The underpotential deposition that should not be : Cu(1x1) on Au(111)

Peer reviewedPostprin

In Silico Whole Genome Association Scan for Murine Prepulse Inhibition

Background The complex trait of prepulse inhibition (PPI) is a sensory gating measure related to schizophrenia and can be measured in mice. Large-scale public repositories of inbred mouse strain genotypes and phenotypes such as PPI can be used to detect Quantitative Trait Loci (QTLs) in silico. However, the method has been criticized for issues including insufficient number of strains, not controlling for false discoveries, the complex haplotype structure of inbred mice, and failing to account for genotypic and phenotypic subgroups. Methodology/Principal Findings We have implemented a method that addresses these issues by incorporating phylogenetic analyses, multilevel regression with mixed effects, and false discovery rate (FDR) control. A genome-wide scan for PPI was conducted using over 17,000 single nucleotide polymorphisms (SNPs) in 37 strains phenotyped. Eighty-nine SNPs were significant at a false discovery rate (FDR) of 5%. After accounting for long-range linkage disequilibrium, we found 3 independent QTLs located on murine chromosomes 1 and 13. One of the PPI positives corresponds to a region of human chromosome 6p which includes DTNBP1, a gene implicated in schizophrenia. Another region includes the gene Tsn which alters PPI when knocked out. These genes also appear to have correlated expression with PPI. Conclusions/Significance These results support the usefulness of using an improved in silico mapping method to identify QTLs for complex traits such as PPI which can be then be used for to help identify loci influencing schizophrenia in humans

A population-based study of anxiety as a precursor for depression in childhood and adolescence

BACKGROUND: Anxiety and depression co-occur in children and adolescents with anxiety commonly preceding depression. Although there is some evidence to suggest that the association between early anxiety and later depression is explained by a shared genetic aetiology, the contribution of environmental factors is less well examined and it is unknown whether anxiety itself is a phenotypic risk factor for later depression. These explanations of the association between early anxiety and later depression were evaluated. METHODS: Anxiety and depressive symptoms were assessed longitudinally in a U.K. population-based sample of 676 twins aged 5–17 at baseline. At baseline, anxiety and depression were assessed by parental questionnaire. Depression was assessed three years later by parental and adolescent questionnaire. RESULTS: Shared genetic effects between early anxiety and later depression were found. A model of a phenotypic risk effect from early anxiety on later depression provided a poor fit to the data. However, there were significant genetic effects specific to later depression, showing that early anxiety and later depression do not index entirely the same genetic risk. CONCLUSIONS: Anxiety and depression are associated over time because they share a partly common genetic aetiology rather than because the anxiety phenotype leads to later depression

Heritability estimates of the Big Five personality traits based on common genetic variants

According to twin studies, the Big Five personality traits have substantial heritable components explaining 40–60% of the variance, but identification of associated genetic variants has remained elusive. Consequently, knowledge regarding the molecular genetic architecture of personality and to what extent it is shared across the different personality traits is limited. Using genomic-relatedness-matrix residual maximum likelihood analysis (GREML), we here estimated the heritability of the Big Five personality factors (extraversion, agreeableness, conscientiousness, neuroticism and openness for experience) in a sample of 5011 European adults from 527 469 single-nucleotide polymorphisms across the genome. We tested for the heritability of each personality trait, as well as for the genetic overlap between the personality factors. We found significant and substantial heritability estimates for neuroticism (15%, s.e.=0.08, P=0.04) and openness (21%, s.e.=0.08, P<0.01), but not for extraversion, agreeableness and conscientiousness. The bivariate analyses showed that the variance explained by common variants entirely overlapped between neuroticism and openness (rG=1.00, P <0.001), despite low phenotypic correlation (r=−0.09, P <0.001), suggesting that the remaining unique heritability may be determined by rare or structural variants. As far as we are aware of, this is the first study estimating the shared and unique heritability of all Big Five personality traits using the GREML approach. Findings should be considered exploratory and suggest that detectable heritability estimates based on common variants is shared between neuroticism and openness to experiences

Item response analysis of the Positive and Negative Syndrome Scale

<p>Abstract</p> <p>Background</p> <p>Statistical models based on item response theory were used to examine (a) the performance of individual Positive and Negative Syndrome Scale (PANSS) items and their options, (b) the effectiveness of various subscales to discriminate among individual differences in symptom severity, and (c) the appropriateness of cutoff scores recently recommended by Andreasen and her colleagues (2005) to establish symptom remission.</p> <p>Methods</p> <p>Option characteristic curves were estimated using a nonparametric item response model to examine the probability of endorsing each of 7 options within each of 30 PANSS items as a function of standardized, overall symptom severity. Our data were baseline PANSS scores from 9205 patients with schizophrenia or schizoaffective disorder who were enrolled between 1995 and 2003 in either a large, naturalistic, observational study or else in 1 of 12 randomized, double-blind, clinical trials comparing olanzapine to other antipsychotic drugs.</p> <p>Results</p> <p>Our analyses show that the majority of items forming the Positive and Negative subscales of the PANSS perform very well. We also identified key areas for improvement or revision in items and options within the General Psychopathology subscale. The Positive and Negative subscale scores are not only more discriminating of individual differences in symptom severity than the General Psychopathology subscale score, but are also more efficient on average than the 30-item total score. Of the 8 items recently recommended to establish symptom remission, 1 performed markedly different from the 7 others and should either be deleted or rescored requiring that patients achieve a lower score of 2 (rather than 3) to signal remission.</p> <p>Conclusion</p> <p>This first item response analysis of the PANSS supports its sound psychometric properties; most PANSS items were either very good or good at assessing overall severity of illness. These analyses did identify some items which might be further improved for measuring individual severity differences or for defining remission thresholds. Findings also suggest that the Positive and Negative subscales are more sensitive to change than the PANSS total score and, thus, may constitute a "mini PANSS" that may be more reliable, require shorter administration and training time, and possibly reduce sample sizes needed for future research.</p

MI-GWAS: a SAS platform for the analysis of inherited and maternal genetic effects in genome-wide association studies using log-linear models

<p>Abstract</p> <p>Background</p> <p>Several platforms for the analysis of genome-wide association data are available. However, these platforms focus on the evaluation of the genotype inherited by affected (i.e. case) individuals, whereas for some conditions (e.g. birth defects) the genotype of the mothers of affected individuals may also contribute to risk. For such conditions, it is critical to evaluate associations with both the maternal and the inherited (i.e. case) genotype. When genotype data are available for case-parent triads, a likelihood-based approach using log-linear modeling can be used to assess both the maternal and inherited genotypes. However, available software packages for log-linear analyses are not well suited to the analysis of typical genome-wide association data (e.g. including missing data).</p> <p>Results</p> <p>An integrated platform, Maternal and Inherited Analyses for Genome-wide Association Studies <b>(</b>MI-GWAS) for log-linear analyses of maternal and inherited genetic effects in large, genome-wide datasets, is described. MI-GWAS uses SAS and LEM software in combination to appropriately format data, perform the log-linear analyses and summarize the results. This platform was evaluated using existing genome-wide data and was shown to perform accurately and relatively efficiently.</p> <p>Conclusions</p> <p>The MI-GWAS platform provides a valuable tool for the analysis of association of a phenotype or condition with maternal and inherited genotypes using genome-wide data from case-parent triads. The source code for this platform is freely available at <url>http://www.sph.uth.tmc.edu/sbrr/mi-gwas.htm</url>.</p

Genetic dissection of photoperiod response based on GWAS of pre-anthesis phase duration in spring barley

Heading time is a complex trait, and natural variation in photoperiod responses is a major factor controlling time to heading, adaptation and grain yield. In barley, previous heading time studies have been mainly conducted under field conditions to measure total days to heading. We followed a novel approach and studied the natural variation of time to heading in a world-wide spring barley collection (218 accessions), comprising of 95 photoperiod-sensitive (Ppd-H1) and 123 accessions with reduced photoperiod sensitivity (ppd-H1) to long-day (LD) through dissecting pre-anthesis development into four major stages and sub-phases. The study was conducted under greenhouse (GH) conditions (LD; 16/8 h; ∼20/∼16°C day/night). Genotyping was performed using a genome-wide high density 9K single nucleotide polymorphisms (SNPs) chip which assayed 7842 SNPs. We used the barley physical map to identify candidate genes underlying genome-wide association scans (GWAS). GWAS for pre-anthesis stages/sub-phases in each photoperiod group provided great power for partitioning genetic effects on floral initiation and heading time. In addition to major genes known to regulate heading time under field conditions, several novel QTL with medium to high effects, including new QTL having major effects on developmental stages/sub-phases were found to be associated in this study. For example, highly associated SNPs tagged the physical regions around HvCO1 (barley CONSTANS1) and BFL (BARLEY FLORICAULA/LEAFY) genes. Based upon our GWAS analysis, we propose a new genetic network model for each photoperiod group, which includes several newly identified genes, such as several HvCO-like genes, belonging to different heading time pathways in barley

Dysbindin Promotes the Post-Endocytic Sorting of G Protein-Coupled Receptors to Lysosomes

BackgroundDysbindin, a cytoplasmic protein long known to function in the biogenesis of specialized lysosome-related organelles (LROs), has been reported to reduce surface expression of D2 dopamine receptors in neurons. Dysbindin is broadly expressed, and dopamine receptors are members of the large family of G protein-coupled receptors (GPCRs) that function in diverse cell types. Thus we asked if dysbindin regulates receptor number in non-neural cells, and further investigated the cellular basis of this regulation.Methodology/principal findingsWe used RNA interference to deplete endogenous dysbindin in HEK293 and HeLa cells, then used immunochemical and biochemical methods to assess expression and endocytic trafficking of epitope-tagged GPCRs. Dysbindin knockdown up-regulated surface expression of D2 receptors compared to D1 receptors, as reported previously in neurons. This regulation was not mediated by a change in D2 receptor endocytosis. Instead, dysbindin knockdown specifically reduced the subsequent trafficking of internalized D2 receptors to lysosomes. This distinct post-endocytic sorting function explained the minimal effect of dysbindin depletion on D1 receptors, which recycle efficiently and traverse the lysosomal pathway to only a small degree. Moreover, dysbindin regulated the delta opioid receptor, a more distantly related GPCR that is also sorted to lysosomes after endocytosis. Dysbindin was not required for lysosomal trafficking of all signaling receptors, however, as its depletion did not detectably affect down-regulation of the EGF receptor tyrosine kinase. Dysbindin co-immunoprecipitated with GASP-1 (or GPRASP-1), a cytoplasmic protein shown previously to modulate lysosomal trafficking of D2 dopamine and delta opioid receptors by direct interaction, and with HRS that is a core component of the conserved ESCRT machinery mediating lysosome biogenesis and sorting.Conclusions/significanceThese results identify a distinct, and potentially widespread function of dysbindin in promoting the sorting of specific GPCRs to lysosomes after endocytosis

Use of NON-PARAMETRIC Item Response Theory to develop a shortened version of the Positive and Negative Syndrome Scale (PANSS)

<p>Abstract</p> <p>Background</p> <p>Nonparametric item response theory (IRT) was used to examine (a) the performance of the 30 Positive and Negative Syndrome Scale (PANSS) items and their options ((levels of severity), (b) the effectiveness of various subscales to discriminate among differences in symptom severity, and (c) the development of an abbreviated PANSS (Mini-PANSS) based on IRT and a method to link scores to the original PANSS.</p> <p>Methods</p> <p>Baseline PANSS scores from 7,187 patients with Schizophrenia or Schizoaffective disorder who were enrolled between 1995 and 2005 in psychopharmacology trials were obtained. Option characteristic curves (OCCs) and Item Characteristic Curves (ICCs) were constructed to examine the probability of rating each of seven options within each of 30 PANSS items as a function of subscale severity, and summed-score linking was applied to items selected for the Mini-PANSS.</p> <p>Results</p> <p>The majority of items forming the Positive and Negative subscales (i.e. 19 items) performed very well and discriminate better along symptom severity compared to the General Psychopathology subscale. Six of the seven Positive Symptom items, six of the seven Negative Symptom items, and seven out of the 16 General Psychopathology items were retained for inclusion in the Mini-PANSS. Summed score linking and linear interpolation was able to produce a translation table for comparing total subscale scores of the Mini-PANSS to total subscale scores on the original PANSS. Results show scores on the subscales of the Mini-PANSS can be linked to scores on the original PANSS subscales, with very little bias.</p> <p>Conclusions</p> <p>The study demonstrated the utility of non-parametric IRT in examining the item properties of the PANSS and to allow selection of items for an abbreviated PANSS scale. The comparisons between the 30-item PANSS and the Mini-PANSS revealed that the shorter version is comparable to the 30-item PANSS, but when applying IRT, the Mini-PANSS is also a good indicator of illness severity.</p

Pre-divorce problems in 3-year-olds: a prospective study in boys and girls

Objective: We examined to what extent internalizing and externalizing problems at age 3 preceded and predicted parental divorce, and if divorce and the time lapse since divorce were related to internalizing and externalizing problems at age 12. Methods: Parental ratings of internalizing and externalizing problems were collected with the Child Behavior Checklist (CBCL) in a large sample (N = 6,426) of 3-yearold children. All these children were followed through the age of 12 years, at which parents completed the CBCL again, while teachers completed the Teacher's Report Form. Children whose parents divorced between age 3 and age 12 were compared with children whose families remained intact. Results: Girls whose parents divorced between ages 3 and 12 already showed more externalizing problems at age 3 than girls whose parents stayed married. Higher levels of externalizing problems in girls at age 3 predicted later parental divorce. Parental reports indicated that 12-year-olds with divorced parents showed more internalizing and externalizing problems than children with married parents. Levels of teacher-reported problems were not different between children with married versus divorced parents. However, children whose parents divorced between ages 3 and 12 showed more teacher-rated internalizing problems at age 12 when the divorce was more recent than when the divorce was less recent. Parental ratings of both internalizing and externalizing problems at age 12 were not associated with the time lapse since divorce. Conclusion: Externalizing problems in girls precede and predict later parental divorce. Post-divorce problems in children vary by raters, and may depend on the time lapse since divorce