduced APP rates during the study window. Efforts to reduce the use of poorly evidenced prescribing should focus on adjuvant medications as well as APP.


Assuntos
Antipsicóticos/uso terapêutico , Clozapina/uso terapêutico , Resistência a Medicamentos/efeitos dos fármacos , Esquizofrenia/tratamento farmacológico , Adolescente , Adulto , Idoso , Antidepressivos/uso terapêutico , Benzodiazepinas/uso terapêutico , Estudos de Coortes , Quimioterapia Combinada/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimedicação , Psicotrópicos/uso terapêutico , Adulto Jovem
8.
J Am Acad Child Adolesc Psychiatry ; 54(4): 322-7, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25791149

RESUMO

OBJECTIVE: Twin studies and genome-wide complex trait analysis (GCTA) are not in agreement regarding heritability estimates for behavioral traits in children from the general population. This has sparked a debate on the possible difference in genetic architecture between behavioral traits and psychiatric disorders. In this study, we test whether polygenic risk scores associated with variation in attention-deficit/hyperactivity disorder (ADHD) trait levels in children from the general population predict ADHD diagnostic status and severity in an independent clinical sample. METHOD: Single nucleotide polymorphisms (SNPs) with p < .5 from a genome-wide association study of ADHD traits in 4,546 children (mean age, 7 years 7 months) from the Avon Longitudinal Study of Parents and Children (ALSPAC; general population sample) were selected to calculate polygenic risk scores in 508 children with an ADHD diagnosis (independent clinical sample) and 5,081 control participants. Polygenic scores were tested for association with case-control status and severity of disorder in the clinical sample. RESULTS: Increased polygenic score for ADHD traits predicted ADHD case-control status (odds ratio = 1.17 [95% CI = 1.08-1.28], p = .0003), higher ADHD symptom severity (ß = 0.29 [95% CI = 0.04-0.54], p = 0.02), and symptom domain severity in the clinical sample. CONCLUSION: This study highlights the relevance of additive genetic variance in ADHD, and provides evidence that shared genetic factors contribute to both behavioral traits in the general population and psychiatric disorders at least in the case of ADHD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Adolescente , Estudos de Casos e Controles , Criança , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Estudos Longitudinais , Masculino , Índice de Gravidade de Doença , Reino Unido
9.
J Child Psychol Psychiatry ; 56(6): 648-56, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25280069

RESUMO

BACKGROUND: The genetic architecture of ADHD is complex, with rare and common variants involved. Common genetic variants (as indexed by a composite risk score) associated with clinical ADHD significantly predict ADHD and autistic-like behavioural traits in children from the general population, suggesting that ADHD lies at the extreme of normal trait variation. ADHD and other neurodevelopmental disorders share neurocognitive difficulties in several domains (e.g. impaired cognitive ability and executive functions). We hypothesised that ADHD composite genetic risk scores derived from clinical ADHD cases would also contribute to variation in neurocognitive abilities in the general population. METHODS: Children (N = 6,832) from a UK population cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC), underwent neurocognitive testing. Parent-reported measures of their children's ADHD and autistic-like traits were used to construct a behavioural latent variable of 'neurodevelopmental traits'. Composite genetic risk scores for ADHD were calculated for ALSPAC children based on findings from an independent ADHD case-control genome-wide association study. Structural equation modelling was used to assess associations between ADHD composite genetic risk scores and IQ, working memory, inhibitory control and facial emotion recognition, as well as the latent 'neurodevelopmental trait' measure. RESULTS: The results confirmed that neurocognitive and neurodevelopmental traits are correlated in children in the general population. Composite genetic risk scores for ADHD were independently associated with lower IQ (ß = -.05, p < .001) and working memory performance (ß = -.034, p = .013), even after accounting for the relationship with latent neurodevelopmental behavioural trait scores. No associations were found between composite genetic risk scores and inhibitory control or emotion recognition (p > .05). CONCLUSIONS: These findings suggest that common genetic variants relevant to clinically diagnosed ADHD have pleiotropic effects on neurocognitive traits as well as behavioural dimensions in the general population. This further suggests that the well-recognised association between cognition and neurodevelopmental behavioural traits is underpinned at a biological level.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Inteligência/fisiologia , Memória de Curto Prazo/fisiologia , Habilidades Sociais , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Risco , Reino Unido/epidemiologia
10.
J Am Acad Child Adolesc Psychiatry ; 53(7): 761-70.e26, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24954825

RESUMO

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) often co-occur and share genetic risks. The aim of this analysis was to determine more broadly whether ADHD and ASD share biological underpinnings. METHOD: We compared copy number variant (CNV) data from 727 children with ADHD and 5,081 population controls to data from 996 individuals with ASD and an independent set of 1,287 controls. Using pathway analyses, we investigated whether CNVs observed in individuals with ADHD have an impact on genes in the same biological pathways as on those observed in individuals with ASD. RESULTS: The results suggest that the biological pathways affected by CNVs in ADHD overlap with those affected by CNVs in ASD more than would be expected by chance. Moreover, this was true even when specific CNV regions common to both disorders were excluded from the analysis. After correction for multiple testing, genes involved in 3 biological processes (nicotinic acetylcholine receptor signalling pathway, cell division, and response to drug) showed significant enrichment for case CNV hits in the combined ADHD and ASD sample. CONCLUSION: The results of this study indicate the presence of significant overlap of shared biological processes disrupted by large rare CNVs in children with these 2 neurodevelopmental conditions.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtornos Globais do Desenvolvimento Infantil/genética , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Criança , Transtornos Globais do Desenvolvimento Infantil/epidemiologia , Pré-Escolar , Comorbidade , Variações do Número de Cópias de DNA , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Reino Unido/epidemiologia
11.
Biol Psychiatry ; 76(8): 664-71, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-24673882

RESUMO

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) can be viewed as the extreme end of traits in the general population. Epidemiological and twin studies suggest that ADHD frequently co-occurs with and shares genetic susceptibility with autism spectrum disorder (ASD) and ASD-related traits. The aims of this study were to determine whether a composite of common molecular genetic variants, previously found to be associated with clinically diagnosed ADHD, predicts ADHD and ASD-related traits in the general population. METHODS: Polygenic risk scores were calculated in the Avon Longitudinal Study of Parents and Children (ALSPAC) population sample (N = 8229) based on a discovery case-control genome-wide association study of childhood ADHD. Regression analyses were used to assess whether polygenic scores predicted ADHD traits and ASD-related measures (pragmatic language abilities and social cognition) in the ALSPAC sample. Polygenic scores were also compared in boys and girls endorsing any (rating ≥ 1) ADHD item (n = 3623). RESULTS: Polygenic risk for ADHD showed a positive association with ADHD traits (hyperactive-impulsive, p = .0039; inattentive, p = .037). Polygenic risk for ADHD was also negatively associated with pragmatic language abilities (p = .037) but not with social cognition (p = .43). In children with a rating ≥ 1 for ADHD traits, girls had a higher polygenic score than boys (p = .003). CONCLUSIONS: These findings provide molecular genetic evidence that risk alleles for the categorical disorder of ADHD influence hyperactive-impulsive and attentional traits in the general population. The results further suggest that common genetic variation that contributes to ADHD diagnosis may also influence ASD-related traits, which at their extreme are a characteristic feature of ASD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Predisposição Genética para Doença , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Criança , Transtornos Globais do Desenvolvimento Infantil/epidemiologia , Transtornos Globais do Desenvolvimento Infantil/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Estudos Longitudinais , Masculino , Fenótipo , Escalas de Graduação Psiquiátrica , Fatores de Risco
12.
J Autism Dev Disord ; 44(1): 204-15, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23748436

RESUMO

Attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) often co-occur. Factor analyses of ASD traits in children with and without ASD indicate the presence of social and restrictive-repetitive behaviour (RRB) factors. This study used exploratory factor analyses to determine the structure of ASD traits (assessed using the Social Communication Questionnaire) in children with ADHD. Distinct factors were observed for 'social' and 'rigidity' traits, corresponding to previous factor analyses in clinical ASD and population samples. This indicates that the split between social-communicative and RRB dimensions is unaffected by ADHD in children. Moreover, the study also finds that there is some overlap across hyperactive-impulsive symptoms and RRB traits in children with ADHD, which merits further investigation.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno Autístico/complicações , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Transtorno Autístico/diagnóstico , Transtorno Autístico/psicologia , Criança , Pré-Escolar , Comunicação , Feminino , Humanos , Masculino , Fenótipo , Inquéritos e Questionários
13.
Nat Genet ; 45(10): 1150-9, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23974872

RESUMO

Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Esquizofrenia/genética , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Suécia
14.
Br J Psychiatry ; 203(2): 107-11, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23703318

RESUMO

BACKGROUND: There is recent evidence of some degree of shared genetic susceptibility between adult schizophrenia and childhood attention-deficit hyperactivity disorder (ADHD) for rare chromosomal variants. AIMS: To determine whether there is overlap between common alleles conferring risk of schizophrenia in adults with those that do so for ADHD in children. METHOD: We used recently published Psychiatric Genome-wide Association Study (GWAS) Consortium (PGC) adult schizophrenia data to define alleles over-represented in people with schizophrenia and tested whether those alleles were more common in 727 children with ADHD than in 2067 controls. RESULTS: Schizophrenia risk alleles discriminated ADHD cases from controls (P = 1.04 × 10(-4), R(2) = 0.45%); stronger discrimination was given by alleles that were risk alleles for both adult schizophrenia and adult bipolar disorder (also derived from a PGC data-set) (P = 9.98 × 10(-6), R(2) = 0.59%). CONCLUSIONS: This increasing evidence for a small, but significant, shared genetic susceptibility between adult schizophrenia and childhood ADHD highlights the importance of research work across traditional diagnostic boundaries.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Esquizofrenia/genética , Adolescente , Adulto , Alelos , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Herança Multifatorial , Polimorfismo de Nucleotídeo Único
15.
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
16.
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
17.
Nat Genet ; 43(5): 429-35, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21460840

RESUMO

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Doença de Alzheimer/genética , Antígenos CD/genética , Antígenos de Diferenciação Mielomonocítica/genética , Proteínas do Citoesqueleto/genética , Proteínas de Membrana/genética , Receptor EphA1/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Bases de Dados Genéticas , Feminino , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Família Multigênica , Polimorfismo de Nucleotídeo Único , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico
18.
Am J Med Genet B Neuropsychiatr Genet ; 156B(3): 370-8, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21305692

RESUMO

Genome-wide association studies (GWAS) have identified several susceptibility loci for bipolar disorder (BP), most notably ANK3. However, most of the inherited risk for BP remains unexplained. One reason for the limited success may be the genetic heterogeneity of BP. Clinical sub-phenotypes of BP may identify more etiologically homogeneous subsets of patients, which can be studied with increased power to detect genetic variation. Here, we report on a mega-analysis of two widely studied sub-phenotypes of BP, age at onset and psychotic symptoms, which are familial and clinically significant. We combined data from three GWAS: NIMH Bipolar Disorder Genetic Association Information Network (GAIN-BP), NIMH Bipolar Disorder Genome Study (BiGS), and a German sample. The combined sample consisted of 2,836 BP cases with information on sub-phenotypes and 2,744 controls. Imputation was performed, resulting in 2.3 million SNPs available for analysis. No SNP reached genome-wide significance for either sub-phenotype. In addition, no SNP reached genome-wide significance in a meta-analysis with an independent replication sample. We had 80% power to detect associations with a common SNP at an OR of 1.6 for psychotic symptoms and a mean difference of 1.8 years in age at onset. Age at onset and psychotic symptoms in BP may be influenced by many genes of smaller effect sizes or other variants not measured well by SNP arrays, such as rare alleles.


Assuntos
Transtorno Bipolar/epidemiologia , Transtorno Bipolar/genética , Estudo de Associação Genômica Ampla , Transtornos Psicóticos/epidemiologia , Transtornos Psicóticos/genética , Idade de Início , Transtorno Bipolar/complicações , Demografia , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Transtornos Psicóticos/complicações , Adulto Jovem
19.
Biol Psychiatry ; 69(5): 472-8, 2011 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-20832056

RESUMO

BACKGROUND: Genome-wide association studies have detected a small number of weak but strongly supported schizophrenia risk alleles. Moreover, a substantial polygenic component to the disorder consisting of a large number of such alleles has been reported by the International Schizophrenia Consortium. METHOD: We report a Japanese genome-wide association study of schizophrenia comprising 575 cases and 564 controls. We attempted to replicate 97 markers, representing a nonredundant panel of markers derived mainly from the top 150 findings, in up to three data sets totaling 1990 cases and 5389 controls. We then attempted to replicate the observation of a polygenic component to the disorder in the Japanese and to determine whether this overlaps that seen in UK populations. RESULTS: Single-locus analysis did not reveal genome-wide support for any locus in the genome-wide association study sample (best p = 6.2 × 10(-6)) or in the complete data set in which the best supported locus was SULT6B1 (rs11895771: p = 3.7 × 10(-5) in the meta-analysis). Of loci previously supported by genome-wide association studies, we obtained in the Japanese support for NOTCH4 (rs2071287: p(meta) = 5.1 × 10(-5)). Using the approach reported by the International Schizophrenia Consortium, we replicated the observation of a polygenic component to schizophrenia within the Japanese population (p = .005). Our trans Japan-UK analysis of schizophrenia also revealed a significant correlation (best p = 7.0 × 10(-5)) in the polygenic component across populations. CONCLUSIONS: These results indicate a shared polygenic risk of schizophrenia between Japanese and Caucasian samples, although we did not detect unequivocal evidence for a novel susceptibility gene for schizophrenia.


Assuntos
Estudo de Associação Genômica Ampla , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático , Feminino , Seguimentos , Frequência do Gene , Marcadores Genéticos , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Controle de Qualidade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Reino Unido/epidemiologia
20.
Hum Mol Genet ; 20(2): 387-91, 2011 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-21037240

RESUMO

Recent findings from genetic epidemiology and from genome-wide association studies point strongly to a partial overlap in the genes that contribute susceptibility to schizophrenia and bipolar disorder (BD). Previous data have also directly implicated one of the best supported schizophrenia-associated loci, zinc finger binding protein 804A (ZNF804A), as showing trans-disorder effects, and the same is true for one of the best supported bipolar loci, calcium channel, voltage-dependent, L type, alpha 1C subunit (CACNA1C) which has also been associated with schizophrenia. We have undertaken a cross-phenotype study based upon the remaining variants that show genome-wide evidence for association in large schizophrenia and BD meta-analyses. These comprise in schizophrenia, SNPs in or in the vicinity of transcription factor 4 (TCF4), neurogranin (NRGN) and an extended region covering the MHC locus on chromosome 6. For BD, the strongly supported variants are in the vicinity of ankyrin 3, node of Ranvier (ANK3) and polybromo-1 (PBRM1). Using data sets entirely independent of their original discoveries, we observed strong evidence that the PBRM1 locus is also associated with schizophrenia (P = 0.00015) and nominally significant evidence (P < 0.05) that the NRGN and the extended MHC region are associated with BD. Moreover, considering this highly restricted set of loci as a group, the evidence for trans-disorder effects is compelling (P = 4.7 × 10(-5)). Including earlier reported data for trans-disorder effects for ZNF804A and CACNA1C, six out of eight of the most robustly associated loci for either disorder show trans-disorder effects.


Assuntos
Transtorno Bipolar/diagnóstico , Transtorno Bipolar/genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Esquizofrenia/diagnóstico , Esquizofrenia/genética , Anquirinas/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Humanos , Complexo Principal de Histocompatibilidade/genética , Neurogranina/genética , Proteínas Nucleares/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Fator de Transcrição 4 , Fatores de Transcrição/genética
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