Identity-by-descent analysis of a large Tourette’s syndrome pedigree from Costa Rica implicates genes involved in neuronal development and signal transduction:Molecular psychiatry

Tourette Syndrome (TS) is a heritable, early-onset neuropsychiatric disorder that typically begins in early childhood. Identifying rare genetic variants that make a significant contribution to risk in affected families may provide important insights into the molecular aetiology of this complex and heterogeneous syndrome. Here we present a whole-genome sequencing (WGS) analysis from the 11-generation pedigree (>500 individuals) of a densely affected Costa Rican family which shares ancestry from six founder pairs. By conducting an identity-by-descent (IBD) analysis using WGS data from 19 individuals from the extended pedigree we have identified putative risk haplotypes that were not seen in controls, and can be linked with four of the six founder pairs. Rare coding and non-coding variants present on the haplotypes and only seen in haplotype carriers show an enrichment in pathways such as regulation of locomotion and signal transduction, suggesting common mechanisms by which the haplotype-specific variants may be contributing to TS-risk in this pedigree. In particular we have identified a rare deleterious missense variation in RAPGEF1 on a chromosome 9 haplotype and two ultra-rare deleterious intronic variants in ERBB4 and IKZF2 on the same chromosome 2 haplotype. All three genes play a role in neurodevelopment. This study, using WGS data in a pedigree-based approach, shows the importance of investigating both coding and non-coding variants to identify genes that may contribute to disease risk. Together, the genes and variants identified on the IBD haplotypes represent biologically relevant targets for investigation in other pedigree and population-based TS data

Self-Reported vs. Measured Height, Weight, and BMI in Young Adults

Self-reported height and weight, if accurate, provide a simple and economical method to track changes in body weight over time. Literature suggests adults tend to under-report their own weight and that the gap between self-reported weight and actual weight increases with obesity. This study investigates the extent of discrepancy in self-reported height, weight, and subsequent Body Mass Index (BMI) versus actual measurements in young adults. Physically measured and self-reported height and weight were taken from 1562 students. Male students marginally overestimated height, while females were closer to target. Males, on average, closely self-reported weight. Self-reported anthropometrics remained statistically correlated to actual measures in both sexes. Categorical variables of calculated BMI from both self-reported and actual height and weight resulted in significant agreement for both sexes. Researcher measured BMI (via anthropometric height and weight) and sex were both found to have association with self-reported weight while only sex was related to height difference. Regression examining weight difference and BMI was significant, specifically with a negative slope indicating increased BMI led to increased underestimation of weight in both sexes. This study suggests self-reported anthropometric measurements in young adults can be used to calculate BMI for weight classification purposes. Further investigation is needed to better assess self-reported vs measured height and weight discrepancies across populations

Contextualizing genetic risk score for disease screening and rare variant discovery.

Studies of the genetic basis of complex traits have demonstrated a substantial role for common, small-effect variant polygenic burden (PB) as well as large-effect variants (LEV, primarily rare). We identify sufficient conditions in which GWAS-derived PB may be used for well-powered rare pathogenic variant discovery or as a sample prioritization tool for whole-genome or exome sequencing. Through extensive simulations of genetic architectures and generative models of disease liability with parameters informed by empirical data, we quantify the power to detect, among cases, a lower PB in LEV carriers than in non-carriers. Furthermore, we uncover clinically useful conditions wherein the risk derived from the PB is comparable to the LEV-derived risk. The resulting summary-statistics-based methodology (with publicly available software, PB-LEV-SCAN) makes predictions on PB-based LEV screening for 36 complex traits, which we confirm in several disease datasets with available LEV information in the UK Biobank, with important implications on clinical decision-making

Doing time and motion diffractively: Academic life everywhere and all the time

This article offers a diffractive methodological intervention into workplace studies of academic life. In its engagement of a playful, performative research and writing practice the article speaks back to technocratic organisational and sociological workplace ‘time and motion’ studies which centre on the human and rational, and presume a linear teleology of cause and effect. As a counterpoint, we deploy posthumanist new materialist research practices which refuse human-centric approaches and aim to give matter its due. As a means to analyse what comes out of our joint workspaces photo project we produce two ‘passes’ through data – two diffractive experiments which destabilise what normally counts as ‘findings’ and their academic presentation. The article deploys the motif of ‘starting somewhere else’ to signal both our intention to keep data animated, alive and interactive, and to utilise visual and written modes of seriality as enabling constraints which produce a more generative focus on the mundane, emergent, unforeseen, and happenstance in studies of daily working life

Prevalence and clinical correlates of explosive outbursts in Tourette Syndrome

The aim of this study was to examine the prevalence and clinical correlates of explosive outbursts in two large samples of individuals with Tourette syndrome (TS), including one collected primarily from non-clinical sources. Participants included 218 TS-affected individuals who were part of a genetic study (N=104 from Costa Rica (CR) and N=114 from the US). The relationships between explosive outbursts and comorbid attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), tic severity, and prenatal and perinatal complications were examined using regression analyses. Twenty percent of participants had explosive outbursts, with no significant differences in prevalence between the CR (non-clinical) and the US (primarily clinical) samples. In the overall sample, ADHD, greater tic severity, and lower age of tic onset were strongly associated with explosive outbursts. ADHD, prenatal exposure to tobacco, and male gender were significantly associated with explosive outbursts in the US sample. Lower age of onset and greater severity of tics were significantly associated with explosive outbursts in the CR sample. This study confirms previous studies that suggest that clinically significant explosive outbursts are common in TS and associated with ADHD and tic severity. An additional potential risk factor, prenatal exposure to tobacco, was also identified

Development and Validation of the Vending Evaluation for Nutrient-Density (VEND)ing Audit.

Background: This paper describes the development and validation of the Vending Evaluation for Nutrient-Density (VEND)ingaudit to comprehensively evaluate vended products based upon healthfulness, price and promotion, and machine accessibility. Methods: A novel vending nutrient-density score was created to determine the healthfulness of vended snack/beverage products. Field tested in United States colleges, VENDing audit (∑nutrient-density + 10 × % healthy products) and Support sub-scores (price + promotion + accessibility) were calculated for snack/beverage machines. Higher scores indicate more healthful vending options and supports for choosing healthfully. Nutrition Environment Measures Survey-Vending (NEMS-V) was used to validate the nutrient-density score for a sub-sample of machines. Sensitivity and specificity were computed by comparing the number of healthy snacks/beverages determined by NEMS-V and the VENDing nutrient-density scores. Results:Researchers conducted the VENDing audit on 228 snack/beverage vending machines at 9 universities within the United States and used both VENDing and NEMS-V on 33 snack and 52 beverage vending machines. Mean VENDing audit scores were 4.5 ± 2.0 (2.6, 3.4) and 2.6 ± 2.0 (0, 12) for snack/beverage machines, respectively. The number of products considered healthy assessed with both the VENDing nutrient-density scores and the NEMS-V were positively correlated for beverages (r = 0.687, p \u3c 0.001) and snacks (r = 0.366, p \u3c 0.05). The sensitivity was excellent for beverages (0.83) and moderate for snacks (0.69); while the specificity was moderate for both beverages (0.66) and snacks (0.50). Conclusions: The VENDing audit uses unique, valid, and reliable nutrient-density scoring to evaluate snacks/beverages along a continuum of healthful criteria and comprehensively evaluates the full vending environment

Lifetime Prevalence, Age of Risk, and Etiology of Comorbid Psychiatric Disorders in Tourette Syndrome

IMPORTANCE: Tourette syndrome (TS) is characterized by high rates of psychiatric comorbidity; however, few studies have fully characterized these comorbidities. Furthermore, most studies have included relatively few participants (<200), and none has examined the ages of highest risk for each TS-associated comorbidity or their etiologic relationship to TS. OBJECTIVE: To characterize the lifetime prevalence, clinical associations, ages of highest risk, and etiology of psychiatric comorbidity among individuals with TS. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional structured diagnostic interviews conducted between April 1, 1992, and December 31, 2008, of participants with TS (n = 1374) and TS-unaffected family members (n = 1142). MAIN OUTCOMES AND MEASURES: Lifetime prevalence of comorbid DSM-IV-TR disorders, their heritabilities, ages of maximal risk, and associations with symptom severity, age at onset, and parental psychiatric history. RESULTS: The lifetime prevalence of any psychiatric comorbidity among individuals with TS was 85.7%; 57.7% of the population had 2 or more psychiatric disorders. The mean (SD) number of lifetime comorbid diagnoses was 2.1 (1.6); the mean number was 0.9 (1.3) when obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) were excluded, and 72.1% of the individuals met the criteria for OCD or ADHD. Other disorders, including mood, anxiety, and disruptive behavior, each occurred in approximately 30% of the participants. The age of greatest risk for the onset of most comorbid psychiatric disorders was between 4 and 10 years, with the exception of eating and substance use disorders, which began in adolescence (interquartile range, 15–19 years for both). Tourette syndrome was associated with increased risk of anxiety (odds ratio [OR], 1.4; 95% CI, 1.0–1.9; P = .04) and decreased risk of substance use disorders (OR, 0.6; 95% CI, 0.3–0.9; P = .02) independent from comorbid OCD and ADHD; however, high rates of mood disorders among participants with TS (29.8%) may be accounted for by comorbid OCD (OR, 3.7; 95% CI, 2.9–4.8; P < .001). Parental history of ADHD was associated with a higher burden of non-OCD, non-ADHD comorbid psychiatric disorders (OR, 1.86; 95% CI, 1.32–2.61; P < .001). Genetic correlations between TS and mood (RhoG, 0.47), anxiety (RhoG, 0.35), and disruptive behavior disorders (RhoG, 0.48), may be accounted for by ADHD and, for mood disorders, by OCD. CONCLUSIONS AND RELEVANCE: This study is, to our knowledge, the most comprehensive of its kind. It confirms the belief that psychiatric comorbidities are common among individuals with TS, demonstrates that most comorbidities begin early in life, and indicates that certain comorbidities may be mediated by the presence of comorbid OCD or ADHD. In addition, genetic analyses suggest that some comorbidities may be more biologically related to OCD and/or ADHD rather than to TS

Negative Effects of Paternal Age on Children's Neurocognitive Outcomes Can Be Explained by Maternal Education and Number of Siblings

Background: Recent findings suggest advanced paternal age may be associated with impaired child outcomes, in particular, neurocognitive skills. Such patterns are worrisome given relatively universal trends in advanced countries toward delayed nuptiality and fertility. But nature and nurture are both important for child outcomes, and it is important to control for both when drawing inferences about either pathway. Methods and Findings: We examined cross-sectional patterns in six developmental outcome measures among children in the U.S. Collaborative Perinatal Project (n = 31,346). Many of these outcomes at 8 mo, 4 y, and 7 y of age (Bayley scales, Stanford Binet Intelligence Scale, Graham-Ernhart Block Sort Test, Wechsler Intelligence Scale for Children, Wide Range Achievement Test) are negatively correlated with paternal age when important family characteristics such as maternal education and number of siblings are not included as covariates. But controlling for family characteristics in general and mother’s education in particular renders the effect of paternal age statistically insignificant for most developmental measures. Conclusions: Assortative mating produces interesting relationships between maternal and paternal characteristics that can inject spurious correlation into observational studies via omitted variable bias. Controlling for both nature and nurture reveals little residual evidence of a link between child neurocognitive outcomes and paternal age in these data. Result

Rare Copy Number Variants in \u3cem\u3eNRXN1\u3c/em\u3e and \u3cem\u3eCNTN6\u3c/em\u3e Increase Risk for Tourette Syndrome

Tourette syndrome (TS) is a model neuropsychiatric disorder thought to arise from abnormal development and/or maintenance of cortico-striato-thalamo-cortical circuits. TS is highly heritable, but its underlying genetic causes are still elusive, and no genome-wide significant loci have been discovered to date. We analyzed a European ancestry sample of 2,434 TS cases and 4,093 ancestry-matched controls for rare (\u3c 1% frequency) copy-number variants (CNVs) using SNP microarray data. We observed an enrichment of global CNV burden that was prominent for large (\u3e 1 Mb), singleton events (OR = 2.28, 95% CI [1.39–3.79], p = 1.2 × 10−3) and known, pathogenic CNVs (OR = 3.03 [1.85–5.07], p = 1.5 × 10−5). We also identified two individual, genome-wide significant loci, each conferring a substantial increase in TS risk (NRXN1 deletions, OR = 20.3, 95% CI [2.6–156.2]; CNTN6 duplications, OR = 10.1, 95% CI [2.3–45.4]). Approximately 1% of TS cases carry one of these CNVs, indicating that rare structural variation contributes significantly to the genetic architecture of TS

Peaceful Uses Bona Fides: Criteria for Evaluation and Case Studies

This study applies a set of indicators to assess the peaceful nature of a state’s nuclear program. Evaluation of a country’s nuclear program relative to these indicators can help the international community to take appropriate actions to ensure that the growth of the global nuclear energy industry proceeds peacefully and to minimize nuclear proliferation risks