A neurogenetic model for the study of schizophrenia spectrum disorders: The International 22q11.2 Deletion Syndrome Brain Behavior Consortium

Rare copy number variants contribute significantly to the risk for schizophrenia, with the 22q11.2 locus consistently implicated. Individuals with the 22q11.2 deletion syndrome (22q11DS) have an estimated 25-fold increased risk for schizophrenia spectrum disorders, compared to individuals in the general population. The International 22q11DS Brain Behavior Consortium is examining this highly informative neurogenetic syndrome phenotypically and genomically. Here we detail the procedures of the effort to characterize the neuropsychiatric and neurobehavioral phenotypes associated with 22q11DS, focusing on schizophrenia and subthreshold expression of psychosis. The genomic approach includes a combination of whole genome sequencing and genome-wide microarray technologies, allowing the investigation of all possible DNA variation and gene pathways influencing the schizophrenia-relevant phenotypic expression. A phenotypically rich data set provides a psychiatrically well-characterized sample of unprecedented size (n=1,616) that informs the neurobehavioral developmental course of 22q11DS. This combined set of phenotypic and genomic data will enable hypothesis testing to elucidate the mechanisms underlying the pathogenesis of schizophrenia spectrum disorders

Bicycle Use for Transport in an Australian and a Belgian City: Associations with Built-Environment Attributes

The walkability attributes of neighborhood environments (residential density, land use mixture, and connectedness of streets) have been found to be associated with higher rates of walking. However, relatively less is known about the associations of walkability attributes with bicycle use for transport. We examined the relationships between adults' bicycle use for transport and measures of neighborhood walkability in two settings: an Australian city (Adelaide) with low rates of bicycle use and a Belgian city (Ghent) with high rates of bicycle use. A total of 2,159 and 382 participants were recruited in Adelaide and Ghent, respectively. A walkability index was derived from objectively measured data in Adelaide, while a similar index was derived from perceived measures in Ghent. Logistic regression models were employed to examine associations of bicycle use with different levels of walkability. There were higher rates of bicycle ownership for Ghent compared to Adelaide participants (96% versus 61%), and there was a higher prevalence of bicycle use for transport for Ghent compared to Adelaide participants (50% vs. 14%). Despite the large differences in bicycle ownership and use, living in a high-walkable neighborhood was associated with significantly higher odds of bicycle use for transport in both cities, after adjusting for relevant confounding factors. Built-environment innovations that are increasingly being advocated by health authorities and transport planners, primarily to promote higher rates of walking for transport, should also impact positively on bicycle use

A neurogenetic model for the study of schizophrenia spectrum disorders: The International 22q11.2 Deletion Syndrome Brain Behavior Consortium

Rare copy number variants contribute significantly to the risk for schizophrenia, with the 22q11.2 locus consistently implicated. Individuals with the 22q11.2 deletion syndrome (22q11DS) have an estimated 25-fold increased risk for schizophrenia spectrum disorders, compared to individuals in the general population. The International 22q11DS Brain Behavior Consortium is examining this highly informative neurogenetic syndrome phenotypically and genomically. Here we detail the procedures of the effort to characterize the neuropsychiatric and neurobehavioral phenotypes associated with 22q11DS, focusing on schizophrenia and subthreshold expression of psychosis. The genomic approach includes a combination of whole genome sequencing and genome-wide microarray technologies, allowing the investigation of all possible DNA variation and gene pathways influencing the schizophrenia-relevant phenotypic expression. A phenotypically rich data set provides a psychiatrically well-characterized sample of unprecedented size (n=1,616) that informs the neurobehavioral developmental course of 22q11DS. This combined set of phenotypic and genomic data will enable hypothesis testing to elucidate the mechanisms underlying the pathogenesis of schizophrenia spectrum disorders

A Genetics-First Approach to Dissecting the Heterogeneity of Autism: Phenotypic Comparison of Autism Risk Copy Number Variants

OBJECTIVE: Certain copy number variants (CNVs) greatly increase the risk of autism. The authors conducted a genetics-first study to investigate whether heterogeneity in the clinical presentation of autism is underpinned by specific genotype-phenotype relationships. METHODS: This international study included 547 individuals (mean age, 12.3 years [SD=4.2], 54% male) who were ascertained on the basis of having a genetic diagnosis of a rare CNV associated with high risk of autism (82 16p11.2 deletion carriers, 50 16p11.2 duplication carriers, 370 22q11.2 deletion carriers, and 45 22q11.2 duplication carriers), as well as 2,027 individuals (mean age, 9.1 years [SD=4.9], 86% male) with autism of heterogeneous etiology. Assessments included the Autism Diagnostic Interview-Revised and IQ testing. RESULTS: The four genetic variant groups differed in autism symptom severity, autism subdomain profile, and IQ profile. However, substantial variability was observed in phenotypic outcome in individual genetic variant groups (74%-97% of the variance, depending on the trait), whereas variability between groups was low (1%-21%, depending on the trait). CNV carriers who met autism criteria were compared with individuals with heterogeneous autism, and a range of profile differences were identified. When clinical cutoff scores were applied, 54% of individuals with one of the four CNVs who did not meet full autism diagnostic criteria had elevated levels of autistic traits. CONCLUSIONS: Many CNV carriers do not meet full diagnostic criteria for autism but nevertheless meet clinical cutoffs for autistic traits. Although profile differences between variants were observed, there is considerable variability in clinical symptoms in the same variant

Bikeability and methodological issues using the active commuting route environment scale (ACRES) in a metropolitan setting

<p>Abstract</p> <p>Background</p> <p>Route environments can positively influence people's active commuting and thereby contribute to public health. The Active Commuting Route Environment Scale (ACRES) was developed to study active commuters' perceptions of their route environments. However, bicycle commuters represent a small portion of the population in many cities and thus are difficult to study using population-based material. Therefore, the aim of this study is to expand the state of knowledge concerning the criterion-related validity of the ACRES and the representativity using an advertisement-recruited sample. Furthermore, by comparing commuting route environment profiles of inner urban and suburban areas, we provide a novel basis for understanding the relationship between environment and bikeability.</p> <p>Methods</p> <p>Bicycle commuters from Greater Stockholm, Sweden, advertisement- (n = 1379) and street-recruited (n = 93), responded to the ACRES. Traffic planning and environmental experts from the Municipality of Stockholm (n = 24) responded to a modified version of the ACRES. The criterion-related validity assessments were based on whether or not differences between the inner urban and the suburban route environments, as indicated by the experts and by four existing objective measurements, were reflected by differences in perceptions of these environments. Comparisons of ratings between advertisement- and street-recruited participants were used for the assessments of representativity. Finally, ratings of inner urban and suburban route environments were used to evaluate commuting route environment profiles.</p> <p>Results</p> <p>Differences in ratings of the inner urban and suburban route environments by the advertisement-recruited participants were in accord with the existing objective measurements and corresponded reasonably well with those of the experts. Overall, there was a reasonably good correspondence between the advertisement- and street-recruited participants' ratings. Distinct differences in commuting route environment profiles were noted between the inner urban and suburban areas. Suburban route environments were rated as safer and more stimulating for bicycle-commuting than the inner urban ones. In general, the findings applied to both men and women.</p> <p>Conclusions</p> <p>The overall results show: considerable criterion-related validity of the ACRES; ratings of advertisement-recruited participants mirroring those of street-recruited participants; and a higher degree of bikeability in the suburban commuting route environments than in the inner urban ones.</p

Neighborhood built environment and physical activity of Japanese older adults: results from the Aichi Gerontological Evaluation Study (AGES)

<p>Abstract</p> <p>Background</p> <p>Although many studies have reported the association between neighborhood built environment (BE) and physical activity (PA), less is known about the associations for older populations or in countries besides the US and Australia. The aim of this paper is to examine the associations for older adult populations in Japan.</p> <p>Methods</p> <p>Our analyses were based on cross-sectional data from the Aichi Gerontological Evaluation Study (AGES), conducted in 2003. The respondents were older adults, aged 65 years or over (n = 9,414), from 8 municipalities across urban, suburban, and rural areas. The frequency of leisure time sports activity and total walking time were used as the outcome variables. Using geographic information systems (GIS), we measured residential density, street connectivity, number of local destinations, access to recreational spaces, and land slope of the respondents' neighborhoods, based on network distances with multiple radii (250 m, 500 m, 1,000 m). An ordinal logistic regression model was used to analyze the association between PA and BE measures.</p> <p>Results</p> <p>Population density and presence of parks or green spaces had positive associations with the frequency of sports activity, regardless of the selected buffer zone. The analysis of total walking time, however, showed only a few associations.</p> <p>Conclusions</p> <p>Our findings provide mixed support for the association between PA and the characteristics of BE measures, previously used in Western settings. Some characteristics of the neighborhood built environment may facilitate leisure time sports activity, but not increase the total walking time for Japanese older adults.</p

CXCR4 Mediated Chemotaxis Is Regulated by 5T4 Oncofetal Glycoprotein in Mouse Embryonic Cells

5T4 oncofetal molecules are highly expressed during development and upregulated in cancer while showing only low levels in some adult tissues. Upregulation of 5T4 expression is a marker of loss of pluripotency in the early differentiation of embryonic stem (ES) cells and forms an integrated component of an epithelial-mesenchymal transition, a process important during embryonic development and metastatic spread of epithelial tumors. Investigation of the transcriptional changes in early ES differentiation showed upregulation of CXCL12 and down-regulation of a cell surface protease, CD26, which cleaves this chemokine. CXCL12 binds to the widely expressed CXCR4 and regulates key aspects of development, stem cell motility and tumour metastasis to tissues with high levels of CXCL12. We show that the 5T4 glycoprotein is required for optimal functional cell surface expression of the chemokine receptor CXCR4 and CXCL12 mediated chemotaxis in differentiating murine embryonic stem cells and embryo fibroblasts (MEF). Cell surface expression of 5T4 and CXCR4 molecules is co-localized in differentiating ES cells and MEF. By contrast, differentiating ES and MEF derived from 5T4 knockout (KO) mice show only intracellular CXCR4 expression but infection with adenovirus encoding mouse 5T4 restores CXCL12 chemotaxis and surface co-localization with 5T4 molecules. A series of chimeric constructs with interchanged domains of 5T4 and the glycoprotein CD44 were used to map the 5T4 sequences relevant for CXCR4 membrane expression and function in 5T4KO MEF. These data identified the 5T4 transmembrane domain as sufficient and necessary to enable CXCR4 cell surface expression and chemotaxis. Furthermore, some monoclonal antibodies against m5T4 can inhibit CXCL12 chemotaxis of differentiating ES cells and MEF which is not mediated by simple antigenic modulation. Collectively, these data support a molecular interaction of 5T4 and CXCR4 occurring at the cell surface which directly facilitates the biological response to CXCL12. The regulation of CXCR4 surface expression by 5T4 molecules is a novel means to control responses to the chemokine CXCL12 for example during embryogenesis but can also be selected to advantage the spread of a 5T4 positive tumor from its primary site

Physical activity as a possible mechanism behind the relationship between green space and health: A multilevel analysis

Background: The aim of this study was to investigate whether physical activity (in general, and more specifically, walking and cycling during leisure time and for commuting purposes, sports and gardening) is an underlying mechanism in the relationship between the amount of green space in people's direct living environment and self-perceived health. To study this, we first investigated whether the amount of green space in the living environment is related to the level of physical activity. When an association between green space and physical activity was found, we analysed whether this could explain the relationship between green space and health. Methods: The study includes 4.899 Dutch people who were interviewed about physical activity, self-perceived health and demographic and socioeconomic background. The amount of green space within a one-kilometre and a three-kilometre radius around the postal code coordinates was calculated for each individual. Multivariate multilevel analyses and multilevel logistic regression analyses were performed at two levels and with controls for socio-demographic characteristics and urbanicity. Results: No relationship was found between the amount of green space in the living environment and whether or not people meet the Dutch public health recommendations for physical activity, sports and walking for commuting purposes. People with more green space in their living environment walked and cycled less often and fewer minutes during leisure time; people with more green space garden more often and spend more time on gardening. Furthermore, if people cycle for commuting purposes they spend more time on this if they live in a greener living environment. Whether or not people garden, the time spent on gardening and time spent on cycling for commuting purposes did not explain the relationship between green space and health. Conclusion: Our study indicates that the amount of green space in the living environment is scarcely related to the level of physical activity. Furthermore, the amount of physical activity undertaken in greener living environments does not explain the relationship between green space and health.

Assessing the influence of the built environment on physical activity for utility and recreation in suburban metro Vancouver

<p>Abstract</p> <p>Background</p> <p>Physical inactivity and associated co-morbidities such as obesity and cardiovascular disease are estimated to have large societal costs. There is increasing interest in examining the role of the built environment in shaping patterns of physical activity. However, few studies have: (1) simultaneously examined physical activity for leisure and utility; (2) selected study areas with a range of built environment characteristics; and (3) assessed the built environment using high-resolution land use data.</p> <p>Methods</p> <p>Data on individuals used for this study are from a survey of 1602 adults in selected sites across suburban Metro Vancouver. Four types of physical activity were assessed: walking to work/school, walking for errands, walking for leisure and moderate physical activity for exercise. The built environment was assessed by constructing one-kilometre road network buffers around each respondent's postal code. Measures of the built environment include terciles of recreational and park land, residential land, institutional land, commercial land and land use mix.</p> <p>Results</p> <p>Logistic regression analyses showed that walking to work/school and moderate physical activity were not associated with any built environment measure. Living in areas with lower land use mix, lower commercial and lower recreational land increased the odds of low levels of walking for errands. Individuals living in the lower third of land use mix and institutional land were more likely to report low levels of walking for leisure.</p> <p>Conclusions</p> <p>These results suggest that walking for errands and leisure have a greater association with the built environment than other dimensions of physical activity.</p

Enhanced Maternal Origin of the 22q11.2 Deletion in Velocardiofacial and DiGeorge Syndromes

Velocardiofacial and DiGeorge syndromes, also known as 22q11.2 deletion syndrome (22q11DS), are congenital-anomaly disorders caused by a de novo hemizygous 22q11.2 deletion mediated by meiotic nonallelic homologous recombination events between low-copy repeats, also known as segmental duplications. Although previous studies exist, each was of small size, and it remains to be determined whether there are parent-of-origin biases for the de novo 22q11.2 deletion. To address this question, we genotyped a total of 389 DNA samples from 22q11DS-affected families. A total of 219 (56%) individuals with 22q11DS had maternal origin and 170 (44%) had paternal origin of the de novo deletion, which represents a statistically significant bias for maternal origin (p = 0.0151). Combined with many smaller, previous studies, 465 (57%) individuals had maternal origin and 345 (43%) had paternal origin, amounting to a ratio of 1.35 or a 35% increase in maternal compared to paternal origin (p = 0.000028). Among 1,892 probands with the de novo 22q11.2 deletion, the average maternal age at time of conception was 29.5, and this is similar to data for the general population in individual countries. Of interest, the female recombination rate in the 22q11.2 region was about 1.6–1.7 times greater than that for males, suggesting that for this region in the genome, enhanced meiotic recombination rates, as well as other as-of-yet undefined 22q11.2-specific features, could be responsible for the observed excess in maternal origin