Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity

A. Palotie on työryhmän UK10K Consortium jäsen.Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1, BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF similar to 0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 x 10(-3)), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies.Peer reviewe

Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel

Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants

Whole-genome sequence-based analysis of thyroid function

Tiina Paunio on työryhmän UK10K Consortium jäsen.Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N = 2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF >= 1%) associated with TSH and FT4 (N = 16,335). For TSH, we identify a novel variant in SYN2 (MAF = 23.5%, P = 6.15 x 10(-9)) and a new independent variant in PDE8B (MAF = 10.4%, P = 5.94 x 10(-14)). For FT4, we report a low-frequency variant near B4GALT6/ SLC25A52 (MAF = 3.2%, P = 1.27 x 10(-9)) tagging a rare TTR variant (MAF = 0.4%, P = 2.14 x 10(-11)). All common variants explain >= 20% of the variance in TSH and FT4. Analysis of rare variants (MAFPeer reviewe

Evaluating the Impact of an App-Delivered Mindfulness Meditation Program to Reduce Stress and Anxiety During Pregnancy: Pilot Longitudinal Study.

BACKGROUND: Stress and anxiety during pregnancy are extremely prevalent and are associated with numerous poor outcomes, among the most serious of which are increased rates of preterm birth and low birth weight infants. Research supports that while in-person mindfulness training is effective in reducing pregnancy stress and anxiety, there are barriers limiting accessibility. OBJECTIVE: The aim of this paper is to determine if mindfulness meditation training with the Headspace app is effective for stress and anxiety reduction during pregnancy. METHODS: A longitudinal, single-arm trial was implemented with 20 pregnant women who were instructed to practice meditation via the Headspace app twice per day during the month-long trial. Validated scales were used to measure participants levels of stress and anxiety pre- and postintervention. Physiological measures reflective of stress (heart rate variability and sleep) were collected via the Oura Ring. RESULTS: Statistically significant reductions were found in self-reported levels of stress (P=.005), anxiety (P=.01), and pregnancy anxiety (P<.0001). Hierarchical linear modeling revealed a statistically significant reduction in the physiological data reflective of stress in 1 of 6 heart rate variability metrics, the low-frequency power band, which decreased by 13% (P=.006). A total of 65% of study participants (n=13) reported their sleep improved during the trial, and 95% (n=19) stated that learning mindfulness helped with other aspects of their lives. Participant retention was 100%, with 65% of participants (n=13) completing about two-thirds of the intervention, and 50% of participants (n=10) completing ≥95%. CONCLUSIONS: This study found evidence to support the Headspace app as an effective intervention to aid in stress and anxiety reduction during pregnancy

Cigarettes play the equalizer: discrimination experiences and readiness to quit cigarette smoking among African Americans experiencing homelessness: a qualitative analysis.

BACKGROUND: Approximately 70-80% of people experiencing homelessness in the United States use tobacco. Smoking cessation programs specifically for this population have been found to be less effective for African American participants. The purpose of this study was to explore discrimination experiences and their impact on smoking habits and readiness to quit cigarette smoking while experiencing homelessness. METHODS: In the qualitative phase of this mixed methods study, five focus groups were conducted for African Americans residing in a homeless shelter in Skid Row, Los Angeles, CA. Using a semi-structured interview guide, we asked participants about discrimination experiences, how smoking habits were impacted by these experiences, and tools needed to successfully abstain from cigarette smoking. Qualitative descriptive content analysis was used to explore discrimination experiences and its association with readiness to quit cigarette smoking. RESULTS: Of the 17 participants, 14 (82.4%) were male, and the average age was 46.8 years. Using a qualitative In Vivo coding method, three themes were revealed: Experiencing Discrimination while Black, The Psychosocial Fabric-Why Quitting Cigarette Smoking is a Challenge, and The Lesser of Two Evils-Choosing to Smoke over More Harmful Options. Participants discussed working in the blue-collar workforce while Black, identifying as a double minority, smoking to cope with stress, early exposure to cigarettes, smoking being a central part of ones belonging to a group, and the legality of cigarette smoking. DISCUSSION: Our findings show that African Americans experiencing homelessness (1) may experience discrimination in multiple settings, regardless of housing status, (2) could have grown up around cigarette smoking and remain surrounded by it while experiencing homelessness, and (3) may experience a calming effect with smoking, which slows some from reacting negatively to adverse situations. CONCLUSION: Barriers to successfully abstaining from smoking are multifactorial among African Americans experiencing homelessness and should be addressed individually. Future research should explore the cultural tailoring of interventions that support cessation efforts unique to minoritized populations to improve smoking cessation programs offered to this population

Discrimination, Mental Health, and Readiness to Quit Smoking.

We conducted a cross-sectional study, examining the mediation effects of depression and anxiety on the association between discrimination and readiness to quit cigarette smoking among African American adult cigarette smokers experiencing homelessness. Using a convenience sample, participants were recruited from a homeless shelter in Southern California. Scores of discrimination, depressive, and anxiety symptoms, and readiness to quit smoking were analyzed using linear regression modeling. We enrolled 100 participants; 58 participants were male. In the final model, discrimination had no association with readiness to quit (b = 0.02; 95% CI [-0.04, 0.08]; p = 0.47). The indirect effects of depression (b = 0.04, [0.01, 0.07]; p = 0.02) and anxiety (b = 0.03; [0.01, 0.05]; p = 0.04) reached statistical significance; the direct effects of depression (b = -0.01; [-0.09, 0.04]; p = 0.70) and anxiety (b = -0.00; [-0.09, 0.06]; p = 0.86) did not. Future studies should explore these associations to enhance smoking cessation programs for this population

Evaluating the Impact of an App-Delivered Mindfulness Meditation Program to Reduce Stress and Anxiety During Pregnancy: Pilot Longitudinal Study

BackgroundStress and anxiety during pregnancy are extremely prevalent and are associated with numerous poor outcomes, among the most serious of which are increased rates of preterm birth and low birth weight infants. Research supports that while in-person mindfulness training is effective in reducing pregnancy stress and anxiety, there are barriers limiting accessibility. ObjectiveThe aim of this paper is to determine if mindfulness meditation training with the Headspace app is effective for stress and anxiety reduction during pregnancy. MethodsA longitudinal, single-arm trial was implemented with 20 pregnant women who were instructed to practice meditation via the Headspace app twice per day during the month-long trial. Validated scales were used to measure participant’s levels of stress and anxiety pre- and postintervention. Physiological measures reflective of stress (heart rate variability and sleep) were collected via the Oura Ring. ResultsStatistically significant reductions were found in self-reported levels of stress (P=.005), anxiety (P=.01), and pregnancy anxiety (P<.0001). Hierarchical linear modeling revealed a statistically significant reduction in the physiological data reflective of stress in 1 of 6 heart rate variability metrics, the low-frequency power band, which decreased by 13% (P=.006). A total of 65% of study participants (n=13) reported their sleep improved during the trial, and 95% (n=19) stated that learning mindfulness helped with other aspects of their lives. Participant retention was 100%, with 65% of participants (n=13) completing about two-thirds of the intervention, and 50% of participants (n=10) completing ≥95%. ConclusionsThis study found evidence to support the Headspace app as an effective intervention to aid in stress and anxiety reduction during pregnancy

Brain Changes Linked to Cognitive Symptomatology in Homeless Youth

Youth impacted by homelessness experience diminished cognition due to a variety of reasons including mental health symptoms, alcohol and substance use, and adverse childhood experiences. However, the status of specific brain regions which could impact important cognitive functions in homeless youth remains unclear. In this pilot comparative and correlational study, a series of demographic, psychological, cognitive assessments, and brain magnetic resonance imaging were performed in 10 male youth experiencing homelessness and 9 age-matched healthy male controls (age range: 18-25 years). Participants experiencing homelessness had significantly decreased regional brain gray matter tissue in comparison to the controls. Moreover, there were strong inverse correlations between the brain regions classically associated with executive decision-making (prefrontal cortices), depression (insular lobes), and conflict resolution (anterior cingulate), and the level of the symptoms detected by their questionnaires