Comparative Linkage Meta-Analysis Reveals Regionally-Distinct, Disparate Genetic Architectures: Application to Bipolar Disorder and Schizophrenia

New high-throughput, population-based methods and next-generation sequencing capabilities hold great promise in the quest for common and rare variant discovery and in the search for ”missing heritability.” However, the optimal analytic strategies for approaching such data are still actively debated, representing the latest rate-limiting step in genetic progress. Since it is likely a majority of common variants of modest effect have been identified through the application of tagSNP-based microarray platforms (i.e., GWAS), alternative approaches robust to detection of low-frequency (1–5% MAF) and rare (<1%) variants are of great importance. Of direct relevance, we have available an accumulated wealth of linkage data collected through traditional genetic methods over several decades, the full value of which has not been exhausted. To that end, we compare results from two different linkage meta-analysis methods—GSMA and MSP—applied to the same set of 13 bipolar disorder and 16 schizophrenia GWLS datasets. Interestingly, we find that the two methods implicate distinct, largely non-overlapping, genomic regions. Furthermore, based on the statistical methods themselves and our contextualization of these results within the larger genetic literatures, our findings suggest, for each disorder, distinct genetic architectures may reside within disparate genomic regions. Thus, comparative linkage meta-analysis (CLMA) may be used to optimize low-frequency and rare variant discovery in the modern genomic era

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Using Human-Centered Design and Cocreation to Create the Live 5-2-1-0 Mobile App to Promote Healthy Behaviors in Children: App Design and Development

BackgroundThe prevalence of obesity among Canadian children is rising, partly because of increasingly obesogenic environments that limit opportunities for physical activity and healthy nutrition. Live 5-2-1-0 is a community-based multisectoral childhood obesity prevention initiative that engages stakeholders to promote and support the message of consuming ≥5 servings of vegetables and fruits, having <2 hours of recreational screen time, participating in ≥1 hour of active play, and consuming 0 sugary drinks every day. A Live 5-2-1-0 Toolkit for health care providers (HCPs) was previously developed and piloted in 2 pediatric clinics at British Columbia Children’s Hospital. ObjectiveThis study aimed to co-create, in partnership with children, parents, and HCPs, a Live 5-2-1-0 mobile app that supports healthy behavior change and could be used as part of the Live 5-2-1-0 Toolkit for HCPs. MethodsThree focus groups (FGs) were conducted using human-centered design and participatory approaches. In FG 1, children (separately) and parents and HCPs (together) participated in sessions on app conceptualization and design. Researchers and app developers analyzed and interpreted qualitative data from FG 1 in an ideation session, and key themes were subsequently presented separately to parents, children, and HCPs in FG-2 (co-creation) sessions to identify desired app features. Parents and children tested a prototype in FG 3, provided feedback on usability and content, and completed questionnaires. Thematic analysis and descriptive statistics were used for the qualitative and quantitative data, respectively. ResultsIn total, 14 children (mean age 10.2, SD 1.3 years; 5/14, 36% male; 5/14, 36% White), 12 parents (9/12, 75% aged 40-49 years; 2/12, 17% male; 7/12, 58% White), and 18 HCPs participated; most parents and children (20/26, 77%) participated in ≥2 FGs. Parents wanted an app that empowered children to adopt healthy behaviors using internal motivation and accountability, whereas children described challenge-oriented goals and family-based activities as motivating. Parents and children identified gamification, goal setting, daily steps, family-based rewards, and daily notifications as desired features; HCPs wanted baseline behavior assessments and to track users’ behavior change progress. Following prototype testing, parents and children reported ease in completing tasks, with a median score of 7 (IQR 6-7) on a 7-point Likert scale (1=very difficult; 7=very easy). Children liked most suggested rewards (28/37, 76%) and found 79% (76/96) of suggested daily challenges (healthy behavior activities that users complete to achieve their goal) realistic to achieve. Participant suggestions included strategies to maintain users’ interest and content that further motivates healthy behavior change. ConclusionsCo-creating a mobile health app with children, parents, and HCPs was feasible. Stakeholders desired an app that facilitated shared decision-making with children as active agents in behavior change. Future research will involve clinical implementation and assessment of the usability and effectiveness of the Live 5-2-1-0 app

Effectiveness of Mobile Apps in Promoting Healthy Behavior Changes and Preventing Obesity in Children: Systematic Review

BackgroundMobile apps have been increasingly incorporated into healthy behavior promotion interventions targeting childhood obesity. However, their effectiveness remains unclear. ObjectiveThis paper aims to conduct a systematic review examining the effectiveness of mobile apps aimed at preventing childhood obesity by promoting health behavior changes in diet, physical activity, or sedentary behavior in children aged 8 to 12 years. MethodsMEDLINE, Embase, PsycINFO, CINAHL, and ERIC were systematically searched for peer-reviewed primary studies from January 2008 to July 2021, which included children aged 8 to 12 years; involved mobile app use; and targeted at least one obesity-related factor, including diet, physical activity, or sedentary behavior. Data extraction and risk of bias assessments were conducted by 2 authors. ResultsOf the 13 studies identified, most used a quasi-experimental design (n=8, 62%). Significant improvements in physical activity (4/8, 50% studies), dietary outcomes (5/6, 83% studies), and BMI (2/6, 33% studies) were reported. All 6 multicomponent interventions and 57% (4/7) of standalone interventions reported significant outcomes in ≥1 behavioral change outcome measured (anthropometric, physical activity, dietary, and screen time outcomes). Gamification, behavioral monitoring, and goal setting were common features of the mobile apps used in these studies. ConclusionsApps for health behavior promotion interventions have the potential to increase the adoption of healthy behaviors among children; however, their effectiveness in improving anthropometric measures remains unclear. Further investigation of studies that use more rigorous study designs, as well as mobile apps as a standalone intervention, is needed

Transcriptome and methylome profiling reveals relics of genome dominance in the mesopolyploid Brassica oleracea

Background: Brassica oleracea is a valuable vegetable species that has contributed to human health and nutrition for hundreds of years and comprises multiple distinct cultivar groups with diverse morphological and phytochemical attributes. In addition to this phenotypic wealth, B. oleracea offers unique insights into polyploid evolution, as it results from multiple ancestral polyploidy events and a final Brassiceae-specific triplication event. Further, B. oleracea represents one of the diploid genomes that formed the economically important allopolyploid oilseed, Brassica napus. A deeper understanding of B. oleracea genome architecture provides a foundation for crop improvement strategies throughout the Brassica genus. Results: We generate an assembly representing 75% of the predicted B. oleracea genome using a hybrid Illumina/Roche 454 approach. Two dense genetic maps are generated to anchor almost 92% of the assembled scaffolds to nine pseudo-chromosomes. Over 50,000 genes are annotated and 40% of the genome predicted to be repetitive, thus contributing to the increased genome size of B. oleracea compared to its close relative B. rapa. A snapshot of both the leaf transcriptome and methylome allows comparisons to be made across the triplicated sub-genomes, which resulted from the most recent Brassiceae-specific polyploidy event. Conclusions: Differential expression of the triplicated syntelogs and cytosine methylation levels across the sub-genomes suggest residual marks of the genome dominance that led to the current genome architecture. Although cytosine methylation does not correlate with individual gene dominance, the independent methylation patterns of triplicated copies suggest epigenetic mechanisms play a role in the functional diversification of duplicate genes

Evaluating the efficacy of an empowerment-based self-management consultant intervention: results of a two-year randomized controlled trial

Objectives: This study was conducted to determine if an empowerment-based Diabetes Self-Management Consultant (DSMC) intervention was more effective than a group receiving Mailed metabolic Assessments Only (MAO) in improving diabetes-related quality of life and blood glucose control. Methods: A two-year clinical trial, in which 310 patients with type 2 diabetes were randomized to the DSMC intervention or the MAO group. The DSMC met with the patient to review the baseline assessments, then discussed this review with the patient and the patient's physician. Subsequently patients received monthly telephone calls from the DSMC who used the empowerment approach to help patients identify self-management problems, consider options, set goals and make adjustments to their diabetes self-management plans. Results: The Diabetes Self-Management Consultant (DSMC) intervention resulted in improvements in diabetes related quality of life (PAID) p = 0.008, the diabetes empowerment scale (DES-SF) p = 0.024, A1C p = 0.016, perceived understanding of diabetes p = 0.001 and satisfaction with diabetes care p = 0.019 as compared to the MAO group. Conclusion: The DSMC the intervention resulted in a broad array of modest diabetes related improvements. A promising area for future research would be to test the efficacy of combining an empowerment-based DSMC intervention with case management using algorithm-based medication adjustments for higher risk patients

Outcomes at 18 Months From a Community Health Worker and Peer Leader Diabetes Self-Management Program for Latino Adults

ObjectiveThis study evaluated the effectiveness of a community health worker (CHW) diabetes self-management education (DSME) program, followed by two different approaches to maintain improvements in HbA1c and other clinical and patient-centered outcomes over 18 months.Research design and methodsThe study randomized 222 Latino adults with type 2 diabetes and poor glycemic control from a federally qualified health center to 1) a CHW-led, 6-month DSME program or 2) enhanced usual care (EUC). After the 6-month program, participants randomized to the CHW-led DSME were further randomized to 1) 12 months of CHW-delivered monthly telephone outreach (CHW-only) or 2) 12 months of weekly group sessions delivered by peer leaders (PLs) with telephone outreach to those unable to attend (CHW+PL). The primary outcome was HbA1c. Secondary outcomes were blood pressure, lipid levels, diabetes distress, depressive symptoms, understanding of diabetes self-management, and diabetes social support. Assessments were conducted at baseline and at 6, 12, and 18 months.ResultsParticipants in the CHW intervention at the 6-month follow-up had greater decreases in HbA1c (-0.45% [95% CI -0.87, -0.03]; P &lt; 0.05) and in diabetes distress (-0.3 points [95% CI -0.6, -0.03]; P &lt; 0.05) compared with EUC. CHW+PL participants maintained HbA1c improvements at 12 and 18 months, and CHW-only participants maintained improvements in diabetes distress at 12 and 18 months. CHW+PL participants also had significantly fewer depressive symptoms at 18 months compared with EUC (-2.2 points [95% CI -4.1, -0.3]; P &lt; 0.05). Participants in CHW-led DSME had significant improvements in diabetes social support and in understanding of diabetes self-management at 6 months relative to EUC, but these intervention effects were not sustained at 18 months.ConclusionsThis study demonstrates the effectiveness of a 6-month CHW intervention on key diabetes outcomes and of a volunteer PL program in sustaining key achieved gains. These are scalable models for health care centers in low-resource settings for achieving and maintaining improvements in key diabetes outcomes