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1.
J Surg Res ; 261: 139-145, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33429222

RESUMEN

BACKGROUND: Primary hyperparathyroidism (PHPT) is associated with a poorer quality of life. The role of neuropsychiatric symptoms in asymptomatic patients who do not display classical features of PHPT remains undefined. It is unclear whether parathyroidectomy provides immediate benefit beyond the long-term risk reduction of adverse effects. The aim of the study is to assess the effect on quality of life in patients with asymptomatic PHPT undergoing parathyroidectomy. METHODS: Consecutive patients with PHPT undergoing parathyroidectomy by a single surgeon were recruited from a single center between 2014 and 2019. All patients prospectively completed the validated EQ-5D-3L health status questionnaire preoperatively and postoperatively, comprising two components: (i) five domains including physical and mental health and (ii) visual analog scale (VAS). Biochemical and clinical indices were recorded. RESULTS: Seventy-eight patients were included, 72% female (n = 56), median age 62 y (interquartile range (IQR): 52-70), and 28 (36%) asymptomatic. A global improvement in health-related quality of life was observed with a VAS score increase from 70 (IQR: 50-80) to 80 (IQR: 70-90); P < 0.001. VAS scores also improved significantly in asymptomatic patients increasing from 77 to 85 (P = 0.014), with an overall improvement in all five domains of quality of life. The symptomatic group showed a significant improvement in anxiety/depression levels (P < 0.01), although this was not the primary complaint in any of the cases. CONCLUSIONS: Parathyroidectomy is associated with a significant improvement in the quality of life of patients with asymptomatic PHPT. In symptomatic patients, this includes a reduction in anxiety and depression. Benefits are observed as early as 2 mo postoperatively, and results suggest a potentially important cognitive and social aspect of this disease.


Asunto(s)
Hiperparatiroidismo Primario/cirugía , Paratiroidectomía , Calidad de Vida , Anciano , Enfermedades Asintomáticas , Femenino , Humanos , Hiperparatiroidismo Primario/psicología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Encuestas y Cuestionarios , Escala Visual Analógica
2.
Am J Hum Genet ; 99(3): 555-566, 2016 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-27569549

RESUMEN

Genomic imprinting is a mechanism in which gene expression varies depending on parental origin. Imprinting occurs through differential epigenetic marks on the two parental alleles, with most imprinted loci marked by the presence of differentially methylated regions (DMRs). To identify sites of parental epigenetic bias, here we have profiled DNA methylation patterns in a cohort of 57 individuals with uniparental disomy (UPD) for 19 different chromosomes, defining imprinted DMRs as sites where the maternal and paternal methylation levels diverge significantly from the biparental mean. Using this approach we identified 77 DMRs, including nearly all those described in previous studies, in addition to 34 DMRs not previously reported. These include a DMR at TUBGCP5 within the recurrent 15q11.2 microdeletion region, suggesting potential parent-of-origin effects associated with this genomic disorder. We also observed a modest parental bias in DNA methylation levels at every CpG analyzed across ∼1.9 Mb of the 15q11-q13 Prader-Willi/Angelman syndrome region, demonstrating that the influence of imprinting is not limited to individual regulatory elements such as CpG islands, but can extend across entire chromosomal domains. Using RNA-seq data, we detected signatures consistent with imprinted expression associated with nine novel DMRs. Finally, using a population sample of 4,004 blood methylomes, we define patterns of epigenetic variation at DMRs, identifying rare individuals with global gain or loss of methylation across multiple imprinted loci. Our data provide a detailed map of parental epigenetic bias in the human genome, providing insights into potential parent-of-origin effects.


Asunto(s)
Metilación de ADN/genética , Epigénesis Genética/genética , Genoma Humano/genética , Padres , Disomía Uniparental/genética , Alelos , Síndrome de Angelman/genética , Aberraciones Cromosómicas , Cromosomas Humanos/genética , Cromosomas Humanos Par 15/genética , Estudios de Cohortes , Islas de CpG/genética , Femenino , Impresión Genómica/genética , Humanos , Discapacidad Intelectual/genética , Cariotipo , Masculino , Proteínas Asociadas a Microtúbulos/genética , Síndrome de Prader-Willi/genética , Reproducibilidad de los Resultados , Análisis de Secuencia de ARN
3.
Nat Genet ; 39(3): 319-28, 2007 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-17322880

RESUMEN

Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.


Asunto(s)
Trastorno Autístico/genética , Aberraciones Cromosómicas , Mapeo Cromosómico , Ligamiento Genético , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Trastorno Autístico/diagnóstico , Familia , Femenino , Variación Genética , Humanos , Escala de Lod , Masculino , Factores de Riesgo
4.
Nature ; 459(7246): 528-33, 2009 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-19404256

RESUMEN

Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)-two genes encoding neuronal cell-adhesion molecules-revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 x 10(-8), odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4 x 10(-8) to 2.1 x 10(-10). Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs.


Asunto(s)
Trastorno Autístico/genética , Cromosomas Humanos Par 5/genética , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Encéfalo/metabolismo , Cadherinas/genética , Estudios de Casos y Controles , Adhesión Celular/genética , Moléculas de Adhesión Celular Neuronal/genética , Estudios de Cohortes , Marcadores Genéticos/genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Polimorfismo de Nucleótido Simple/genética , Reproducibilidad de los Resultados
5.
Nature ; 459(7246): 569-73, 2009 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-19404257

RESUMEN

Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with approximately 550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 x 10(-3)). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 x 10(-3)). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 x 10(-6)). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.


Asunto(s)
Trastorno Autístico/genética , Dosificación de Gen/genética , Variación Genética/genética , Genoma Humano/genética , Neuronas/metabolismo , Ubiquitina/metabolismo , Estudios de Casos y Controles , Moléculas de Adhesión Celular Neuronal/genética , Estudios de Cohortes , Europa (Continente)/etnología , Redes Reguladoras de Genes/genética , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Reacción en Cadena de la Polimerasa , Polimorfismo de Nucleótido Simple/genética , Reproducibilidad de los Resultados
6.
Am J Med Genet B Neuropsychiatr Genet ; 165B(8): 619-26, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25228354

RESUMEN

Schizophrenia is a chronic and severe psychiatric disorder that is highly heritable. While both common and rare genetic variants contribute to disease risk, many questions still remain about disease etiology. We performed a genome-wide analysis of copy number variants (CNVs) in 166 schizophrenia subjects and 52 psychiatrically healthy controls. First, overall CNV characteristics were compared between cases and controls. The only statistically significant finding was that deletions comprised a greater proportion of CNVs in cases. High interest CNVs were then identified as conservative using the following filtering criteria: (i) known deleterious CNVs; (ii) CNVs > 1 Mb that were novel (not found in a database of control individuals); and (iii) CNVs < 1 Mb that were novel and that overlapped the coding region of a gene of interest. Cases did not harbor a higher proportion of conservative CNVs in comparison to controls. However, similar to previous reports, cases had a slightly higher proportion of individuals with clinically significant CNVs (known deleterious or conservative CNVs > 1 Mb) or with multiple conservative CNVs. Two case individuals with the highest burden of conservative CNVs also share a recurrent 15q11.2 BP1-2 deletion, indicating a role for a potential multiple-hit CNV model for schizophrenia. In total, we report three 15q11.2 BP1-2 deletion individuals with schizophrenia, adding to a growing body of evidence that this CNV is involved in disease etiology.


Asunto(s)
Variaciones en el Número de Copia de ADN/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Esquizofrenia/genética , Adolescente , Adulto , Femenino , Estudio de Asociación del Genoma Completo/métodos , Humanos , Masculino , Persona de Mediana Edad , Modelos Genéticos , Eliminación de Secuencia/genética , Adulto Joven
7.
Hum Mol Genet ; 20(12): 2482-94, 2011 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-21447600

RESUMEN

We report identification of a novel genetic locus (GLC1P) for normal tension glaucoma (NTG) on chromosome 12q14 using linkage studies of an African-American pedigree (maximum non-parametric linkage score = 19.7, max LOD score = 2.7). Subsequent comparative genomic hybridization and quantitative polymerase chain reaction (PCR) experiments identified a 780 kbp duplication within the GLC1P locus that is co-inherited with NTG in the pedigree. Real-time PCR studies showed that the genes within this duplication [TBK1 (TANK-binding kinase 1), XPOT, RASSF3 and GNS] are all expressed in the human retina. Cohorts of 478 glaucoma patients (including 152 NTG patients), 100 normal control subjects and 400 age-related macular degeneration patients were subsequently tested for copy number variation in GLC1P. Overlapping duplications were detected in 2 (1.3%) of the 152 NTG subjects, one of which had a strong family history of glaucoma. These duplications defined a 300 kbp critical region of GLC1P that spans two genes (TBK1 and XPOT). Microarray expression experiments and northern blot analysis using RNA obtained from human skin fibroblast cells showed that duplication of chromosome 12q14 results in increased TBK1 and GNS transcription. Finally, immunohistochemistry studies showed that TBK1 is expressed in the ganglion cells, nerve fiber layer and microvasculature of the human retina. Together, these data link the duplication of genes on chromosome 12q14 with familial NTG and suggest that an extra copy of the encompassed TBK1 gene is likely responsible for these cases of glaucoma. However, animal studies will be necessary to rule out a role for the other duplicated or neighboring genes.


Asunto(s)
Cromosomas Humanos Par 12/genética , Variaciones en el Número de Copia de ADN/genética , Glaucoma de Baja Tensión/genética , Proteínas Serina-Treonina Quinasas/genética , Negro o Afroamericano , Northern Blotting , Duplicación Cromosómica/genética , Estudios de Cohortes , Hibridación Genómica Comparativa , Ligamiento Genético/genética , Humanos , Análisis por Micromatrices , Linaje , Reacción en Cadena de la Polimerasa , Proteínas Serina-Treonina Quinasas/metabolismo
8.
Neuroimage ; 61(4): 866-75, 2012 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-22440650

RESUMEN

Recently, deriving candidate endophenotypes from brain imaging data has become a valuable approach to study genetic influences on schizophrenia (SZ), whose pathophysiology remains unclear. In this work we utilized a multivariate approach, parallel independent component analysis, to identify genomic risk components associated with brain function abnormalities in SZ. 5157 candidate single nucleotide polymorphisms (SNPs) were derived from genome-wide array based on their possible connections with SZ and further investigated for their associations with brain activations captured with functional magnetic resonance imaging (fMRI) during a sensorimotor task. Using data from 92 SZ patients and 116 healthy controls, we detected a significant correlation (r=0.29; p=2.41 × 10(-5)) between one fMRI component and one SNP component, both of which significantly differentiated patients from controls. The fMRI component mainly consisted of precentral and postcentral gyri, the major activated regions in the motor task. On average, higher activation in these regions was observed in participants with higher loadings of the linked SNP component, predominantly contributed to by 253 SNPs. 138 identified SNPs were from known coding regions of 100 unique genes. 31 identified SNPs did not differ between groups, but moderately correlated with some other group-discriminating SNPs, indicating interactions among alleles contributing toward elevated SZ susceptibility. The genes associated with the identified SNPs participated in four neurotransmitter pathways: GABA receptor signaling, dopamine receptor signaling, neuregulin signaling and glutamate receptor signaling. In summary, our work provides further evidence for the complexity of genomic risk to the functional brain abnormality in SZ and suggests a pathological role of interactions between SNPs, genes and multiple neurotransmitter pathways.


Asunto(s)
Mapeo Encefálico , Encéfalo/fisiopatología , Predisposición Genética a la Enfermedad , Esquizofrenia/genética , Esquizofrenia/fisiopatología , Transmisión Sináptica/genética , Adolescente , Adulto , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Adulto Joven
9.
PLoS Genet ; 5(6): e1000536, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19557195

RESUMEN

The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11-q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3x10(-5)). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3x10(-4)). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3x10(-39)), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts.


Asunto(s)
Trastorno Autístico/genética , Exones , Dosificación de Gen , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Adolescente , Proteínas de Unión al Calcio , Estudios de Casos y Controles , Moléculas de Adhesión Celular Neuronal , Niño , Preescolar , Estudios de Cohortes , Femenino , Duplicación de Gen , Humanos , Masculino , Proteínas del Tejido Nervioso/genética , Moléculas de Adhesión de Célula Nerviosa , Linaje , Eliminación de Secuencia , Ubiquitina-Proteína Ligasas/genética , Adulto Joven
10.
Stem Cell Res ; 59: 102636, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-34953327

RESUMEN

16p11.2 copy number variations have been associated with neurodevelopmental disorders. Human induced pluripotent stem cells were generated from fibroblasts obtained from a patient diagnosed with schizophrenia with a 16p11.2 deletion. The generated cell line was further validated for its pluripotency and potential to differentiate into the three germ layers.

11.
J Vis Exp ; (187)2022 09 16.
Artículo en Inglés | MEDLINE | ID: mdl-36190246

RESUMEN

The precise and timely development of the cerebellum is crucial not only for accurate motor coordination and balance but also for cognition. In addition, disruption in cerebellar development has been implicated in many neurodevelopmental disorders, including autism, attention deficit-hyperactivity disorder (ADHD), and schizophrenia. Investigations of cerebellar development in humans have previously only been possible through post-mortem studies or neuroimaging, yet these methods are not sufficient for understanding the molecular and cellular changes occurring in vivo during early development, which is when many neurodevelopmental disorders originate. The emergence of techniques to generate human-induced pluripotent stem cells (iPSCs) from somatic cells and the ability to further re-differentiate iPSCs into neurons have paved the way for in vitro modeling of early brain development. The present study provides simplified steps toward generating cerebellar cells for applications that require a 2-dimensional (2D) monolayer structure. Cerebellar cells representing early developmental stages are derived from human iPSCs via the following steps: first, embryoid bodies are made in 3-dimensional (3D) culture, then they are treated with FGF2 and insulin to promote cerebellar fate specification, and finally, they are terminally differentiated as a monolayer on poly-l-ornithine (PLO)/laminin-coated substrates. At 35 days of differentiation, iPSC-derived cerebellar cell cultures express cerebellar markers including ATOH1, PTF1α, PAX6, and KIRREL2, suggesting that this protocol generates glutamatergic and GABAergic cerebellar neuronal precursors, as well as Purkinje cell progenitors. Moreover, the differentiated cells show distinct neuronal morphology and are positive for immunofluorescence markers of neuronal identity such as TUBB3. These cells express axonal guidance molecules, including semaphorin-4C, plexin-B2, and neuropilin-1, and could serve as a model for investigating the molecular mechanisms of neurite outgrowth and synaptic connectivity. This method generates human cerebellar neurons useful for downstream applications, including gene expression, physiological, and morphological studies requiring 2D monolayer formats.


Asunto(s)
Células Madre Pluripotentes Inducidas , Insulinas , Semaforinas , Diferenciación Celular/genética , Cerebelo , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Neuronas GABAérgicas/metabolismo , Humanos , Insulinas/metabolismo , Laminina/metabolismo , Neuropilina-1/metabolismo , Semaforinas/metabolismo
12.
Neuroimage ; 57(4): 1591-600, 2011 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-21642004

RESUMEN

BACKGROUND: Disrupted in schizophrenia 1 (DISC1) is known to play a major role during brain development and is a candidate gene for schizophrenia. Cortical thickness is highly heritable and several MRI studies have shown widespread reductions of cortical thickness in patients with schizophrenia. Here, we investigated the effects of variation in DISC1 on cortical thickness. In a subsequent analysis we tested whether the identified DISC1 risk variant is also associated with neural activity during working memory functioning. METHODS: We acquired structural MRI (sMRI), functional MRI (fMRI) and genotype data from 96 healthy volunteers. Separate cortical statistical maps for five single nucleotide polymorphisms (SNP) of DISC1 were generated to detect differences of cortical thickness in genotype groups across the entire cortical surface. Working-memory related load-dependent activation was measured during the Sternberg Item Recognition Paradigm and analyzed using a region-of-interest approach. RESULTS: Phe allele carriers of the DISC1 SNP Leu607Phe had significantly reduced cortical thickness in the left supramarginal gyrus compared to Leu/Leu homozygotes. Neural activity in the left dorsolateral prefrontal cortex (DLPFC) during working memory task was increased in Phe allele carriers, whereas working memory performance did not differ between genotype groups. CONCLUSIONS: This study provides convergent evidence for the effect of DISC1 risk variants on two independent brain-based intermediate phenotypes of schizophrenia. The same risk variant was associated with cortical thickness reductions and signs of neural inefficiency during a working memory task. Our findings provide further evidence for a neurodevelopmental model of schizophrenia.


Asunto(s)
Corteza Cerebral/patología , Memoria a Corto Plazo/fisiología , Proteínas del Tejido Nervioso/genética , Esquizofrenia/genética , Esquizofrenia/patología , Adulto , Mapeo Encefálico , Corteza Cerebral/fisiopatología , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Interpretación de Imagen Asistida por Computador , Imagen por Resonancia Magnética , Masculino , Polimorfismo de Nucleótido Simple , Esquizofrenia/fisiopatología
13.
Hum Genet ; 129(1): 91-100, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-20981449

RESUMEN

Age-related macular degeneration (AMD) is a complex genetic disease, with many loci demonstrating appreciable attributable disease risk. Despite significant progress toward understanding the genetic and environmental etiology of AMD, identification of additional risk factors is necessary to fully appreciate and treat AMD pathology. In this study, we investigated copy number variants (CNVs) as potential AMD risk variants in a cohort of 400 AMD patients and 500 AMD-free controls ascertained at the University of Iowa. We used three publicly available copy number programs to analyze signal intensity data from Affymetrix GeneChip SNP Microarrays. CNVs were ranked based on prevalence in the disease cohort and absence from the control group; high interest CNVs were subsequently confirmed by qPCR. While we did not observe a single-locus "risk CNV" that could account for a major fraction of AMD, we identified several rare and overlapping CNVs containing or flanking compelling candidate genes such as NPHP1 and EFEMP1. These and other candidate genes highlighted by this study deserve further scrutiny as sources of genetic risk for AMD.


Asunto(s)
Variaciones en el Número de Copia de ADN/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Degeneración Macular/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Anciano , Anciano de 80 o más Años , Neovascularización Coroidal/epidemiología , Neovascularización Coroidal/genética , Estudios de Cohortes , Proteínas del Citoesqueleto , Proteínas de la Matriz Extracelular/genética , Femenino , Humanos , Iowa/epidemiología , Degeneración Macular/epidemiología , Masculino , Proteínas de la Membrana/genética , Polimorfismo de Nucleótido Simple , Prevalencia , Factores de Riesgo
14.
Proc Natl Acad Sci U S A ; 105(45): 17573-8, 2008 Nov 11.
Artículo en Inglés | MEDLINE | ID: mdl-18988738

RESUMEN

Understanding how risk genes cumulatively impair brain function in schizophrenia could provide critical insights into its pathophysiology. Working memory impairment in schizophrenia has been associated with abnormal dopamine signaling in the prefrontal cortex, which is likely under complex genetic control. The catechol-O-methyltransferase (COMT) 158Val --> Met polymorphism (rs4680), which affects the availability of prefrontal dopamine signaling, consistently stratifies prefrontal activation during working memory performance. However, the low-dopamine COMT 158Val allele does not confer increased risk for schizophrenia, and its effects on prefrontal function are not specific to the disorder. In the setting of other genetic variants influencing prefrontal dopamine signaling, COMT 158Val --> Met genotype may exert disease-specific effects. A second polymorphism, methylenetetrahydrofolate reductase (MTHFR) 677C --> T (rs1801133), has been associated with overall schizophrenia risk and executive function impairment in patients, and may influence dopamine signaling through mechanisms upstream of COMT effects. We found that the hypofunctional 677T variant was associated with decreased working memory load-dependent activation in the prefrontal and insular cortices in 79 schizophrenia patients, but not in 75 demographically matched healthy controls. Further, significant MTHFR x COMT genotype interactions were observed, which differed by diagnostic group: Reduced prefrontal activation was associated with the 677T and 158Val alleles in patients, but with 677C/C and 158Met/Met genotype in controls. These findings are consistent with epistatic effects of the COMT and MTHFR polymorphisms on prefrontal dopamine signaling, and suggest that in schizophrenia patients, the MTHFR 677T allele exacerbates prefrontal dopamine deficiency. The findings also suggest the importance of weighing COMT effects on prefrontal function within the context of MTHFR genotype.


Asunto(s)
Catecol O-Metiltransferasa/metabolismo , Metilenotetrahidrofolato Reductasa (NADPH2)/metabolismo , Polimorfismo Genético , Corteza Prefrontal/fisiopatología , Esquizofrenia/genética , Transducción de Señal/genética , Catecol O-Metiltransferasa/genética , Dopamina/metabolismo , Genotipo , Humanos , Imagen por Resonancia Magnética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Esquizofrenia/fisiopatología , Estados Unidos
15.
Am J Med Genet B Neuropsychiatr Genet ; 153B(2): 640-647, 2010 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-19760675

RESUMEN

Schizophrenia is a neurodevelopmental psychiatric disorder characterized by a variety of structural brain abnormalities that appear to progress across the course of illness. Schizophrenia also is highly heritable, and one gene that has emerged as a possible susceptibility factor is G72. G72 influences brain development and activity by an as-yet unclear mechanism, and multiple studies have reported associations between G72 and schizophrenia. We were interested in linking these domains of investigation by determining whether G72 also influences the rate of longitudinal structural brain changes in individuals with schizophrenia. As part of the Iowa Longitudinal Study of Recent Onset Psychoses, we genotyped four G72 polymorphisms previously associated with schizophrenia in 110 subjects with schizophrenia or schizoaffective disorder from whom we had obtained two brain MRI scans an average of 3 years apart. The four polymorphisms captured three haplotypes, one of which was strongly associated with an increased rate of frontal lobe volume decrement. This same haplotype was also associated with more severe psychotic symptoms at the time of the second scan. These data thus suggest that variation in G72 modulates the progressive brain changes that characterize schizophrenia.


Asunto(s)
Proteínas Portadoras/genética , Lóbulo Frontal/patología , Imagen por Resonancia Magnética/métodos , Trastornos Psicóticos/genética , Esquizofrenia/genética , Adulto , Encéfalo/patología , Femenino , Variación Genética , Genotipo , Haplotipos , Humanos , Péptidos y Proteínas de Señalización Intracelular , Estudios Longitudinales , Masculino , Polimorfismo Genético
16.
Abdom Imaging ; 34(6): 783-7, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17901913

RESUMEN

BACKGROUND: To evaluate the value of early computed tomography (CT) on identifying clinically "unexpected" diagnosis in patients presenting with "non specific" acute abdominal pain. MATERIALS AND METHODS: All patients presenting to on-call surgeons with acute abdominal pain were eligible study participants. Patients were randomised to CT within one hour of admission or supine abdominal and erect chest radiography. Ninety-nine patients randomized to CT arm were reviewed for the purpose of this study. The number and severity of unexpected and/or incidental diagnoses detected on the CT were assessed. RESULTS: In 20 of the 99 patients CT revealed primary or secondary diagnoses, which were unexpected following the initial clinical examination and led to completely different therapeutic options. In 15 of those 20 patients CT revealed clinically unexpected conditions, whereas in two patients severe complications of the clinically suspected diagnosis were detected on CT. Five patients had significant incidental findings in addition to their primary diagnosis on CT. In two of these patient CT also revealed clinically unexpected diagnoses. CONCLUSION: Early CT has the advantage of detecting unexpected clinically significant primary and secondary diagnoses in patients presenting with acute abdominal pain and best guides the surgeon to the appropriate patient management.


Asunto(s)
Dolor Abdominal/diagnóstico por imagen , Enfermedades Gastrointestinales/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Medios de Contraste , Diagnóstico Diferencial , Diagnóstico Precoz , Femenino , Humanos , Yopamidol , Masculino , Estudios Prospectivos
17.
Schizophr Res ; 106(2-3): 192-9, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18799289

RESUMEN

Transcription factors, including the basic helix-loop-helix (bHLH) family, regulate numerous genes and play vital roles in controlling gene expression. Consequently, transcription factor mutations can lead to phenotypic pleiotropy, and may be a candidate mechanism underlying the complex genetics and heterogeneous phenotype of schizophrenia. Neurogenin1 (NEUROG1; a.k.a. Ngn1 or Neurod3), a bHLH transcription factor encoded on a known schizophrenia linkage region in 5q31.1, induces glutamatergic and suppresses GABAergic neuronal differentiation during embryonic neurodevelopment. The goal of this study is to investigate NEUROG1 effects on schizophrenia risk and on phenotypic features of schizophrenia. We tested 392 patients with schizophrenia or schizoaffective disorder and 226 healthy normal volunteers for association with NEUROG1. Major alleles on two NEUROG1-associated SNPs (rs2344484-C-allele and rs8192558-G-allele) were significantly more prevalent among patients (p

Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Encéfalo/patología , Trastornos del Conocimiento/diagnóstico , Susceptibilidad a Enfermedades/patología , Imagen por Resonancia Magnética , Proteínas del Tejido Nervioso/genética , Esquizofrenia/genética , Adulto , Trastornos del Conocimiento/genética , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Femenino , Predisposición Genética a la Enfermedad , Variación Genética , Humanos , Masculino , Pruebas Neuropsicológicas , Fenotipo , Polimorfismo de Nucleótido Simple , Esquizofrenia/diagnóstico , Esquizofrenia/patología , Psicología del Esquizofrénico
18.
Arch Gen Psychiatry ; 64(6): 709-17, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17548752

RESUMEN

CONTEXT: Autism is a heritable neurodevelopmental disorder characterized biologically by enlargement of the head and brain and abnormalities of serotonin neurotransmission. OBJECTIVE: To evaluate whether 5-HTTLPR, a functional promoter polymorphism of the serotonin transporter gene SLC6A4, influences cerebral cortical structure volumes in young male children with autism. DESIGN: Association study of a genetic variant with quantitative traits. SETTING: Autism research centers at the University of North Carolina (UNC), Chapel Hill, and the University of Washington (UW), Seattle. PARTICIPANTS: Forty-four male children, 2 to 4 years old, with autism participating in longitudinal brain magnetic resonance imaging studies. MAIN OUTCOME MEASURES: Cerebral cortical and cerebellar gray and white matter volumes. RESULTS: We found that 5-HTTLPR genotype influenced gray matter volumes of the cerebral cortex (F(2,23) = 7.29, P = .004) and of 3 lobe-based subregions in the UNC sample of 29 children (frontal lobe gray matter: F(2,23) = 6.36, P = .01). The 5-HTTLPR short allele appeared to be additively associated with increasing gray matter volumes, an observation affirmed by tests of linear genotype effects (cortical gray matter: F(1,24) = 14.11, P = .001; frontal lobe gray matter: F(1,24) = 13.20, P = .001). Genotype did not influence cerebellar volumes. Confirmation was pursued by means of the UW sample of 15 children. While effects were not significant in the UW sample alone, the patterns of adjusted means resembled those found in the UNC sample. Positive Cochran-Mantel-Haenszel test results supported the concordance of relationships across the 2 sites, and analyses of covariance of the combined sample that included a site covariate showed significant linear genotype effects on structure volumes (cortical gray matter: F(1,38) = 5.73, P = .02; frontal lobe gray matter: F(1,38) = 11.73, P = .002). Effect sizes of 5-HTTLPR genotype on total cortical and frontal lobe gray matter volumes were 10% and 16%, respectively. CONCLUSION: The SLC6A4 promoter polymorphism 5-HTTLPR influences cerebral cortical gray matter volumes in young male children with autism.


Asunto(s)
Trastorno Autístico/genética , Trastorno Autístico/patología , Corteza Cerebral/patología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Factores de Edad , Cerebelo/patología , Preescolar , Femenino , Lóbulo Frontal/patología , Variación Genética , Genotipo , Humanos , Hipertrofia/patología , Imagen por Resonancia Magnética , Masculino , Polimorfismo Genético , Factores Sexuales
19.
Am J Med Genet B Neuropsychiatr Genet ; 147B(7): 1145-51, 2008 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-18361446

RESUMEN

Monoamine oxidase A (MAOA) is an enzyme expressed in the brain that metabolizes dopamine, norepinephrine, epinephrine, and serotonin. Abnormalities of serotonin neurotransmission have long been implicated in the psychopathology of autism. A polymorphism exists within the promoter region of the MAOA gene that influences MAOA expression levels so that "low activity" alleles are associated with increased neurotransmitter levels in the brain. Individuals with autism often exhibit elevated serotonin levels. Additional studies indicate that the "low activity" allele may be associated with lower IQ and more severe autistic symptoms. In this study we genotyped the MAOA promoter polymorphism in a group of 29 males (age 2-3 years) with autism and a group of 39 healthy pediatric controls for whom brain MRI data was available. We found a consistent association between the "low activity" allele and larger brain volumes for regions of the cortex in children with autism but not in controls. We did not find evidence for over-transmission of the "low activity" allele in a separate sample of 114 affected sib pair families. Nor did we find any unknown SNPs in yet another sample of 96 probands. Future studies will determine if there is a more severe clinical phenotype associated with both the "low activity" genotype and the larger brain volumes in our sample.


Asunto(s)
Trastorno Autístico/genética , Corteza Cerebral/anomalías , Repeticiones de Minisatélite , Monoaminooxidasa/genética , Alelos , Trastorno Autístico/patología , Estudios de Casos y Controles , Corteza Cerebral/patología , Preescolar , Salud de la Familia , Impresión Genómica , Genotipo , Humanos , Imagen por Resonancia Magnética , Masculino , Monoaminooxidasa/fisiología , Tamaño de los Órganos , Fenotipo , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas/genética
20.
Am J Psychiatry ; 164(12): 1890-9, 2007 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18056245

RESUMEN

OBJECTIVE: Factors underlying progressive brain volume changes in schizophrenia remain poorly understood. The authors investigated whether a gene polymorphism influencing neuroplasticity may contribute to longitudinal brain volume alterations. METHOD: High-resolution magnetic resonance (MR) images of the whole brain were obtained for 119 patients with recent-onset schizophrenia spectrum disorders. Changes in brain volumes over an average of 3 years were compared between brain-derived neurotrophic factor (BDNF) val66met genotype groupings. Exploratory analyses were conducted to examine relationships between antipsychotic treatment and brain volume changes as well as the effects of BDNF genotype on changes in cognition and symptoms. RESULTS: Significant genotype effects were observed on within-subject changes in volumes of frontal lobe gray matter, lateral ventricles, and sulcal CSF. Met allele carriers had significantly greater reductions in frontal gray matter volume, with reciprocal volume increases in the lateral ventricles and sulcal (especially frontal and temporal) CSF than Val homozygous patients. Independent of BDNF genotype, more antipsychotic exposure between MRI scans correlated with greater volume reductions in frontal gray matter, particularly among patients who were initially treatment naive. There were no statistically significant genotype effects on within-subject changes in cognition or symptoms. CONCLUSIONS: BDNF(Met) variant may be one of several factors affecting progressive brain volume changes in schizophrenia.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/genética , Encéfalo/patología , Variación Genética , Polimorfismo Genético/genética , Esquizofrenia/genética , Esquizofrenia/patología , Adulto , Antipsicóticos/uso terapéutico , Atrofia/patología , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/psicología , Femenino , Lóbulo Frontal/patología , Genotipo , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética/estadística & datos numéricos , Masculino , Metionina/genética , Plasticidad Neuronal/genética , Pruebas Neuropsicológicas , Esquizofrenia/tratamiento farmacológico , Psicología del Esquizofrénico , Índice de Severidad de la Enfermedad , Valina/genética
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