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1.
Nature ; 604(7906): 509-516, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35396579

RESUMO

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3-50, P < 2.14 × 10-6) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-D-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach.


Assuntos
Mutação , Transtornos do Neurodesenvolvimento , Esquizofrenia , Estudos de Casos e Controles , Exoma , Predisposição Genética para Doença/genética , Humanos , Transtornos do Neurodesenvolvimento/genética , Receptores de N-Metil-D-Aspartato/genética , Esquizofrenia/genética
2.
Int J Mol Sci ; 24(20)2023 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-37895019

RESUMO

The study of neurodevelopmental molecular mechanisms in schizophrenia requires the development of adequate biological models such as patient-derived cells and their derivatives. We previously utilized cell lines with neural progenitor properties (CNON) derived from the superior or middle turbinates of patients with schizophrenia and control groups to study schizophrenia-specific gene expression. In this study, we analyzed single-cell RNA seq data from two CNON cell lines (one derived from an individual with schizophrenia (SCZ) and the other from a control group) and two biopsy samples from the middle turbinate (MT) (also from an individual with SCZ and a control). We compared our data with previously published data regarding the olfactory neuroepithelium and demonstrated that CNON originated from a single cell type present both in middle turbinate and the olfactory neuroepithelium and expressed in multiple markers of mesenchymal cells. To define the relatedness of CNON to the developing human brain, we also compared CNON datasets with scRNA-seq data derived from an embryonic brain and found that the expression profile of the CNON closely matched the expression profile one of the cell types in the embryonic brain. Finally, we evaluated the differences between SCZ and control samples to assess the utility and potential benefits of using CNON single-cell RNA seq to study the etiology of schizophrenia.


Assuntos
Células-Tronco Neurais , Esquizofrenia , Humanos , Conchas Nasais/patologia , Esquizofrenia/genética , Esquizofrenia/metabolismo , Células Cultivadas , Neurônios/metabolismo , Células-Tronco Neurais/metabolismo
3.
Mov Disord ; 36(8): 1899-1910, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33942911

RESUMO

BACKGROUND: Persistent motor or vocal tic disorder (PMVT) has been hypothesized to be a forme fruste of Tourette syndrome (TS). Although the primary diagnostic criterion for PMVT (presence of motor or vocal tics, but not both) is clear, less is known about its clinical presentation. OBJECTIVE: The goals of this study were to compare the prevalence and number of comorbid psychiatric disorders, tic severity, age at tic onset, and family history for TS and PMVT. METHODS: We analyzed data from two independent cohorts using generalized linear equations and confirmed our findings using meta-analyses, incorporating data from previously published literature. RESULTS: Rates of obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) were lower in PMVT than in TS in all analyses. Other psychiatric comorbidities occurred with similar frequencies in PMVT and TS in both cohorts, although meta-analyses suggested lower rates of most psychiatric disorders in PMVT compared with TS. ADHD and OCD increased the odds of comorbid mood, anxiety, substance use, and disruptive behaviors, and accounted for observed differences between PMVT and TS. Age of tic onset was approximately 2 years later, and tic severity was lower in PMVT than in TS. First-degree relatives had elevated rates of TS, PMVT, OCD, and ADHD compared with population prevalences, with rates of TS equal to or greater than PMVT rates. CONCLUSIONS: Our findings support the hypothesis that PMVT and TS occur along a clinical spectrum in which TS is a more severe and PMVT a less severe manifestation of a continuous neurodevelopmental tic spectrum disorder. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtorno Obsessivo-Compulsivo , Transtornos de Tique , Tiques , Síndrome de Tourette , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Comorbidade , Humanos , Transtorno Obsessivo-Compulsivo/epidemiologia , Transtornos de Tique/epidemiologia , Tiques/epidemiologia , Síndrome de Tourette/epidemiologia
4.
Mol Psychiatry ; 25(9): 2036-2046, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-30087453

RESUMO

Anorexia nervosa (AN) and obsessive-compulsive disorder (OCD) are often comorbid and likely to share genetic risk factors. Hence, we examine their shared genetic background using a cross-disorder GWAS meta-analysis of 3495 AN cases, 2688 OCD cases, and 18,013 controls. We confirmed a high genetic correlation between AN and OCD (rg = 0.49 ± 0.13, p = 9.07 × 10-7) and a sizable SNP heritability (SNP h2 = 0.21 ± 0.02) for the cross-disorder phenotype. Although no individual loci reached genome-wide significance, the cross-disorder phenotype showed strong positive genetic correlations with other psychiatric phenotypes (e.g., rg = 0.36 with bipolar disorder and 0.34 with neuroticism) and negative genetic correlations with metabolic phenotypes (e.g., rg = -0.25 with body mass index and -0.20 with triglycerides). Follow-up analyses revealed that although AN and OCD overlap heavily in their shared risk with other psychiatric phenotypes, the relationship with metabolic and anthropometric traits is markedly stronger for AN than for OCD. We further tested whether shared genetic risk for AN/OCD was associated with particular tissue or cell-type gene expression patterns and found that the basal ganglia and medium spiny neurons were most enriched for AN-OCD risk, consistent with neurobiological findings for both disorders. Our results confirm and extend genetic epidemiological findings of shared risk between AN and OCD and suggest that larger GWASs are warranted.


Assuntos
Anorexia Nervosa , Transtorno Obsessivo-Compulsivo , Anorexia Nervosa/genética , Índice de Massa Corporal , Comorbidade , Estudo de Associação Genômica Ampla , Humanos , Transtorno Obsessivo-Compulsivo/genética , Fenótipo
5.
Ear Hear ; 41(4): 983-989, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31985533

RESUMO

OBJECTIVE: A small subset of children with congenital hearing loss have abnormal cochleovestibular nerves (i.e., absent, aplastic, or deficient cochlear nerves), with largely unknown etiology. Our objective was to investigate the underlying pathways and identify novel genetic variants responsible for cochleovestibular malformations and nerve abnormalities. It is our hypothesis that several cochleovestibular nerve abnormalities might share common causative pathways. DESIGN: We used a family-based exome sequencing approach to study 12 children with known rare inner ear and/or cochleovestibular nerve malformations. RESULTS: Our results highlight a diverse molecular etiology and suggest that genes important in the developing otic vesicle and cranial neural crest, e.g., MASP1, GREB1L, SIX1, TAF1, are likely to underlie inner ear and/or cochleovestibular nerve malformations. CONCLUSIONS: We show that several cochleovestibular nerve malformations are neurocristopathies, which is consistent with the fact that cochleovestibular nerve development is based on otic placode-derived neurons in close association with neural crest-derived glia cells. In addition, we suggest potential genetic markers for more severely affected phenotypes, which may help prognosticate individual cochlear implantation outcomes. Developing better strategies for identifying which children with abnormal nerves will benefit from a cochlear implantation is crucial, as outcomes are usually far less robust and extremely variable in this population, and current neuroimaging and electrophysiologic parameters cannot accurately predict outcomes. Identification of a suitable treatment early will reduce the use of multiple interventions during the time-sensitive period for language development.


Assuntos
Implante Coclear , Surdez , Orelha Interna , Perda Auditiva Neurossensorial , Nervo Coclear , Feminino , Perda Auditiva Neurossensorial/genética , Proteínas de Homeodomínio , Humanos , Lactente , Masculino
6.
Compr Psychiatry ; 94: 152123, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31518848

RESUMO

BACKGROUND: This study addresses the strength of associations between trichotillomania (TTM) and other DSM-IV Axis I conditions in a large sample (n = 2606) enriched for familial obsessive-compulsive disorder (OCD), to inform TTM classification. METHODS: We identified participants with TTM in the Johns Hopkins OCD Family Study (153 families) and the OCD Collaborative Genetics Study, a six-site genetic linkage study of OCD (487 families). We used logistic regression (with generalized estimating equations) to assess the strength of associations between TTM and other DSM-IV disorders. RESULTS: TTM had excess comorbidity with a number of conditions from different DSM-IV chapters, including tic disorders, alcohol dependence, mood disorders, anxiety disorders, impulse-control disorders, and bulimia nervosa. However, association strengths (odds ratios) were highest for kleptomania (6.6), pyromania (5.8), OCD (5.6), skin picking disorder (4.4), bulimia nervosa (3.5), and pathological nail biting (3.4). CONCLUSIONS: TTM is comorbid with a number of psychiatric conditions besides OCD, and it is strongly associated with other conditions involving impaired impulse control. Though DSM-5 includes TTM as an OCD-related disorder, its comorbidity pattern also emphasizes the impulsive, appetitive aspects of this condition that may be relevant to classification.


Assuntos
Transtornos Disruptivos, de Controle do Impulso e da Conduta/epidemiologia , Transtorno Obsessivo-Compulsivo/epidemiologia , Tricotilomania/epidemiologia , Adulto , Comorbidade , Manual Diagnóstico e Estatístico de Transtornos Mentais , Transtornos Disruptivos, de Controle do Impulso e da Conduta/genética , Feminino , Ligação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Transtorno Obsessivo-Compulsivo/genética , Tricotilomania/genética , Adulto Jovem
7.
Hum Genet ; 137(6-7): 459-470, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29955957

RESUMO

Congenital inner ear malformations affecting both the osseous and membranous labyrinth can have a devastating impact on hearing and language development. With the exception of an enlarged vestibular aqueduct, non-syndromic inner ear malformations are rare, and their underlying molecular biology has thus far remained understudied. To identify molecular factors that might be important in the developing inner ear, we adopted a family-based trio exome sequencing approach in young unrelated subjects with severe inner ear malformations. We identified two previously unreported de novo loss-of-function variants in GREB1L [c.4368G>T;p.(Glu1410fs) and c.982C>T;p.(Arg328*)] in two affected subjects with absent cochleae and eighth cranial nerve malformations. The cochlear aplasia in these affected subjects suggests that a developmental arrest or problem at a very early stage of inner ear development exists, e.g., during the otic pit formation. Craniofacial Greb1l RNA expression peaks in mice during this time frame (E8.5). It also peaks in the developing inner ear during E13-E16, after which it decreases in adulthood. The crucial function of Greb1l in craniofacial development is also evidenced in knockout mice, which develop severe craniofacial abnormalities. In addition, we show that Greb1l-/- zebrafish exhibit a loss of abnormal sensory epithelia innervation. An important role for Greb1l in sensory epithelia innervation development is supported by the eighth cranial nerve deficiencies seen in both affected subjects. In conclusion, we demonstrate that GREB1L is a key player in early inner ear and eighth cranial nerve development. Abnormalities in cochleovestibular anatomy can provide challenges for cochlear implantation. Combining a molecular diagnosis with imaging techniques might aid the development of individually tailored therapeutic interventions in the future.


Assuntos
Surdez/genética , Doenças do Labirinto/genética , Proteínas de Neoplasias/genética , Proteínas/genética , Proteínas de Peixe-Zebra/genética , Animais , Surdez/fisiopatologia , Modelos Animais de Doenças , Orelha Interna/crescimento & desenvolvimento , Orelha Interna/fisiopatologia , Células Epiteliais/patologia , Gânglios Parassimpáticos/crescimento & desenvolvimento , Gânglios Parassimpáticos/fisiopatologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Doenças do Labirinto/fisiopatologia , Proteínas de Membrana , Camundongos , Camundongos Knockout , Peixe-Zebra
8.
Br J Psychiatry ; 213(1): 430-436, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29947313

RESUMO

BACKGROUND: Many studies have identified changes in the brain associated with obsessive-compulsive disorder (OCD), but few have examined the relationship between genetic determinants of OCD and brain variation.AimsWe present the first genome-wide investigation of overlapping genetic risk for OCD and genetic influences on subcortical brain structures. METHOD: Using single nucleotide polymorphism effect concordance analysis, we measured genetic overlap between the first genome-wide association study (GWAS) of OCD (1465 participants with OCD, 5557 controls) and recent GWASs of eight subcortical brain volumes (13 171 participants). RESULTS: We found evidence of significant positive concordance between OCD risk variants and variants associated with greater nucleus accumbens and putamen volumes. When conditioning OCD risk variants on brain volume, variants influencing putamen, amygdala and thalamus volumes were associated with risk for OCD. CONCLUSIONS: These results are consistent with current OCD neurocircuitry models. Further evidence will clarify the relationship between putamen volume and OCD risk, and the roles of the detected variants in this disorder.Declaration of interestThe authors have declared that no competing interests exist.


Assuntos
Variação Genética , Núcleo Accumbens/fisiopatologia , Transtorno Obsessivo-Compulsivo/genética , Putamen/fisiopatologia , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Imageamento por Ressonância Magnética , Masculino , Transtorno Obsessivo-Compulsivo/patologia , Tamanho do Órgão , Polimorfismo de Nucleotídeo Único
9.
Compr Psychiatry ; 81: 53-59, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29268152

RESUMO

BACKGROUND: Hoarding behavior may distinguish a clinically and possibly etiologically distinct subtype of obsessive-compulsive disorder (OCD). Little is known about the relationship between executive dysfunction and hoarding in individuals with OCD. METHODS: The study sample included 431 adults diagnosed with DSM-IV OCD. Participants were assessed by clinicians for Axis I disorders, personality disorders, indecision, and hoarding. Executive functioning domains were evaluated using a self-report instrument, the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A). We compared scores on these domains in the 143 hoarding and 288 non-hoarding participants, separately in men and women. We used logistic regression to evaluate relationships between executive function scores and hoarding, and correlation and linear regression analyses to evaluate relationships between executive function scores and hoarding severity, in women. RESULTS: In men, the hoarding group had a significantly higher mean score than the non-hoarding group only on the shift dimension. In contrast, in women, the hoarding group had higher mean scores on the shift scale and all metacognition dimensions, i.e., those that assess the ability to systematically solve problems via planning and organization. The relationships in women between hoarding and scores on initiating tasks, planning/organizing, organization of materials, and the metacognition index were independent of other clinical features. Furthermore, the severity of hoarding in women correlated most strongly with metacognition dimensions. CONCLUSIONS: Self-reported deficits in planning and organization are associated with the occurrence and severity of hoarding in women, but not men, with OCD. This may have implications for elucidating the etiology of, and developing effective treatments for, hoarding in OCD.


Assuntos
Função Executiva , Colecionismo/epidemiologia , Colecionismo/psicologia , Transtorno Obsessivo-Compulsivo/epidemiologia , Transtorno Obsessivo-Compulsivo/psicologia , Autorrelato , Adolescente , Adulto , Idoso , Manual Diagnóstico e Estatístico de Transtornos Mentais , Função Executiva/fisiologia , Feminino , Colecionismo/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Transtorno Obsessivo-Compulsivo/diagnóstico , Adulto Jovem
10.
Compr Psychiatry ; 75: 117-124, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28359017

RESUMO

BACKGROUND: Clinicians have long considered doubt to be a fundamental characteristic of obsessive-compulsive disorder (OCD). However, the clinical relevance of doubt in OCD has not been addressed. METHODS: Participants included 1182 adults with OCD who had participated in family and genetic studies of OCD. We used a clinical measure of the severity of doubt, categorized as none, mild, moderate, severe, or extreme. We evaluated the relationship between doubt and OCD clinical features, Axis I disorders, personality and personality disorder dimensions, impairment, and treatment response. RESULTS: The severity of doubt was inversely related to the age at onset of OCD symptoms. Doubt was strongly related to the number of checking symptoms and, to a lesser extent, to the numbers of contamination/cleaning and hoarding symptoms. Doubt also was related to the lifetime prevalence of recurrent major depression and generalized anxiety disorder; to the numbers of avoidant, dependent, and obsessive-compulsive personality disorder traits; and to neuroticism and introversion. Moreover, doubt was strongly associated with global impairment and poor response to cognitive behavioral treatment (CBT), even adjusting for OCD severity and other correlates of doubt. CONCLUSIONS: Doubt is associated with important clinical features of OCD, including impairment and cognitive-behavioral treatment response.


Assuntos
Emoções , Transtorno Obsessivo-Compulsivo/psicologia , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Transtornos de Ansiedade/psicologia , Terapia Cognitivo-Comportamental , Transtorno da Personalidade Compulsiva/psicologia , Transtorno Depressivo Maior/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuroticismo , Transtornos da Personalidade/psicologia , Adulto Jovem
11.
Compr Psychiatry ; 73: 43-52, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27915218

RESUMO

BACKGROUND: Hoarding behavior may indicate a clinically and possibly etiologically distinct subtype of obsessive-compulsive disorder (OCD). Empirical evidence supports a relationship between hoarding and emotional over-attachment to objects. However, little is known about the relationship between hoarding and parental attachment in OCD. METHOD: The study sample included 894 adults diagnosed with DSM-IV OCD who had participated in family and genetic studies of OCD. Participants were assessed for Axis I disorders, personality disorders, and general personality dimensions. The Parental Bonding Instrument (PBI) was used to assess dimensions of perceived parental rearing (care, overprotection, and control). We compared parental PBI scores in the 334 hoarding and 560 non-hoarding participants, separately in men and women. We used logistic regression to evaluate the relationship between parenting scores and hoarding in women, adjusting for other clinical features associated with hoarding. RESULTS: In men, there were no significant differences between hoarding and non-hoarding groups in maternal or paternal parenting scores. In women, the hoarding group had a lower mean score on maternal care (23.4 vs. 25.7, p<0.01); a higher mean score on maternal protection (9.4 vs. 7.7, p<0.001); and a higher mean score on maternal control (7.0 vs. 6.2, p<0.05), compared to the non-hoarding group. The magnitude of the relationships between maternal bonding dimensions and hoarding in women did not change after adjustment for other clinical features. Women who reported low maternal care/high maternal protection had significantly greater odds of hoarding compared to women with high maternal care/low maternal protection (OR=2.54, 95% CI=1.60-4.02, p<0.001). CONCLUSIONS: Perceived poor maternal care, maternal overprotection, and maternal overcontrol are associated with hoarding in women with OCD. Parenting dimensions are not related to hoarding in men. These findings provide further support for a hoarding subtype of OCD and for sex-specific differences in etiologic pathways for hoarding in OCD.


Assuntos
Colecionismo/psicologia , Apego ao Objeto , Transtorno Obsessivo-Compulsivo/psicologia , Poder Familiar/psicologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Caracteres Sexuais , Adulto Jovem
12.
PLoS Genet ; 10(1): e1004100, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24453991

RESUMO

The Nrf family of transcription factors mediates adaptive responses to stress and longevity, but the identities of the crucial Nrf targets, and the tissues in which they function in multicellular organisms to promote survival, are not known. Here, we use whole transcriptome RNA sequencing to identify 810 genes whose expression is controlled by the SKN-1/Nrf2 negative regulator WDR-23 in the nervous system of Caenorhabditis elegans. Among the genes identified is the synaptic cell adhesion molecule nlg-1/neuroligin. We find that the synaptic abundance of NLG-1 protein increases following pharmacological treatments that generate oxidative stress or by the genetic activation of skn-1. Increasing nlg-1 dosage correlates with increased survival in response to oxidative stress, whereas genetic inactivation of nlg-1 reduces survival and impairs skn-1-mediated stress resistance. We identify a canonical SKN-1 binding site in the nlg-1 promoter that binds to SKN-1 in vitro and is necessary for SKN-1 and toxin-mediated increases in nlg-1 expression in vivo. Together, our results suggest that SKN-1 activation in the nervous system can confer protection to organisms in response to stress by directly regulating nlg-1/neuroligin expression.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Moléculas de Adesão Celular Neuronais/genética , Proteínas de Ligação a DNA/genética , Longevidade/genética , Estresse Oxidativo/genética , Fatores de Transcrição/genética , Transcrição Gênica , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Proteínas de Caenorhabditis elegans/biossíntese , Moléculas de Adesão Celular Neuronais/biossíntese , Sobrevivência Celular , Proteínas de Ligação a DNA/biossíntese , Regulação da Expressão Gênica no Desenvolvimento , Sistema Nervoso/crescimento & desenvolvimento , Regiões Promotoras Genéticas , Fatores de Transcrição/biossíntese , Ativação Transcricional/genética
13.
BMC Genomics ; 17(1): 966, 2016 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-27881084

RESUMO

BACKGROUND: Recently, measurement of RNA at single cell resolution has yielded surprising insights. Methods for single-cell RNA sequencing (scRNA-seq) have received considerable attention, but the broad reliability of single cell methods and the factors governing their performance are still poorly known. RESULTS: Here, we conducted a large-scale control experiment to assess the transfer function of three scRNA-seq methods and factors modulating the function. All three methods detected greater than 70% of the expected number of genes and had a 50% probability of detecting genes with abundance greater than 2 to 4 molecules. Despite the small number of molecules, sequencing depth significantly affected gene detection. While biases in detection and quantification were qualitatively similar across methods, the degree of bias differed, consistent with differences in molecular protocol. Measurement reliability increased with expression level for all methods and we conservatively estimate measurements to be quantitative at an expression level greater than ~5-10 molecules. CONCLUSIONS: Based on these extensive control studies, we propose that RNA-seq of single cells has come of age, yielding quantitative biological information.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Técnicas de Amplificação de Ácido Nucleico , RNA/genética , Análise de Célula Única , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Análise de Sequência de RNA , Análise de Célula Única/métodos
14.
Dev Neurosci ; 38(5): 375-383, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28030860

RESUMO

The long noncoding RNA MSNP1AS (moesin pseudogene 1, antisense) is a functional element that was previously associated with autism spectrum disorder (ASD) with genome-wide significance. Expression of MSNP1AS was increased 12-fold in the cerebral cortex of individuals with ASD and 22-fold in individuals with a genome-wide significantly associated ASD genetic marker on chromosome 5p14.1. Overexpression of MSNP1AS in human neuronal cells caused decreased expression of moesin protein, which is involved in neuronal process stability. In this study, we hypothesize that MSNP1AS knockdown impacts global transcriptome levels. We transfected the human neural progenitor cell line SK- N-SH with constructs that caused a 50% suppression of MSNP1AS expression. After 24 h, cells were harvested for total RNA isolation. Strand-specific RNA sequencing analysis indicated altered expression of 1,352 genes, including altered expression of 318 genes following correction for multiple comparisons. Expression of the OAS2 gene was increased >150-fold, a result that was validated by quantitative PCR. Gene ontology analysis of the 318 genes with altered expression following correction for multiple comparisons indicated that upregulated genes were significantly enriched for genes involved in immune response, and downregulated genes were significantly enriched for genes involved in chromatin remodeling. These data indicate multiple transcriptional and translational functions of MSNP1AS that impact ASD-relevant biological processes. Chromatin remodeling and immune response are biological processes implicated by genes with rare mutations associated with ASD. Our data suggest that the functional elements implicated by association of common genetic variants impact the same biological processes, suggesting a possible shared common molecular pathway of ASD.


Assuntos
Transtorno do Espectro Autista/genética , Inativação Gênica/fisiologia , Células-Tronco Neurais/metabolismo , RNA Longo não Codificante/genética , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Humanos , Mutação/genética , Células-Tronco Neurais/citologia
15.
Depress Anxiety ; 33(2): 128-35, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26594839

RESUMO

BACKGROUND: To determine possible dimensions that underlie obsessive-compulsive personality disorder (OCPD) and to investigate their clinical correlates, familiality, and genetic linkage. METHODS: Participants were selected from 844 adults assessed with the Structured Instrument for the Diagnosis of DSM-IV Personality Disorders (SIDP) in the OCD Collaborative Genetics Study (OCGS) that targeted families with obsessive-compulsive disorder (OCD) affected sibling pairs. We conducted an exploratory factor analysis, which included the eight SIDP-derived DSM-IV OCPD traits and the indecision trait from the DSM-III, assessed clinical correlates, and estimated sib-sib correlations to evaluate familiality of the factors. Using MERLIN and MINX, we performed genome-wide quantitative trait locus (QTL) linkage analysis to test for allele sharing among individuals. RESULTS: Two factors were identified: Factor 1: order/control (perfectionism, excessive devotion to work, overconscientiousness, reluctance to delegate, and rigidity); and Factor 2: hoarding/indecision (inability to discard and indecisiveness). Factor 1 score was associated with poor insight, whereas Factor 2 score was associated with task incompletion. A significant sib-sib correlation was found for Factor 2 (rICC = .354, P < .0001) but not Factor 1 (rICC = .129, P = .084). The linkage findings were different for the two factors. When Factor 2 was analyzed as a quantitative trait, a strong signal was detected on chromosome 10 at marker d10s1221: KAC LOD = 2.83, P = .0002; and marker d10s1225: KAC LOD = 1.35, P = .006. CONCLUSIONS: The results indicate two factors of OCPD, order/control and hoarding/indecision. The hoarding/indecision factor is familial and shows modest linkage to a region on chromosome 10.


Assuntos
Transtorno da Personalidade Compulsiva/fisiopatologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtorno da Personalidade Compulsiva/classificação , Transtorno da Personalidade Compulsiva/genética , Análise Fatorial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
16.
PLoS Genet ; 9(3): e1003354, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23555279

RESUMO

The Nrf family of transcription factors plays a critical role in mediating adaptive responses to cellular stress and defends against neurodegeneration, aging, and cancer. Here, we report a novel role for the Caenorhabditis elegans Nrf homolog SKN-1 in regulating synaptic transmission at neuromuscular junctions (NMJs). Activation of SKN-1, either by acute pharmacological treatment with the mitochondrial toxin sodium arsenite or by mutations that cause constitutive SKN-1 activation, results in defects in neuromuscular function. Additionally, elimination of the conserved WD40 repeat protein WDR-23, a principal negative regulator of SKN-1, results in impaired locomotion and synaptic vesicle and neuropeptide release from cholinergic motor axons. Mutations that abolish skn-1 activity restore normal neuromuscular function to wdr-23 mutants and animals treated with toxin. We show that negative regulation of SKN-1 by WDR-23 in the intestine, but not at neuromuscular junctions, is necessary and sufficient for proper neuromuscular function. WDR-23 isoforms differentially localize to the outer membranes of mitochondria and to nuclei, and the effects of WDR-23 on neuromuscular function are dependent on its interaction with cullin E3 ubiquitin ligase. Finally, whole-transcriptome RNA sequencing of wdr-23 mutants reveals an increase in the expression of known SKN-1/Nrf2-regulated stress-response genes, as well as neurotransmission genes not previously implicated in SKN-1/Nrf2 responses. Together, our results indicate that SKN-1/Nrf2 activation may be a mechanism through which cellular stress, detected in one tissue, affects cellular function of a distal tissue through endocrine signaling. These results provide insight into how SKN-1/Nrf2 might protect the nervous system from damage in response to oxidative stress.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Proteínas de Ligação a DNA , Sistema Nervoso , Estresse Oxidativo/efeitos dos fármacos , Fatores de Transcrição , Animais , Arsenitos/farmacologia , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Núcleo Celular/genética , Núcleo Celular/metabolismo , Proteínas Culina , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Membranas Mitocondriais/efeitos dos fármacos , Mutação , Sistema Nervoso/efeitos dos fármacos , Sistema Nervoso/metabolismo , Junção Neuromuscular/genética , Junção Neuromuscular/fisiologia , Compostos de Sódio/farmacologia , Transmissão Sináptica/genética , Transmissão Sináptica/fisiologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
17.
Genomics ; 102(2): 112-22, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23583670

RESUMO

We investigated the genome-wide distribution of CNVs in the Alzheimer's disease (AD) Neuroimaging Initiative (ADNI) sample (146 with AD, 313 with Mild Cognitive Impairment (MCI), and 181 controls). Comparison of single CNVs between cases (MCI and AD) and controls shows overrepresentation of large heterozygous deletions in cases (p-value<0.0001). The analysis of CNV-Regions identifies 44 copy number variable loci of heterozygous deletions, with more CNV-Regions among affected than controls (p=0.005). Seven of the 44 CNV-Regions are nominally significant for association with cognitive impairment. We validated and confirmed our main findings with genome re-sequencing of selected patients and controls. The functional pathway analysis of the genes putatively affected by deletions of CNV-Regions reveals enrichment of genes implicated in axonal guidance, cell-cell adhesion, neuronal morphogenesis and differentiation. Our findings support the role of CNVs in AD, and suggest an association between large deletions and the development of cognitive impairment.


Assuntos
Doença de Alzheimer/genética , Transtornos Cognitivos/genética , Disfunção Cognitiva/genética , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Idoso , Idoso de 80 Anos ou mais , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Neuroimagem , Polimorfismo de Nucleotídeo Único/genética , Deleção de Sequência
18.
Am J Med Genet B Neuropsychiatr Genet ; 165B(4): 326-36, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24798771

RESUMO

Some individuals with obsessive-compulsive disorder (OCD) have autistic-like traits, including deficits in social and communication behaviors (pragmatics). The objective of this study was to determine if pragmatic impairment aggregates in OCD families and discriminates a clinically and genetically distinct subtype of OCD. We conducted clinical examinations on, and collected DNA samples from, 706 individuals with OCD in 221 multiply affected OCD families. Using the Pragmatic Rating Scale (PRS), we compared the prevalence of pragmatic impairment in OCD-affected relatives of probands with and without pragmatic impairment. We also compared clinical features of OCD-affected individuals in families having at least one, versus no, individual with pragmatic impairment, and assessed for linkage to OCD in the two groups of families. The odds of pragmatic impairment were substantially greater in OCD-affected relatives of probands with pragmatic impairment. Individuals in high-PRS families had greater odds of separation anxiety disorder and social phobia, and a greater number of schizotypal personality traits. In high-PRS families, there was suggestive linkage to OCD on chromosome 12 at marker D12S1064 and on chromosome X at marker DXS7132 whereas, in low-PRS families, there was suggestive linkage to chromosome 3 at marker D3S2398. Pragmatic impairment aggregates in OCD families. Separation anxiety disorder, social phobia, and schizotypal personality traits are part of a clinical spectrum associated with pragmatic impairment in these families. Specific regions of chromosomes 12 and X are linked to OCD in high-PRS families. Thus, pragmatic impairment may distinguish a clinically and genetically homogeneous subtype of OCD.


Assuntos
Comunicação , Ligação Genética , Predisposição Genética para Doença , Relações Interpessoais , Transtorno Obsessivo-Compulsivo/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Comportamento Cooperativo , Demografia , Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Escalas de Graduação Psiquiátrica , Adulto Jovem
19.
medRxiv ; 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38410442

RESUMO

Background: Accurate diagnosis of bipolar disorder (BD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A key reason is that the first manic episode is often preceded by a depressive one, making it difficult to distinguish BD from unipolar major depressive disorder (MDD). Aims: Here, we use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores that may aid early differential diagnosis. Methods: Based on individual genotypes from case-control cohorts of BD and MDD shared through the Psychiatric Genomics Consortium, we compile case-case-control cohorts, applying a careful merging and quality control procedure. In a resulting cohort of 51,149 individuals (15,532 BD cases, 12,920 MDD cases and 22,697 controls), we perform a variety of GWAS and polygenic risk scores (PRS) analyses. Results: While our GWAS is not well-powered to identify genome-wide significant loci, we find significant SNP-heritability and demonstrate the ability of the resulting PRS to distinguish BD from MDD, including BD cases with depressive onset. We replicate our PRS findings, but not signals of individual loci in an independent Danish cohort (iPSYCH 2015 case-cohort study, N=25,966). We observe strong genetic correlation between our case-case GWAS and that of case-control BD. Conclusions: We find that MDD and BD, including BD with a depressive onset, are genetically distinct. Further, our findings support the hypothesis that Controls - MDD - BD primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BD and, importantly, BD with depressive onset from MDD.

20.
Am J Med Genet B Neuropsychiatr Genet ; 162B(8): 898-906, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24123842

RESUMO

BACKGROUND: Prior genome-scans of bipolar disorder have revealed chromosome 6q22 as a promising candidate region. However, linkage disequilibrium (LD) mapping studies have yet to identify replicated susceptibility loci. METHODS: We analyzed 1,422 LD-tagging single nucleotide polymorphisms (SNPs) in 83 genes to test single-marker and locus-wide evidence of association with bipolar disorder in the NIMH Genetics Initiative bipolar pedigrees and the Portuguese Island Collection (PIC) (N = 1,093 in 528 informative pairs). Both studies previously demonstrated significant evidence of linkage to 6q. SNPs were genotyped using an Illumina iSelect genotyping array which employs the Infinium assay. Evidence of single-marker association was assessed using the generalized disequilibrium test (GDT). Empirical estimates of gene-wide significance were obtained by permutation (via 100,000 gene-dropping simulations) of Fisher's combined test of P-values for each locus. RESULTS: No single variant yielded significant experiment-wide evidence of association, for either the combined sample or in each subsample. Our gene-dropping simulations identified nominally significant gene-wide associations with multiple loci, of which NT5DC1 in the NIMH subsample and CCNC in the PIC were the strongest candidates. However, no one gene consistently exceeded empirical significance criteria in both independent samples or survived Bonferroni correction for the number of genes tested. CONCLUSIONS: Using a gene-based approach to family-based association, we identified gene-wide associations with several genes, though no single locus was significantly associated with bipolar disorder in both cohorts. This suggests that chromosome 6q may harbor multiple susceptibility loci or that complex patterns of LD in this region may confound approaches based on common SNPs. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.


Assuntos
Algoritmos , Transtorno Bipolar/genética , Cromossomos Humanos Par 6/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Marcadores Genéticos , Humanos , Desequilíbrio de Ligação/genética , Portugal
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