Modulation of cognition and neuronal plasticity in gain- and loss-of-function mouse models of the schizophrenia risk gene Tcf4.

The transcription factor TCF4 was confirmed in several large genome-wide association studies as one of the most significant schizophrenia (SZ) susceptibility genes. Transgenic mice moderately overexpressing Tcf4 in forebrain (Tcf4tg) display deficits in fear memory and sensorimotor gating. As second hit, we exposed Tcf4tg animals to isolation rearing (IR), chronic social defeat (SD), enriched environment (EE), or handling control (HC) conditions and examined mice with heterozygous deletion of the exon 4 (Tcf4Ex4δ+/-) to unravel gene-dosage effects. We applied multivariate statistics for behavioral profiling and demonstrate that IR and SD cause strong cognitive deficits of Tcf4tg mice, whereas EE masked the genetic vulnerability. We observed enhanced long-term depression in Tcf4tg mice and enhanced long-term potentiation in Tcf4Ex4δ+/- mice indicating specific gene-dosage effects. Tcf4tg mice showed higher density of immature spines during development as assessed by STED nanoscopy and proteomic analyses of synaptosomes revealed concurrently increased levels of proteins involved in synaptic function and metabolic pathways. We conclude that environmental stress and Tcf4 misexpression precipitate cognitive deficits in 2-hit mouse models of relevance for schizophrenia.

Dissociation of accumulated genetic risk and disease severity in patients with schizophrenia.

Genotype-phenotype correlations of common monogenic diseases revealed that the degree of deviation of mutant genes from wild-type structure and function often predicts disease onset and severity. In complex disorders such as schizophrenia, the overall genetic risk is still often >50% but genotype-phenotype relationships are unclear. Recent genome-wide association studies (GWAS) replicated a risk for several single-nucleotide polymorphisms (SNPs) regarding the endpoint diagnosis of schizophrenia. The biological relevance of these SNPs, however, for phenotypes or severity of schizophrenia has remained obscure. We hypothesized that the GWAS 'top-10' should as single markers, but even more so upon their accumulation, display associations with lead features of schizophrenia, namely positive and negative symptoms, cognitive deficits and neurological signs (including catatonia), and/or with age of onset of the disease prodrome as developmental readout and predictor of disease severity. For testing this hypothesis, we took an approach complementary to GWAS, and performed a phenotype-based genetic association study (PGAS). We utilized the to our knowledge worldwide largest phenotypical database of schizophrenic patients (n>1000), the GRAS (Göttingen Research Association for Schizophrenia) Data Collection. We found that the 'top-10' GWAS-identified risk SNPs neither as single markers nor when explored in the sense of a cumulative genetic risk, have any predictive value for disease onset or severity in the schizophrenic patients, as demonstrated across all core symptoms. We conclude that GWAS does not extract disease genes of general significance in schizophrenia, but may yield, on a hypothesis-free basis, candidate genes relevant for defining disease subgroups.

The longitudinal nonparametric test as a new tool to explore gene-gene and gene-time effects in cohorts.

Current approaches for analysis of longitudinal genetic epidemiological data of quantitative traits are typically restricted to normality assumptions of the trait. We introduce the longitudinal nonparametric test (LNPT) for cohorts with quantitative follow-up data to test for overall main effects of genes and for gene-gene and gene-time interactions. The LNPT is a rank procedure and does not depend on normality assumptions of the trait. We demonstrate by simulations that the LNPT is powerful, keeps the type-1 error level, and has very good small sample size behavior. For phenotypes with normal residuals, loss of power compared to parametric approaches (linear mixed models) was small for the quite general scenarios, which we simulated. For phenotypes with non-normal residuals, gain in power by the LNPT can be substantial. In contrast to parametric approaches, the LNPT is invariant with respect to monotone transformations of the trait. It is mathematically valid for arbitrary trait distribution.

Issues in association mapping with high-density SNP data and diverse family structures.

Genetic association studies have the potential to identify causative genetic variants with small effects in complex diseases, but it is not at all clear which study designs best balance power with sample size, especially when taking into account the difficulty of obtaining a sample of the necessary structure. The 14 contributions from the Genetic Analysis Workshop 15 group 3 used data sets with rheumatoid arthritis as primary phenotype from problem 2 (real data) and Problem 3 (simulated data) to investigate design and analysis problems that arise in candidate-gene, candidate-region, and genome-wide association studies. We identified three major themes that were addressed by multiple groups: (1) comparing family-based and case-control study designs with each other and with hybrid designs incorporating both related and unrelated individuals; (2) exploring and comparing techniques of combining information from multiple, correlated single-nucleotide polymorphisms; and (3) comparing analyses that select the model(s) of best fit with the ultimate aim of detecting the joint effects of several unlinked single-nucleotide polymorphisms. These contributions achieved some success in improving upon existing methods. For example, tests using related cases and unrelated controls can achieve higher power than the tests using unrelated cases and unrelated controls. Aside from these successes, the group 3 contributions highlight some interesting areas for future research.

Learning strategies for the maximally stable diluted binary perceptron

I show analytically that an optimally chosen continuous precursor J in the hypercube is highly correlated to the maximally stable diluted binary perceptron which solves the same storage problem. J allows the construction of a diluted binary perceptron D by a simple rule. Performing simulations for perceptrons of size N=100 I demonstrate that D is highly stable and can be improved in an efficient manner by partial enumeration thereby incorporating information from the precursor components. The precursor highlights the vector components on which partial enumeration improves the stability of the vector most efficiently. Moreover, it discriminates for each vector component i at least one of the three possible values D(i)=-1,0,1 as being extremely unlikely.

Correlations between hidden units in multilayer neural networks and replica symmetry breaking.

We consider feed-forward neural networks with one hidden layer, tree architecture, and a fixed hidden-to-output Boolean function. Focusing on the saturation limit of the storage problem the influence of replica symmetry breaking on the distribution of local fields at the hidden units is investigated. These field distributions determine the probability of finding a specific activation pattern of the hidden units as well as the corresponding correlation coefficients and therefore quantify the division of labor among the hidden units. We find that although modifying the storage capacity and the distribution of local fields markedly replica symmetry breaking has only a minor effect on the correlation coefficients. Detailed numerical results are provided for the PARITY, COMMITTEE, and AND machines with K=3 hidden units and nonoverlapping receptive fields.

Design-oriented functional capacity evaluation: the available motions inventory--a review.

The accommodation of a task to the unique abilities of an individual with a disability is becoming increasingly the responsibility of the employer. Functional capacity evaluation (FCE) provides the information necessary for rational design decisions when modifying work stations. The currently used FCE systems have been designed to assess an individual's performance for a range of reasons other than industrial task accommodation. The Available Motions Inventory (AMI) is a system that has been developed specifically to address the design issues raised when accommodating an industrial task to a person with a neuromuscular impairment. This system has a unique scoring system that allows intra-individual ability comparisons that support task allocation decisions. Some general principles of task design are developed for persons with cerebral palsy, but the strength of assessment lies in its application to a specific individual performing a specific task.

The effect of lower body positive pressure on the exercise capacity of individuals with spinal cord injury.

The purpose of this study was to determine the effect lower body positive pressure (LBPP) has on the cardiovascular/exercise capacities of individuals with spinal cord injury (SCI) during both arm crank exercise (ACE) and wheelchair exercise performed on a treadmill (WCTM). Ten male adults (age = 31.1 +/- 10 yr) with SCI and five male nondisabled (ND) adults (31.2 +/- 10 yr) participated in this study. The ND subjects performed ACE only. For subjects with SCI, significantly higher (P < 0.025) peak VO2 (1042 +/- 212 vs 839 +/- 218 ml.min-1), peak VE (46 +/- 17 vs 35 +/- 9 l.min-1), and work rate (50 +/- 15 vs 40 +/- 13 W) were seen during ACE with LBPP. No significant differences for peak VO2, VE, or work rate were seen for the ND subjects with LBPP during ACE. In addition, significantly higher peak VO2 (960 +/- 322 vs 828 +/- 312 ml.min-1) was recorded with LBPP for the subjects with SCI during WCTM. Cardiac output (Q, l.min-1; CO2 rebreathing method) was measured at 50% peak VO2 for both ND subjects and subjects with SCI during ACE. Subjects with SCI demonstrated significantly higher SV (94 +/- 20 vs 84 +/- 20 ml) with LBPP. No differences were observed in SV at 50% peak VO2 during ACE for the ND subjects with LBPP. The results of this study suggest that for individuals with SCI, LBPP augments exercise capacity by preventing the redistribution of blood to the lower extremities.

Anthropometry of Korean female industrial workers.

This paper presents the results of an anthropometric survey conducted on Korean female workers in the garment industry. The data was collected as part of a project to modify work stations that utilized equipment from other countries. A set of 23 body dimensions were taken from a sample of 101 workers (aged 18-28 years). The anthropometric measurements are presented and compared with those of the Western and Japanese female. The results indicate that the body dimensions of the Korean female are different from those of both the Western and the Japanese female. The ratio of sitting height to standing height for the Korean female is closer to that of the Western female than it is the Japanese female.

An improved method for monitoring heat stress levels in the workplace.

Studies in 15 industries revealed characteristic empirical relationships between workplace environmental conditions and outside weather conditions. These relationships, expressed in the form of predictive models for Wet Bulb Globe Temperature, can be used to estimate WBGT from weather forecasts, weather reports, or current meterorological measurements.