21 research outputs found
Increased BDNF levels and NTRK2 gene association suggest a disruption of BDNF/TrkB signaling in autism
The brain-derived neurotrophic factor (BDNF), a neurotrophin fundamental for brain development and function, has previously been implicated in autism. In this study, the levels of BDNF in platelet-rich plasma were compared between autistic and control children, and the role of two genetic factors that might regulate this neurotrophin and contribute to autism etiology, BDNF and NTRK2, was examined. We found that BDNF levels in autistic children (n = 146) were significantly higher (t = 6.82; P < 0.0001) than in control children (n = 50) and were positively correlated with platelet serotonin distribution (r = 0.22; P = 0.004). Heritability of BDNF was estimated at 30% and therefore candidate genes BDNF and NTRK2 were tested for association with BDNF level distribution in this sample, and with autism in 469 trio families. Genetic association analysis provided no evidence for BDNF or NTRK2 as major determinants of the abnormally increased BDNF levels in autistic children. A significant association with autism was uncovered for six single nucleotide polymorphisms (SNPs) [0.004 (Z((1df)) = 2.85) < P < 0.039 (Z((1df)) = 2.06)] and multiple haplotypes [5 × 10(-4) (χ((3df)) = 17.77) < P < 0.042 (χ((9df)) = 17.450)] in the NTRK2 gene. These results do not withstand correction for multiple comparisons, however, reflect a trend toward association that supports a role of NTRK2 as a susceptibility factor for the disorder. Genetic variation in the BDNF gene had no impact on autism risk. By substantiating the previously observed increase in BDNF levels in autistic children in a larger patient set, and suggesting a genetic association between NTRK2 and autism, this study integrates evidence from multiple levels supporting the hypothesis that alterations in BDNF/tyrosine kinase B (TrkB) signaling contribute to an increased vulnerability to autism
Dysfunction of the Heteromeric KV7.3/KV7.5 Potassium Channel is Associated with Autism Spectrum Disorders
Heterozygous mutations in the KCNQ3 gene on chromosome 8q24 encoding the voltage-gated potassium channel KV7.3 subunit have previously been associated with rolandic epilepsy and idiopathic generalized epilepsy (IGE) including benign neonatal convulsions. We identified a de novo t(3;8) (q21;q24) translocation truncating KCNQ3 in a boy with childhood autism. In addition, we identified a c.1720C > T [p.P574S] nucleotide change in three unrelated individuals with childhood autism and no history of convulsions. This nucleotide change was previously reported in patients with rolandic epilepsy or IGE and has now been annotated as a very rare SNP (rs74582884) in dbSNP. The p.P574S KV7.3 variant significantly reduced potassium current amplitude in Xenopus laevis oocytes when co-expressed with KV7.5 but not with KV7.2 or KV7.4. The nucleotide change did not affect trafficking of heteromeric mutant KV7.3/2, KV7.3/4, or KV7.3/5 channels in HEK 293 cells or primary rat hippocampal neurons. Our results suggest that dysfunction of the heteromeric KV7.3/5 channel is implicated in the pathogenesis of some forms of autism spectrum disorders, epilepsy, and possibly other psychiatric disorders and therefore, KCNQ3 and KCNQ5 are suggested as candidate genes for these disorders
Using data envelopment analysis to support the design of process improvement interventions in electricity distribution
A significant number of studies have documented the use of Data Envelopment Analysis (DEA) for efficiency measurement in the context of electricity distribution, particularly at the level of the distribution
utilities. However, their aim has been predominantly descriptive and classificatory, without any attempt
to ‘open’ the black box of the transformation process. In contrast, our aim is to explore the potential of DEA to contribute to the design of effective process improvement interventions within a distribution utility.
In particular, in this paper, we study an important question within the context of DEA analysis: that is, to investigate whether differences in efficiency can be attributed to a particular managerial programme or design feature. We use two different methodologies to undertake this type of analysis. Firstly, we apply Mann–Whitney rank statistics to the scores obtained from DEA in order to evaluate the statistical significance of the differences observed between an intervention programme and its control group programme.
Secondly, we undertake dynamic analysis with the Malmquist Productivity Index in order to study the impact of the introduction of a new technology on a group of units. Our case study focuses on the performance evaluation of medium-voltage power lines belonging to one of the service areas in the Public
Electricity Distribution System in Portugal. The results from our case study show that the application of DEA for process improvement interventions has great potential and should be explored in other
contexts
Recurrent duplications of the annexin A1 gene (ANXA1) in autism spectrum disorders
Validating the potential pathogenicity of copy number variants (CNVs) identified in genome-wide studies of autism spectrum disorders (ASD) requires detailed assessment of case/control frequencies, inheritance patterns, clinical correlations, and functional impact. Here, we characterize a small recurrent duplication in the annexin A1 (ANXA1) gene, identified by the Autism Genome Project (AGP) study
Near‐infrared and visible‐light periocular recognition with Gabor features using frequency‐adaptive automatic eye detection
Mitochondrial Mutations in Subjects with Psychiatric Disorders
A considerable body of evidence supports the role of mitochondrial dysfunction in psychiatric disorders and mitochondrial DNA (mtDNA) mutations are known to alter brain energy metabolism, neurotransmission, and cause neurodegenerative disorders. Genetic studies focusing on common nuclear genome variants associated with these disorders have produced genome wide significant results but those studies have not directly studied mtDNA variants. The purpose of this study is to investigate, using next generation sequencing, the involvement of mtDNA variation in bipolar disorder, schizophrenia, major depressive disorder, and methamphetamine use. MtDNA extracted from multiple brain regions and blood were sequenced (121 mtDNA samples with an average of 8,800x coverage) and compared to an electronic database containing 26,850 mtDNA genomes. We confirmed novel and rare variants, and confirmed next generation sequencing error hotspots by traditional sequencing and genotyping methods. We observed a significant increase of non-synonymous mutations found in individuals with schizophrenia. Novel and rare non-synonymous mutations were found in psychiatric cases in mtDNA genes: ND6, ATP6, CYTB, and ND2. We also observed mtDNA heteroplasmy in brain at a locus previously associated with schizophrenia (T16519C). Large differences in heteroplasmy levels across brain regions within subjects suggest that somatic mutations accumulate differentially in brain regions. Finally, multiplasmy, a heteroplasmic measure of repeat length, was observed in brain from selective cases at a higher frequency than controls. These results offer support for increased rates of mtDNA substitutions in schizophrenia shown in our prior results. The variable levels of heteroplasmic/multiplasmic somatic mutations that occur in brain may be indicators of genetic instability in mtDNA
Induction of immune response in broiler chickens immunized with recombinant FliC and challenged by Salmonella Typhimurium
Genetic and Functional Analyses of SHANK2 Mutations Suggest a Multiple Hit Model of Autism Spectrum Disorders
Peer reviewe
Pharmacogenetics of risperidone therapy in autism: association analysis of eight candidate genes with drug efficacy and adverse drug reactions
Little has been reported on the factors, genetic or other, that underlie the variability in individual response, particularly for autism. In this study we simultaneously explored the effects of multiple candidate genes on clinical improvement and occurrence of adverse drug reactions, in 45 autistic patients who received monotherapy with risperidone up to 1 year. Candidate genes involved in the pharmacokinetics (CYP2D6 and ABCB1) and pharmacodynamics (HTR2A, HTR2C, DRD2, DRD3, HTR6) of the drug, and the brain-derived neurotrophic factor (BDNF) gene, were analysed. Using the generalized estimating equation method these genes were tested for association with drug efficacy, assessed with the Autism Treatment Evaluation Checklist, and with safety and tolerability measures, such as prolactin levels, body mass index (BMI), waist circumference and neurological adverse effects, including extrapyramidal movements. Our results confirm that risperidone therapy was very effective in reducing some autism symptoms and caused few serious adverse effects. After adjusting for confounding factors, the HTR2A c.-1438G>A, DRD3 Ser9Gly, HTR2C c.995G>A and ABCB1 1236C>T polymorphisms were predictors for clinical improvement with risperidone therapy. The HTR2A c.-1438G>A, HTR2C c.68G>C (p.C33S), HTR6 c.7154-2542C>T and BDNF c.196G>A (p.V66M) polymorphisms influenced prolactin elevation. HTR2C c.68G>C and CYP2D6 polymorphisms were associated with risperidone-induced increase in BMI or waist circumference. We thus identified for the first time several genes implicated in risperidone efficacy and safety in autism patients. Although association results require replication, given the small sample size, the study makes a preliminary contribution to the personalized therapy of risperidone in autism
Supplementary Material for: Mitochondrial Complex I Deficiency in Schizophrenia and Bipolar Disorder and Medication Influence
<p>Subjects with schizophrenia (SZ) and bipolar disorder (BD) show
decreased protein and transcript levels for mitochondrial complex I. In
vitro results suggest antipsychotic and antidepressant drugs may be
responsible. We measured complex I activity in BD, SZ, and controls and
presence of antipsychotic and antidepressant medications, mitochondrial
DNA (mtDNA) copy number, and the mtDNA “common deletion” in the brain.
Complex I activity in the prefrontal cortex was decreased by 45% in SZ
compared to controls (<i>p</i> = 0.02), while no significant difference was found in BD. Complex I activity was significantly decreased (<i>p</i>
= 0.01) in pooled cases (SZ and BD) that had detectable psychotropic
medications and drugs compared to pooled cases with no detectable
levels. Subjects with age at onset in their teens and psychotropic
medications showed decreased (<i>p</i> < 0.05) complex I activity
compared to subjects with an adult age at onset. Both SZ and BD groups
displayed significant increases (<i>p</i> < 0.05) in mtDNA copy
number compared to controls; however, common deletion burden was not
altered. Complex I deficiency is found in SZ brain tissue, and
psychotropic medications may play a role in mitochondrial dysfunction.
Studies of medication-free first-episode psychosis patients are needed
to elucidate whether mitochondrial pathophysiology occurs independent of
medication effects.</p