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1.
JAMA Psychiatry ; 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31596458

RESUMO

Importance: The Consortium on the Genetics of Schizophrenia (COGS) uses quantitative neurophysiological and neurocognitive endophenotypes with demonstrated deficits in schizophrenia as a platform from which to explore the underlying neural circuitry and genetic architecture. Many of these endophenotypes are associated with poor functional outcome in schizophrenia. Some are also endorsed as potential treatment targets by the US Food and Drug Administration. Objective: To build on prior assessments of heritability, association, and linkage in the COGS phase 1 (COGS-1) families by reporting a genome-wide association study (GWAS) of 11 schizophrenia-related endophenotypes in the independent phase 2 (COGS-2) cohort of patients with schizophrenia and healthy comparison participants (HCPs). Design, Setting, and Participants: A total of 1789 patients with schizophrenia and HCPs of self-reported European or Latino ancestry were recruited through a collaborative effort across the COGS sites and genotyped using the PsychChip. Standard quality control filters were applied, and more than 6.2 million variants with a genotyping call rate of greater than 0.99 were available after imputation. Association was performed for data sets stratified by diagnosis and ancestry using linear regression and adjusting for age, sex, and 5 principal components, with results combined through weighted meta-analysis. Data for COGS-1 were collected from January 6, 2003, to August 6, 2008; data for COGS-2, from June 30, 2010, to February 14, 2014. Data were analyzed from October 28, 2016, to May 4, 2018. Main Outcomes and Measures: A genome-wide association study was performed to evaluate association for 11 neurophysiological and neurocognitive endophenotypes targeting key domains of schizophrenia related to inhibition, attention, vigilance, learning, working memory, executive function, episodic memory, and social cognition. Results: The final sample of 1533 participants included 861 male participants (56.2%), and the mean (SD) age was 41.8 (13.6) years. In total, 7 genome-wide significant regions (P < 5 × 10-8) and 2 nearly significant regions (P < 9 × 10-8) containing several genes of interest, including NRG3 and HCN1, were identified for 7 endophenotypes. For each of the 11 endophenotypes, enrichment analyses performed at the level of P < 10-4 compared favorably with previous association results in the COGS-1 families and showed extensive overlap with regions identified for schizophrenia diagnosis. Conclusions and Relevance: These analyses identified several genomic regions of interest that require further exploration and validation. These data seem to demonstrate the utility of endophenotypes for resolving the genetic architecture of schizophrenia and characterizing the underlying biological dysfunctions. Understanding the molecular basis of these endophenotypes may help to identify novel treatment targets and pave the way for precision-based medicine in schizophrenia and related psychotic disorders.

2.
Mol Psychiatry ; 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492941

RESUMO

Based on the discovery by the Resilience Project (Chen R. et al. Nat Biotechnol 34:531-538, 2016) of rare variants that confer resistance to Mendelian disease, and protective alleles for some complex diseases, we posited the existence of genetic variants that promote resilience to highly heritable polygenic disorders1,0 such as schizophrenia. Resilience has been traditionally viewed as a psychological construct, although our use of the term resilience refers to a different construct that directly relates to the Resilience Project, namely: heritable variation that promotes resistance to disease by reducing the penetrance of risk loci, wherein resilience and risk loci operate orthogonal to one another. In this study, we established a procedure to identify unaffected individuals with relatively high polygenic risk for schizophrenia, and contrasted them with risk-matched schizophrenia cases to generate the first known "polygenic resilience score" that represents the additive contributions to SZ resistance by variants that are distinct from risk loci. The resilience score was derived from data compiled by the Psychiatric Genomics Consortium, and replicated in three independent samples. This work establishes a generalizable framework for finding resilience variants for any complex, heritable disorder.

3.
Artigo em Inglês | MEDLINE | ID: mdl-30503783

RESUMO

Genome-wide association studies of case-control status have advanced the understanding of the genetic basis of psychiatric disorders. Further progress may be gained by increasing sample size but also by new analysis strategies that advance the exploitation of existing data, especially for clinically important quantitative phenotypes. The functionally-informed efficient region-based test strategy (FIERS) introduced herein uses prior knowledge on biological function and dependence of genotypes within a powerful statistical framework with improved sensitivity and specificity for detecting consistent genetic effects across studies. As proof of concept, FIERS was used for the first genome-wide single nucleotide polymorphism (SNP)-based investigation on bipolar disorder (BD) that focuses on an important aspect of disease course, the functional outcome. FIERS identified a significantly associated locus on chromosome 15 (hg38: chr15:48965004 - 49464789 bp) with consistent effect strength between two independent studies (GAIN/TGen: European Americans, BOMA: Germans; n = 1592 BD patients in total). Protective and risk haplotypes were found on the most strongly associated SNPs. They contain a CTCF binding site (rs586758); CTCF sites are known to regulate sets of genes within a chromatin domain. The rs586758 - rs2086256 - rs1904317 haplotype is located in the promoter flanking region of the COPS2 gene, close to microRNA4716, and the EID1, SHC4, DTWD1 genes as plausible biological candidates. While implication with BD is novel, COPS2, EID1, and SHC4 are known to be relevant for neuronal differentiation and function and DTWD1 for psychopharmacological side effects. The test strategy FIERS that enabled this discovery is equally applicable for tag SNPs and sequence data.

4.
J Am Coll Health ; : 1-5, 2018 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-29601286

RESUMO

OBJECTIVE: To evaluate the demographics and clinical utilization patterns among college students during the initial 12 months of a novel, multi-disciplinary, collaborative, college mental health program (CMHP). PARTICIPANTS: Undergraduate and graduate students receiving treatment at the CMHP from Jan-Dec 2015. METHODS: De-identified data was obtained via electronic health records for all students receiving care through the CMHP. RESULTS: 1.2 FTE clinical providers treated 278 undergraduate and graduate students during the year (65.1% < age 26, 53.6% female, 49.6% caucasian). There were 1822 CMHP outpatient visits, 318 other medical visits and 103 total emergency room (ER)/inpatient visits. Ten students were identified as high utilizers of ER/inpatient services, while charges to the CMHP totaled $470,157 and total charges to the Health System were $2,378,315. CONCLUSIONS: Students with complex psychiatric/medical co-morbidities received cost effective, convenient and integrative treatment. Over time, we hope to intervene earlier and decrease ER/inpatient visits.

5.
J Huntingtons Dis ; 7(1): 51-59, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29480208

RESUMO

BACKGROUND: Psychotic symptoms of delusions and hallucinations occur in about 5% of persons with Huntington's disease (HD). The mechanisms underlying these occurrences are unknown, but the same symptoms also occur in schizophrenia, and thus genetic risk factors for schizophrenia may be relevant to the development of psychosis in HD. OBJECTIVE: To investigate the possible role of genes associated with schizophrenia in the occurrence of psychotic symptoms in HD. METHODS: DNA from subjects with HD and psychosis (HD+P; n = 47), subjects with HD and no psychosis (HD-P; n = 126), and controls (CTLs; n = 207) was genotyped using the Infinium PsychArray-24 v1.1 BeadChip. The allele frequencies of single-nucleotide polymorphisms (SNPs) that were previously associated with schizophrenia and related psychiatric disorders were compared between these groups. RESULTS: Of the 30 candidate genes tested, 10 showed an association with psychosis in HD. The majority of these genes, including CTNNA2, DRD2, ERBB4, GRID2, GRIK4, GRM1, NRG1, PCNT, RELN, and SLC1A2, demonstrate network interactions related to glutamate signaling. CONCLUSIONS: This study suggests genetic associations between several previously identified candidate genes for schizophrenia and the occurrence of psychotic symptoms in HD. These data support the potential role of genes related to glutamate signaling in HD psychosis.

6.
Schizophr Res ; 198: 6-15, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28549722

RESUMO

BACKGROUND: The Consortium on the Genetics of Schizophrenia (COGS) collected case-control endophenotype and genetic information from 2457 patients and healthy subjects (HS) across 5 test sites over 3.5 years. Analysis of the first "wave" (W1) of 1400 subjects identified prepulse inhibition (PPI) deficits in patients vs. HS. Data from the second COGS "wave" (W2), and the combined W(1+2), were used to assess: 1) the replicability of PPI deficits in this design; 2) the impact of response criteria on PPI deficits; and 3) PPI in a large cohort of antipsychotic-free patients. METHODS: PPI in W2 HS (n=315) and schizophrenia patients (n=326) was compared to findings from W1; planned analyses assessed the impact of diagnosis, "wave" (1 vs. 2), and startle magnitude criteria. Combining waves allowed us to assess PPI in 120 antipsychotic-free patients, including many in the early course of illness. RESULTS: ANOVA of all W(1+2) subjects revealed robust PPI deficits in patients across "waves" (p<0.0004). Strict response criteria excluded almost 39% of all subjects, disproportionately impacting specific subgroups; ANOVA in this smaller cohort confirmed no significant effect of "wave" or "wave x diagnosis" interaction, and a significant effect of diagnosis (p<0.002). Antipsychotic-free, early-illness patients had particularly robust PPI deficits. DISCUSSION: Schizophrenia-linked PPI deficits were replicable across two multi-site "waves" of subjects collected over 3.5years. Strict response criteria disproportionately excluded older, male, non-Caucasian patients with low-normal hearing acuity. These findings set the stage for genetic analyses of PPI using the combined COGS wave 1 and 2 cohorts.

7.
Mol Neuropsychiatry ; 2(4): 198-212, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28277566

RESUMO

Bipolar disorder is a severe, lifelong mood disorder for which little is currently understood of the genetic mechanisms underlying risk. By examining related dimensional phenotypes, we may further our understanding of the disorder. Creativity has a historical connection with the bipolar spectrum and is particularly enhanced among unaffected first-degree relatives and those with bipolar spectrum traits. This suggests that some aspects of the bipolar spectrum may confer advantages, while more severe expressions of symptoms negatively influence creative accomplishment. Creativity is a complex, multidimensional construct with both cognitive and affective components, many of which appear to reflect a shared genetic vulnerability with bipolar disorder. It is suggested that a subset of bipolar risk variants confer advantages as positive traits according to an inverted-U-shaped curve with clinically unaffected allele carriers benefitting from the positive traits and serving to maintain the risk alleles in the population. The association of risk genes with creativity in healthy individuals (e.g., NRG1), as well as an overall sharing of common genetic variation between bipolar patients and creative individuals, provides support for this model. Current findings are summarized from a multidisciplinary perspective to demonstrate the feasibility of research in this area to reveal the mechanisms underlying illness.

8.
Sci Rep ; 7: 43629, 2017 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-28240740

RESUMO

Deficits in GABAergic inhibitory neurotransmission are a reliable finding in schizophrenia (SCZ) patients. Previous studies have reported that unaffected first-degree relatives of patients with SCZ demonstrate neurophysiological abnormalities that are intermediate between probands and healthy controls. In this study, first-degree relatives of patients with SCZ and their related probands were investigated to assess frontal cortical inhibition. Long-interval cortical inhibition (LICI) was measured from the dorsolateral prefrontal cortex (DLPFC) using combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG). The study presents an extended sample of 129 subjects (66 subjects have been previously reported): 19 patients with SCZ or schizoaffective disorder, 30 unaffected first-degree relatives of these SCZ patients, 13 obsessive-compulsive disorder (OCD) patients, 18 unaffected first-degree relatives of these OCD patients and 49 healthy subjects. In the DLPFC, cortical inhibition was significantly decreased in patients with SCZ compared to healthy subjects. First-degree relatives of patients with SCZ showed significantly more cortical inhibition than their SCZ probands. No differences were demonstrated between first-degree relatives of SCZ patients and healthy subjects. Taken together, these findings show that more studies are needed to establish an objective biological marker for potential diagnostic usage in severe psychiatric disorders.


Assuntos
Córtex Cerebral/fisiopatologia , Família , Inibição Neural , Esquizofrenia/fisiopatologia , Adulto , Estudos de Casos e Controles , Córtex Cerebral/metabolismo , Eletroencefalografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtorno Obsessivo-Compulsivo/diagnóstico , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Transtorno Obsessivo-Compulsivo/metabolismo , Transtorno Obsessivo-Compulsivo/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Esquizofrenia/diagnóstico , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Estimulação Magnética Transcraniana
9.
J Affect Disord ; 207: 282-290, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27741464

RESUMO

BACKGROUND: Temperament and personality traits have been suggested as endophenotypes for bipolar disorder based on several lines of evidence, including heritability. Previous work suggested an anxious-reactive factor identified across temperament and personality inventories that produced significant group discrimination and could potentially be useful in genetic analyses. We have attempted to further characterize this factor structure in a sample of bipolar patients. METHODS: A sample of 1195 subjects with bipolar I disorder was evaluated, all with complete data available. Dimension reduction across two inventories identified 18 factors explaining 39% of the variance. RESULTS: The two largest factors reflected affective instability and general anxiety/worry, respectively. Subsequent analyses of the clinical features associated with bipolar disorder revealed specificity for the factors in a predictable pattern. Cluster analysis of the factors identified a subgroup defined by a strong lack of general anxiety and low affective instability represented by the first two factors. The remaining subjects could be distinguished into two clusters by the presence of either more positive characteristics, including persistence/drive, spirituality, expressivity, and humor, or more negative characteristics of depression and anxiety. LIMITATIONS: These analyses involved bipolar I subjects only and must be extended to other bipolar spectrum diagnoses, unaffected relatives, and individuals at risk. CONCLUSIONS: These results suggest that temperament and personality measures access latent traits associated with important clinical features of bipolar disorder. By translating clinical variables into quantitative traits, we may identify subgroups of bipolar patients with distinct clinical profiles, thereby facilitating both individual treatment strategies and genetic analyses.


Assuntos
Transtorno Bipolar/psicologia , Escalas de Graduação Psiquiátrica , Temperamento , Transtorno Bipolar/diagnóstico , Análise por Conglomerados , Análise Fatorial , Feminino , Humanos , Masculino , Fenótipo
10.
JAMA Psychiatry ; 74(1): 37-46, 2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-27926742

RESUMO

Importance: Neurophysiologic measures of early auditory information processing (EAP) are used as endophenotypes in genomic studies and biomarkers in clinical intervention studies. Research in schizophrenia has established correlations among measures of EAP, cognition, clinical symptoms, and functional outcome. Clarifying these associations by determining the pathways through which deficits in EAP affect functioning would suggest when and where to therapeutically intervene. Objectives: To characterize the pathways from EAP to outcome and to estimate the extent to which enhancement of basic information processing might improve cognition and psychosocial functioning in schizophrenia. Design, Setting, and Participants: Cross-sectional data were analyzed using structural equation modeling to examine the associations among EAP, cognition, negative symptoms, and functional outcome. Participants were recruited from the community at 5 geographically distributed laboratories as part of the Consortium on the Genetics of Schizophrenia 2 from July 1, 2010, through January 31, 2014. This well-characterized cohort of 1415 patients with schizophrenia underwent EAP, cognitive, and thorough clinical and functional assessment. Main Outcome and Measures: Mismatch negativity, P3a, and reorienting negativity were used to measure EAP. Cognition was measured by the Letter Number Span test and scales from the California Verbal Learning Test-Second Edition, the Wechsler Memory Scale-Third Edition, and the Penn Computerized Neurocognitive Battery. Negative symptoms were measured by the Scale for the Assessment of Negative Symptoms. Functional outcome was measured by the Role Functioning Scale. Results: Participants included 1415 unrelated outpatients diagnosed with schizophrenia or schizoaffective disorder (mean [SD] age, 46 [11] years; 979 males [69.2%] and 619 white [43.7%]). Early auditory information processing had a direct effect on cognition (ß = 0.37, P < .001), cognition had a direct effect on negative symptoms (ß = -0.16, P < .001), and both cognition (ß = 0.26, P < .001) and experiential negative symptoms (ß = -0.75, P < .001) had direct effects on functional outcome. The indirect effect of EAP on functional outcome was significant as well (ß = 0.14, P < .001). Overall, EAP had a fully mediated effect on functional outcome, engaging general rather than modality-specific cognition, with separate pathways that involved or bypassed negative symptoms. Conclusions and Relevance: The data support a model in which EAP deficits lead to poor functional outcome via impaired cognition and increased negative symptoms. Results can be used to help guide mechanistically informed, personalized treatments and support the strategy of using EAP measures as surrogate end points in early-stage procognitive intervention studies.


Assuntos
Transtornos da Percepção Auditiva/diagnóstico , Transtornos da Percepção Auditiva/psicologia , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/psicologia , Modelos Psicológicos , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/psicologia , Esquizofrenia/diagnóstico , Psicologia do Esquizofrênico , Transtornos do Comportamento Social/diagnóstico , Transtornos do Comportamento Social/psicologia , Adulto , Transtornos da Percepção Auditiva/fisiopatologia , Transtornos Cognitivos/fisiopatologia , Variação Contingente Negativa/fisiologia , Estudos Transversais , Avaliação da Deficiência , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Transtornos Psicóticos/fisiopatologia , Transtornos do Comportamento Social/fisiopatologia
11.
Schizophr Res ; 174(1-3): 1-9, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27132484

RESUMO

Past studies describe numerous endophenotypes associated with schizophrenia (SZ), but many endophenotypes may overlap in information they provide, and few studies have investigated the utility of a multivariate index to improve discrimination between SZ and healthy community comparison subjects (CCS). We investigated 16 endophenotypes from the first phase of the Consortium on the Genetics of Schizophrenia, a large, multi-site family study, to determine whether a subset could distinguish SZ probands and CCS just as well as using all 16. Participants included 345 SZ probands and 517 CCS with a valid measure for at least one endophenotype. We used both logistic regression and random forest models to choose a subset of endophenotypes, adjusting for age, gender, smoking status, site, parent education, and the reading subtest of the Wide Range Achievement Test. As a sensitivity analysis, we re-fit models using multiple imputations to determine the effect of missing values. We identified four important endophenotypes: antisaccade, Continuous Performance Test-Identical Pairs 3-digit version, California Verbal Learning Test, and emotion identification. The logistic regression model that used just these four endophenotypes produced essentially the same results as the model that used all 16 (84% vs. 85% accuracy). While a subset of endophenotypes cannot replace clinical diagnosis nor encompass the complexity of the disease, it can aid in the design of future endophenotypic and genetic studies by reducing study cost and subject burden, simplifying sample enrichment, and improving the statistical power of locating those genetic regions associated with schizophrenia that may be the easiest to identify initially.


Assuntos
Endofenótipos , Esquizofrenia/genética , Psicologia do Esquizofrênico , Adolescente , Adulto , Idoso , Família , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Testes Neuropsicológicos , Curva ROC , Esquizofrenia/classificação , Adulto Jovem
12.
J Affect Disord ; 189: 141-9, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26433762

RESUMO

BACKGROUND: Bipolar disorder is a heterogeneous mood disorder associated with several important clinical comorbidities, such as eating disorders. This clinical heterogeneity complicates the identification of genetic variants contributing to bipolar susceptibility. Here we investigate comorbidity of eating disorders as a subphenotype of bipolar disorder to identify genetic variation that is common and unique to both disorders. METHODS: We performed a genome-wide association analysis contrasting 184 bipolar subjects with eating disorder comorbidity against both 1370 controls and 2006 subjects with bipolar disorder only from the Bipolar Genome Study (BiGS). RESULTS: The most significant genome-wide finding was observed bipolar with comorbid eating disorder vs. controls within SOX2-OT (p=8.9×10(-8) for rs4854912) with a secondary peak in the adjacent FXR1 gene (p=1.2×10(-6) for rs1805576) on chromosome 3q26.33. This region was also the most prominent finding in the case-only analysis (p=3.5×10(-7) and 4.3×10(-6), respectively). Several regions of interest containing genes involved in neurodevelopment and neuroprotection processes were also identified. LIMITATIONS: While our primary finding did not quite reach genome-wide significance, likely due to the relatively limited sample size, these results can be viewed as a replication of a recent study of eating disorders in a large cohort. CONCLUSIONS: These findings replicate the prior association of SOX2-OT with eating disorders and broadly support the involvement of neurodevelopmental/neuroprotective mechanisms in the pathophysiology of both disorders. They further suggest that different clinical manifestations of bipolar disorder may reflect differential genetic contributions and argue for the utility of clinical subphenotypes in identifying additional molecular pathways leading to illness.


Assuntos
Transtorno Bipolar/epidemiologia , Transtorno Bipolar/genética , Cromossomos Humanos Par 3/genética , Transtornos da Alimentação e da Ingestão de Alimentos/epidemiologia , Transtornos da Alimentação e da Ingestão de Alimentos/genética , Estudo de Associação Genômica Ampla , Adulto , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
13.
Am J Psychiatry ; 173(4): 385-91, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-26441157

RESUMO

OBJECTIVE: The Consortium on the Genetics of Schizophrenia Family Study evaluated 12 primary and other supplementary neurocognitive and neurophysiological endophenotypes in schizophrenia probands and their families. Previous analyses of prepulse inhibition (PPI) and P50 gating measures in this sample revealed heritability estimates that were lower than expected based on earlier family studies. Here the authors investigated whether gating measures were more heritable in multiply affected families with a positive family history compared with families with only a single affected proband (singleton). METHOD: A total of 296 nuclear families consisting of a schizophrenia proband, at least one unaffected sibling, and both parents underwent a comprehensive endophenotype and clinical characterization. The Family Interview for Genetic Studies was administered to all participants and used to obtain convergent psychiatric symptom information for additional first-degree relatives. Among the families, 97 were multiply affected, and 96 were singletons. RESULTS: Both PPI and P50 gating displayed substantially increased heritability in the 97 multiply affected families (47% and 36%, respectively) compared with estimates derived from the entire sample of 296 families (29% and 20%, respectively). However, no evidence for heritability was observed for either measure in the 96 singleton families. Schizophrenia probands derived from the multiply affected families also displayed a significantly increased severity of clinical symptoms compared with those from singleton families. CONCLUSIONS: PPI and P50 gating measures demonstrate substantially increased heritability in schizophrenia families with a higher genetic vulnerability for illness, providing further support for the commonality of genes underlying both schizophrenia and gating measures.


Assuntos
Encéfalo/fisiopatologia , Endofenótipos , Potenciais Evocados/genética , Família , Inibição Pré-Pulso/genética , Esquizofrenia/genética , Psicologia do Esquizofrênico , Adolescente , Adulto , Idoso , Eletroencefalografia , Potenciais Evocados/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pais , Esquizofrenia/fisiopatologia , Índice de Gravidade de Doença , Irmãos , Adulto Jovem
14.
Schizophr Res ; 170(1): 30-40, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26597662

RESUMO

The Consortium on the Genetics of Schizophrenia Family Study (COGS-1) has previously reported our efforts to characterize the genetic architecture of 12 primary endophenotypes for schizophrenia. We now report the characterization of 13 additional measures derived from the same endophenotype test paradigms in the COGS-1 families. Nine of the measures were found to discriminate between schizophrenia patients and controls, were significantly heritable (31 to 62%), and were sufficiently independent of previously assessed endophenotypes, demonstrating utility as additional endophenotypes. Genotyping via a custom array of 1536 SNPs from 94 candidate genes identified associations for CTNNA2, ERBB4, GRID1, GRID2, GRIK3, GRIK4, GRIN2B, NOS1AP, NRG1, and RELN across multiple endophenotypes. An experiment-wide p value of 0.003 suggested that the associations across all SNPs and endophenotypes collectively exceeded chance. Linkage analyses performed using a genome-wide SNP array further identified significant or suggestive linkage for six of the candidate endophenotypes, with several genes of interest located beneath the linkage peaks (e.g., CSMD1, DISC1, DLGAP2, GRIK2, GRIN3A, and SLC6A3). While the partial convergence of the association and linkage likely reflects differences in density of gene coverage provided by the distinct genotyping platforms, it is also likely an indication of the differential contribution of rare and common variants for some genes and methodological differences in detection ability. Still, many of the genes implicated by COGS through endophenotypes have been identified by independent studies of common, rare, and de novo variation in schizophrenia, all converging on a functional genetic network related to glutamatergic neurotransmission that warrants further investigation.


Assuntos
Endofenótipos , Predisposição Genética para Doença , Esquizofrenia/genética , Esquizofrenia/fisiopatologia , Família , Humanos
15.
Psychiatry Investig ; 12(3): 402-7, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26207136

RESUMO

Although bipolar disorder is highly heritable, the identification of specific genetic variations is limited because of the complex traits underlying the disorder. We performed a genome-wide association study of bipolar disorder using a subphenotype that shows hypersomnia symptom during a major depressive episode. We investigated a total of 2,191 cases, 1,434 controls, and 703,012 single nucleotide polymorphisms (SNPs) in the merged samples obtained from the Translational Genomics Institute and the Genetic Association Information Network. The gene emerging as the most significant by statistical analysis was rs1553441 (odds ratio=0.4093; p=1.20×10(-5); Permuted p=6.0×10(-6)). However, the 5×0(-8) threshold for statistical significance required in a genome-wide association study was not achieved. The functional enrichment pathway analysis showed significant enrichments in the adhesion, development-related, synaptic transmission-related, and cell recognition-related pathways. For further evaluation, each gene of the enriched pathways was reviewed and matched with genes that were suggested to be associated with psychiatric disorders by previous genetic studies. We found that the cadherin 13 and hypocretin (orexin) receptor 2 genes may be involved in the hypersomnia symptom during a major depressive episode of bipolar disorder.

16.
Schizophr Res ; 163(1-3): 38-46, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25749017

RESUMO

Attention/vigilance impairments are present in individuals with schizophrenia across psychotic and remitted states and in their first-degree relatives. An important question is whether deficits in attention/vigilance can be consistently and reliably measured across sites varying in many participant demographic, clinical, and functional characteristics, as needed for large-scale genetic studies of endophenotypes. We examined Continuous Performance Test (CPT) data from phase 2 of the Consortium on the Genetics of Schizophrenia (COGS-2), the largest-scale assessment of cognitive and psychophysiological endophenotypes relevant to schizophrenia. The CPT data from 2251 participants from five sites were examined. A perceptual-load vigilance task (the Degraded Stimulus CPT or DS-CPT) and a memory-load vigilance task (CPT-Identical Pairs or CPT-IP) were utilized. Schizophrenia patients performed more poorly than healthy comparison subjects (HCS) across sites, despite significant site differences in participant age, sex, education, and racial distribution. Patient-HCS differences in signal/noise discrimination (d') in the DS-CPT varied significantly across sites, but averaged a medium effect size. CPT-IP performance showed large patient-HCS differences across sites. Poor CPT performance was independent of or weakly correlated with symptom severity, but was significantly associated with lower educational achievement and functional capacity. Current smoking was associated with poorer CPT-IP d'. Patients taking both atypical and typical antipsychotic medication performed more poorly than those on no or atypical antipsychotic medications, likely reflecting their greater severity of illness. We conclude that CPT deficits in schizophrenia can be reliably detected across sites, are relatively independent of current symptom severity, and are related to functional capacity.


Assuntos
Atenção , Transtornos Psicóticos/psicologia , Psicologia do Esquizofrênico , Adolescente , Adulto , Idoso , Antipsicóticos/uso terapêutico , Endofenótipos , Feminino , Humanos , Masculino , Memória , Pessoa de Meia-Idade , Testes Neuropsicológicos , Escalas de Graduação Psiquiátrica , Transtornos Psicóticos/complicações , Transtornos Psicóticos/genética , Transtornos Psicóticos/fisiopatologia , Esquizofrenia/complicações , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Esquizofrenia/fisiopatologia , Fumar/fisiopatologia , Fumar/psicologia , Adulto Jovem
17.
Schizophr Res ; 163(1-3): 73-9, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25682549

RESUMO

BACKGROUND: Although many endophenotypes for schizophrenia have been studied individually, few studies have examined the extent to which common neurocognitive and neurophysiological measures reflect shared versus unique endophenotypic factors. It may be possible to distill individual endophenotypes into composite measures that reflect dissociable, genetically informative elements. METHODS: The first phase of the Consortium on the Genetics of Schizophrenia (COGS-1) is a multisite family study that collected neurocognitive and neurophysiological data between 2003 and 2008. For these analyses, participants included schizophrenia probands (n=83), their nonpsychotic siblings (n=151), and community comparison subjects (n=209) with complete data on a battery of 12 neurocognitive tests (assessing domains of working memory, declarative memory, vigilance, spatial ability, abstract reasoning, facial emotion processing, and motor speed) and 3 neurophysiological tasks reflecting inhibitory processing (P50 gating, prepulse inhibition and antisaccade tasks). Factor analyses were conducted on the measures for each subject group and across the entire sample. Heritability analyses of factors were performed using SOLAR. RESULTS: Analyses yielded 5 distinct factors: 1) Episodic Memory, 2) Working Memory, 3) Perceptual Vigilance, 4) Visual Abstraction, and 5) Inhibitory Processing. Neurophysiological measures had low associations with these factors. The factor structure of endophenotypes was largely comparable across probands, siblings and controls. Significant heritability estimates for the factors ranged from 22% (Episodic Memory) to 39% (Visual Abstraction). CONCLUSIONS: Neurocognitive measures reflect a meaningful amount of shared variance whereas the neurophysiological measures reflect largely unique contributions as endophenotypes for schizophrenia. Composite endophenotype measures may inform our neurobiological and genetic understanding of schizophrenia.


Assuntos
Endofenótipos , Esquizofrenia/genética , Esquizofrenia/fisiopatologia , Psicologia do Esquizofrênico , Adolescente , Adulto , Idoso , Nível de Alerta/genética , Análise Fatorial , Feminino , Predisposição Genética para Doença , Humanos , Inibição (Psicologia) , Masculino , Memória Episódica , Memória de Curto Prazo , Pessoa de Meia-Idade , Testes Neuropsicológicos , Irmãos , Percepção Visual/genética , Adulto Jovem
18.
Schizophr Res ; 163(1-3): 47-52, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25553977

RESUMO

The impaired ability to make correct antisaccades (i.e., antisaccade performance) is well documented among schizophrenia subjects, and researchers have successfully demonstrated that antisaccade performance is a valid schizophrenia endophenotype that is useful for genetic studies. However, it is unclear how the ascertainment biases that unavoidably result from recruitment differences in schizophrenia subjects identified in family versus case-control studies may influence patient-control differences in antisaccade performance. To assess the impact of ascertainment bias, researchers from the Consortium on the Genetics of Schizophrenia (COGS) compared antisaccade performance and antisaccade metrics (latency and gain) in schizophrenia and control subjects from COGS-1, a family-based schizophrenia study, to schizophrenia and control subjects from COGS-2, a corresponding case-control study. COGS-2 schizophrenia subjects were substantially older; had lower education status, worse psychosocial function, and more severe symptoms; and were three times more likely to be a member of a multiplex family than COGS-1 schizophrenia subjects. Despite these variations, which were likely the result of ascertainment differences (as described in the introduction to this special issue), the effect sizes of the control-schizophrenia differences in antisaccade performance were similar in both studies (Cohen's d effect size of 1.06 and 1.01 in COGS-1 and COGS-2, respectively). This suggests that, in addition to the robust, state-independent schizophrenia-related deficits described in endophenotype studies, group differences in antisaccade performance do not vary based on subject ascertainment and recruitment factors.


Assuntos
Desempenho Psicomotor , Movimentos Sacádicos , Esquizofrenia/fisiopatologia , Psicologia do Esquizofrênico , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Endofenótipos , Projetos de Pesquisa Epidemiológica , Medições dos Movimentos Oculares , Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Esquizofrenia/genética , Adulto Jovem
19.
J Affect Disord ; 172: 453-61, 2015 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25451450

RESUMO

BACKGROUND: Migraine is a common comorbidity among individuals with bipolar disorder, but the underlying mechanisms for this co-occurrence are poorly understood. The aim of this study was to investigate the genetic background of bipolar patients with and without migraine. METHODS: We performed a genome-wide association analysis contrasting 460 bipolar migraneurs with 914 bipolar patients without migraine from the Bipolar Genome Study (BiGS). RESULTS: We identified one genome-wide significant association between migraine in bipolar disorder patients and rs1160720, an intronic single nucleotide polymorphism (SNP) in the NBEA gene (P=2.97 × 10(-8), OR: 1.82, 95% CI: 1.47-2.25), although this was not replicated in a smaller sample of 289 migraine cases. LIMITATIONS: Our study is based on self-reported migraine. CONCLUSIONS: NBEA encodes neurobeachin, a scaffolding protein primarily expressed in the brain and involved in trafficking of vesicles containing neurotransmitter receptors. This locus has not previously been implicated in migraine per se. We found no evidence of association in data from the GWAS migraine meta-analysis consortium (n=118,710 participants) suggesting that the association might be specific to migraine co-morbid with bipolar disorder.


Assuntos
Transtorno Bipolar/complicações , Proteínas de Transporte/genética , Transtornos de Enxaqueca/genética , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Adulto , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/genética , Comorbidade , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Transtornos de Enxaqueca/epidemiologia , Transtornos de Enxaqueca/etiologia
20.
Schizophr Res ; 163(1-3): 32-7, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25497440

RESUMO

The first phase of the Consortium on the Genetics of Schizophrenia (COGS-1) showed performance deficits in learning and memory on the California Verbal Learning Test, Second Edition (CVLT-II) in individuals with schizophrenia (SZ), compared to healthy comparison subjects (HCS). A question is whether the COGS-1 study, which used a family study design (i.e. studying relatively intact families), yielded "milder" SZ phenotypes than those acquired subsequently in the COGS-2 case-control design that did not recruit unaffected family members. CVLT-II performance was compared for the COGS-1 and COGS-2 samples. Analyses focused on learning, recall and recognition variables, with age, gender and education as covariates. Analyses of COGS-2 data explored effects of additional covariates and moderating factors in CVLT-II performance. 324 SZ subjects and 510 HCS had complete CVLT-II and covariate data in COGS-1, while 1356 SZ and 1036 HCS had complete data in COGS-2. Except for recognition memory, analysis of covariance showed significantly worse performance in COGS-2 on all CVLT-II variables for SZ and HCS, and remained significant in the presence of the covariates. Performance in each of the 5 learning trials differed significantly. However, effect sizes comparing cases and controls were comparable across the two studies. COGS-2 analyses confirmed SZ performance deficits despite effects of multiple significant covariates and moderating factors. CVLT-II performance was worse in COGS-2 than in COGS-1 for both the SZ and the HCS in this large cohort, likely due to cohort effects. Demographically corrected data yield a consistent pattern of performance across the two studies in SZ.


Assuntos
Memória de Curto Prazo , Adolescente , Adulto , Idoso , California , Estudos de Casos e Controles , Estudos de Coortes , Endofenótipos , Família , Feminino , Humanos , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Rememoração Mental/efeitos dos fármacos , Pessoa de Meia-Idade , Testes Neuropsicológicos , Recognição (Psicologia)/efeitos dos fármacos , Esquizofrenia/complicações , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Esquizofrenia/fisiopatologia , Psicologia do Esquizofrênico , Percepção da Fala/efeitos dos fármacos , Aprendizagem Verbal/efeitos dos fármacos , Adulto Jovem
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