Demographic, socioeconomic and life-course risk factors for internalized weight stigma in adulthood: evidence from an English birth cohort study.

Background: Obesity is highly stigmatized, with negative obesity-related stereotypes widespread across society. Internalized weight stigma (IWS) is linked to negative outcomes including poor mental health and disordered eating. Previous evidence examining population groups at higher risk of experiencing IWS comes from small, nonrepresentative samples. Here, we re-assess previously reported associations of IWS with demographic, socioeconomic, and wider social factors in a large general population birth cohort study for the first time. Methods: In the Avon Longitudinal Study of Parents and Children (ALSPAC), we explored differences in IWS at age 31 years by sex, ethnicity, socioeconomic factors, sexual orientation, and family and wider social influences, using confounder-adjusted multivariable regression. Findings: In models adjusted for potential confounders and BMI in childhood, adolescence, and adulthood (N = 4060), IWS was higher for females (standardized beta: 0.56, 95% CI: 0.50, 0.61), sexual minorities (0.17 S.D. higher, 95% CI: 0.09, 0.24), and less socioeconomically advantaged individuals (e.g., 0.16 S.D. higher (95% CI: 0.08, 0.24) for participants whose mothers had minimum or no qualifications, compared to a university degree). The social environment during adolescence and young adulthood was important: IWS was higher for people who at age 13 years felt pressure to lose weight from family (by 0.13 S.D., 95% CI: 0.03, 0.23), and the media (by 0.17, 95% CI: 0.10, 0.25), or had experienced bullying (e.g., 0.25 S.D., 95% CI: 0.17, 0.33 for bullying at age 23 years). Interpretation: Internalized weight stigma differs substantially between demographic groups. Risk is elevated for females, sexual minorities, and socioeconomically disadvantaged adults, and this is not explained by differences in BMI. Pressure to lose weight from family and the media in adolescence may have long-lasting effects on IWS. Funding: The ESRC, MRC, NIHR, and Wellcome Trust.

Genetic associations of risk behaviours and educational achievement.

Risk behaviours are common in adolescent and persist into adulthood, people who engage in more risk behaviours are more likely to have lower educational attainment. We applied genetic causal inference methods to explore the causal relationship between adolescent risk behaviours and educational achievement. Risk behaviours were phenotypically associated with educational achievement at age 16 after adjusting for confounders (-0.11, 95%CI: -0.11, -0.09). Genomic-based restricted maximum likelihood (GREML) results indicated that both traits were heritable and have a shared genetic architecture (Risk h 2 = 0.18, 95% CI: -0.11,0.47; education h 2 = 0.60, 95%CI: 0.50,0.70). Consistent with the phenotypic results, genetic variation associated with risk behaviour was negatively associated with education ( r g = -0.51, 95%CI: -1.04,0.02). Lastly, the bidirectional MR results indicate that educational achievement or a closely related trait is likely to affect risk behaviours PGI (ß=-1.04, 95% CI: -1.41, -0.67), but we found little evidence that the genetic variation associated with risk behaviours affected educational achievement (ß=0.00, 95% CI: -0.24,0.24). The results suggest engagement in risk behaviour may be partly driven by educational achievement or a closely related trait.

Psychological predictors of performance-based physical functioning among pediatric pain program participants.

PURPOSE: The purpose of the present study was to evaluate changes in performance-based physical functioning and investigate psychological predictors of physical functioning over time in pediatric patients with chronic pain who completed an interdisciplinary rehabilitation intensive outpatient program (IOP). METHODS: Participants (N = 55; mean age = 14.92 years; 12.7% male, 87.3% female; 83.6% White, 5.6% African-American/Black; 9.1% Latinx) completed baseline measures assessing pain intensity and modifiable psychological factors (i.e., pain catastrophizing, kinesiophobia, anxiety and depressive symptoms). Participants were administered performance-based assessments of physical functioning (i.e., physical endurance, high-level motor abilities) before and after IOP completion. RESULTS: Pain intensity was not significantly associated with physical functioning at either timepoint. There was significant improvement on measures of physical functioning after completion of the IOP when controlling for the effects of sex, race, and ethnicity. Depressive symptoms were associated with baseline physical endurance, ß = - .28, p = .047, while pain catastrophizing was associated with baseline gross motor abilities, ß = - .28, p = .032. CONCLUSION: Participation in an IOP led to significant improvement in physical endurance and high-level motor ability. Depressive symptoms and pain catastrophizing were associated with physical functioning at baseline but not post-program completion. Integration of pain psychology and physical therapy in an IOP can help address the interrelated psychological and physical factors impacting physical functioning to improve outcomes for children with chronic pain.

Maternal depressive symptoms and young people's higher education participation and choice of university: Evidence from a longitudinal cohort study.

BACKGROUND: Participation in higher education has significant and long-lasting consequences for people's socioeconomic trajectories. Maternal depression is linked to poorer educational achievement for children in school, but its impact on university attendance is unclear. METHODS: In an English longitudinal cohort study (N = 8952), we explore whether young people whose mothers experienced elevated depressive symptoms are less likely to attend university, and the role of potential mediators in the young person: educational achievement in school, depressive symptoms, and locus of control. We also examine whether maternal depressive symptoms influence young people's choice of university, and non-attendees' reasons for not participating in higher education. RESULTS: Young people whose mothers experienced more recurrent depressive symptoms were less likely to attend university (OR = 0.88, CI = 0.82,0.94, p < 0.001) per occasion of elevated maternal depressive symptoms) after adjusting for confounders. Mediation analysis indicated this was largely explained by educational achievement in school (e.g., 82.7 % mediated by age 16 achievement) and locus of control at 16. There was mixed evidence for an impact on choice of university. For participants who did not study at university, maternal depressive symptoms were linked to stating as a reason having had other priorities to do with family or children (OR: 1.17, CI = 1.02,1.35). LIMITATIONS: Lack of data on the other parent's depression, loss to follow-up, possibly selective non-response. CONCLUSIONS: Young people whose mothers experience elevated depressive symptoms on multiple occasions are less likely to participate in higher education; educational achievement in secondary school, but not the young people's own depressive symptoms, substantially mediated the effect.

Debugging and consolidating multiple synthetic chromosomes reveals combinatorial genetic interactions.

The Sc2.0 project is building a eukaryotic synthetic genome from scratch. A major milestone has been achieved with all individual Sc2.0 chromosomes assembled. Here, we describe the consolidation of multiple synthetic chromosomes using advanced endoreduplication intercrossing with tRNA expression cassettes to generate a strain with 6.5 synthetic chromosomes. The 3D chromosome organization and transcript isoform profiles were evaluated using Hi-C and long-read direct RNA sequencing. We developed CRISPR Directed Biallelic URA3-assisted Genome Scan, or "CRISPR D-BUGS," to map phenotypic variants caused by specific designer modifications, known as "bugs." We first fine-mapped a bug in synthetic chromosome II (synII) and then discovered a combinatorial interaction associated with synIII and synX, revealing an unexpected genetic interaction that links transcriptional regulation, inositol metabolism, and tRNASerCGA abundance. Finally, to expedite consolidation, we employed chromosome substitution to incorporate the largest chromosome (synIV), thereby consolidating >50% of the Sc2.0 genome in one strain.

Consequences of a telomerase-related fitness defect and chromosome substitution technology in yeast synIX strains.

We describe the complete synthesis, assembly, debugging, and characterization of a synthetic 404,963 bp chromosome, synIX (synthetic chromosome IX). Combined chromosome construction methods were used to synthesize and integrate its left arm (synIXL) into a strain containing previously described synIXR. We identified and resolved a bug affecting expression of EST3, a crucial gene for telomerase function, producing a synIX strain with near wild-type fitness. To facilitate future synthetic chromosome consolidation and increase flexibility of chromosome transfer between distinct strains, we combined chromoduction, a method to transfer a whole chromosome between two strains, with conditional centromere destabilization to substitute a chromosome of interest for its native counterpart. Both steps of this chromosome substitution method were efficient. We observed that wild-type II tended to co-transfer with synIX and was co-destabilized with wild-type IX, suggesting a potential gene dosage compensation relationship between these chromosomes.

Weight stigma, welfare stigma, and political values: Evidence from a representative British survey.

Obesity-related stigma is increasingly recognised as a public health issue, with serious implications for mental and physical health. However, very little is known about what drives inter-individual differences in obesity-stigmatizing views, and how they are distributed in the population. If views about obesity are not independent of a person's wider beliefs and values, this must be understood so that obesity stigma can be effectively tackled. In a representative sample of British adults aged 18-97 (N = 2186), we explore predictors of weight-stigmatizing attitudes. We consider demographics, socioeconomic position, factors related to one's own weight and health, and beliefs about the causes and consequences of obesity. We explore the role of core political values which predict views about other stigmatized groups, and views about welfare recipients, who are frequently linked with obesity in public and political discourse. Finally, we assess to what extent demographic differences in weight-stigmatizing attitudes are explained by individual body mass index (BMI), attitudes, and beliefs. Consistent with previous studies, women were less weight-stigmatizing than men. People in late middle-age were less weight-stigmatizing than younger or older adults. Adjusted for age and gender, an index of weight-stigmatizing views was positively associated with income, and highest in intermediate categories of education and occupational social class. Weight-stigmatizing attitudes were associated with more right-wing values, more authoritarian values, and more stigmatizing views about welfare recipients. Factors including own BMI, beliefs about causes of obesity, welfare-stigmatizing attitudes and authoritarian values contributed to socioeconomic differences. Weight-stigmatizing attitudes show clear differences between demographic groups, but also vary according to wider social attitudes, beliefs, and a person's core political values. Efforts to reduce weight stigma, and other kinds of stigma, may be more effective if they recognise these links.

BMI and well-being in people of East Asian and European ancestry: a Mendelian randomisation study.

Previous studies have linked higher body mass index (BMI) to lower subjective well-being in adult European ancestry populations. However, our understanding of these relationships across different populations is limited. Here, we investigated the association between BMI and well-being in people of (a) East Asian and (b) European ancestry in the China Kadoorie Biobank (CKB) and UK Biobank (UKB), respectively. Mendelian randomisation (MR) methods were used to test the relationship between BMI with (a) health satisfaction and (b) life satisfaction. One-sample MR enabled us to test effects in men and women separately and to test the role of cultural contexts by stratifying our analyses by urban and rural home location in both China and the UK. Further, we implemented a control function method to test the linearity of the BMI-well-being relationship. We found evidence of different associations between BMI and well-being in individuals of East Asian versus European ancestry. For example, a genetically instrumented higher BMI tentatively associated with higher health satisfaction in people of East Asian ancestry, especially in females (ß: 0.041, 95% CI: 0.002, 0.081). In contrast, there was a robust inverse association between higher genetically instrumented BMI and health satisfaction in all European ancestry UKB participants (ß: -0.183, 95% CI: -0.200, -0.165, Pdifference < 1.00E-15). We also showed the importance of considering non-linear relationships in the MR framework by providing evidence of non-linear relationships between BMI and health and life satisfaction. Overall, our study suggests potential setting-specific causality in the relationship between BMI and subjective well-being, with robust differences observed between East Asians and Europeans when considering very similar outcomes. We highlight the importance of (a) considering potential non-linear relationships in causal analyses and (b) testing causal relationships in different populations, as the casual nature of relationships, especially relationships influenced by social processes, may be setting-specific.

Kratom Alkaloids, Cannabinoids, and Chronic Pain: Basis of Potential Utility and Role in Therapy.

Introduction: Chronic neuropathic pain is as a severe detriment to overall quality of life for millions of Americans. Current pharmacological treatment options for chronic neuropathic pain are generally limited in efficacy and may pose serious adverse effects such as risk of abuse, nausea, dizziness, and cardiovascular events. Therefore, many individuals have resorted to methods of pharmacological self-treatment. This narrative review summarizes the existing literature on the utilization of two novel approaches for the treatment of chronic pain, cannabinoid constituents of Cannabis sativa and alkaloid constituents of Mitragyna speciosa (kratom), and speculates on the potential therapeutic benefits of co-administration of these two classes of compounds. Methods: We conducted a narrative review summarizing the primary motivations for use of both kratom and cannabis products based on epidemiological data and summarize the pre-clinical evidence supporting the application of both kratom alkaloids and cannabinoids for the treatment of chronic pain. Data collection was performed using the PubMed electronic database. The following word combinations were used: kratom and cannabis, kratom and pain, cannabis and pain, kratom and chronic pain, and cannabis and chronic pain. Results: Epidemiological evidence reports that the self-treatment of pain is a primary motivator for use of both kratom and cannabinoid products among adult Americans. Further evidence shows that use of cannabinoid products may precede kratom use, and that a subset of individuals concurrently uses both kratom and cannabinoid products. Despite its growing popularity as a form of self-treatment of pain, there remains an immense gap in knowledge of the therapeutic efficacy of kratom alkaloids for chronic pain in comparison to that of cannabis-based products, with only three pre-clinical studies having been conducted to date. Conclusion: There is sufficient epidemiological evidence to suggest that both kratom and cannabis products are used to self-treat pain, and that some individuals actively use both drugs, which may produce potential additive or synergistic therapeutic benefits that have not yet been characterized. Given the lack of pre-clinical investigation into the potential therapeutic benefits of kratom alkaloids against forms of chronic pain, further research is warranted to better understand its application as a treatment alternative.

Educational attainment, health outcomes and mortality: a within-sibship Mendelian randomization study.

BACKGROUND: Previous Mendelian randomization (MR) studies using population samples (population MR) have provided evidence for beneficial effects of educational attainment on health outcomes in adulthood. However, estimates from these studies may have been susceptible to bias from population stratification, assortative mating and indirect genetic effects due to unadjusted parental genotypes. MR using genetic association estimates derived from within-sibship models (within-sibship MR) can avoid these potential biases because genetic differences between siblings are due to random segregation at meiosis. METHODS: Applying both population and within-sibship MR, we estimated the effects of genetic liability to educational attainment on body mass index (BMI), cigarette smoking, systolic blood pressure (SBP) and all-cause mortality. MR analyses used individual-level data on 72 932 siblings from UK Biobank and the Norwegian HUNT study, and summary-level data from a within-sibship Genome-wide Association Study including >140 000 individuals. RESULTS: Both population and within-sibship MR estimates provided evidence that educational attainment decreased BMI, cigarette smoking and SBP. Genetic variant-outcome associations attenuated in the within-sibship model, but genetic variant-educational attainment associations also attenuated to a similar extent. Thus, within-sibship and population MR estimates were largely consistent. The within-sibship MR estimate of education on mortality was imprecise but consistent with a putative effect. CONCLUSIONS: These results provide evidence of beneficial individual-level effects of education (or liability to education) on adulthood health, independently of potential demographic and family-level confounders.

Genome-wide association reveals host-specific genomic traits in Escherichia coli.

BACKGROUND: Escherichia coli is an opportunistic pathogen which colonizes various host species. However, to what extent genetic lineages of E. coli are adapted or restricted to specific hosts and the genomic determinants of such adaptation or restriction is poorly understood. RESULTS: We randomly sampled E. coli isolates from four countries (Germany, UK, Spain, and Vietnam), obtained from five host species (human, pig, cattle, chicken, and wild boar) over 16 years, from both healthy and diseased hosts, to construct a collection of 1198 whole-genome sequenced E. coli isolates. We identified associations between specific E. coli lineages and the host from which they were isolated. A genome-wide association study (GWAS) identified several E. coli genes that were associated with human, cattle, or chicken hosts, whereas no genes associated with the pig host could be found. In silico characterization of nine contiguous genes (collectively designated as nan-9) associated with the human host indicated that these genes are involved in the metabolism of sialic acids (Sia). In contrast, the previously described sialic acid regulon known as sialoregulon (i.e. nanRATEK-yhcH, nanXY, and nanCMS) was not associated with any host species. In vitro growth experiments with a Δnan-9 E. coli mutant strain, using the sialic acids 5-N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc) as sole carbon source, showed impaired growth behaviour compared to the wild-type. CONCLUSIONS: This study provides an extensive analysis of genetic determinants which may contribute to host specificity in E. coli. Our findings should inform risk analysis and epidemiological monitoring of (antimicrobial resistant) E. coli.

Intergenerational effects of parental educational attainment on parenting and childhood educational outcomes: Evidence from MoBa using within-family Mendelian randomization.

The intergenerational transmission of educational attainment from parents to their children is one of the most important and studied relationships in social science. Longitudinal studies have found strong associations between parents' and their children's educational outcomes, which could be due to the effects of parents. Here we provide new evidence about whether parents' educational attainment affects their parenting behaviours and children's early educational outcomes using within-family Mendelian randomization and data from 40,879 genotyped parent-child trios from the Norwegian Mother, Father and Child Cohort (MoBa) study. We found evidence suggesting that parents' educational attainment affects their children's educational outcomes from age 5 to 14. More studies are needed to provide more samples of parent-child trios and assess the potential consequences of selection bias and grandparental effects.

Mediators of the association between childhood body mass index and educational attainment: Analysis of a UK prospective cohort study.

BACKGROUND: Higher body mass index (BMI) in childhood is associated with lower academic achievement. OBJECTIVE: To explore potential pathways linking childhood BMI with educational attainment. METHODS: Using data from the Avon Longitudinal Study of Parents and Children prospective cohort study (N = 6949), we assessed the association between BMI z-scores at 11.7 years and educational attainment at 16 (General Certificate of Secondary Education [GCSE] results). Depressive symptoms, externalizing behaviours, bullying and school enjoyment were considered as potential mediators. Mediators were examined individually and jointly using sequential causal mediation. RESULTS: Higher BMI z-scores were associated with lower GCSE scores (females ß = -3.47 95% CI -5.54, -1.41 males ß = -4.33 95% CI -6.73, -1.94). Together, bullying, externalizing symptoms, depressive symptoms and school enjoyment mediated 41.9% of this association in females, and 23.3% in males. In males, evidence for mediation was weak (confidence intervals for all indirect effects spanned the null). In both females and males, most of the mediation was driven by externalizing symptoms. CONCLUSIONS: The detrimental effect of higher BMI on educational attainment appears to be partly explained by externalizing behaviours, particularly in females. Interventions to support behavioural problems may help the academic achievement of children with a higher body weight.

Mendelian randomisation study of body composition and depression in people of East Asian ancestry highlights potential setting-specific causality.

BACKGROUND: Extensive evidence links higher body mass index (BMI) to higher odds of depression in people of European ancestry. However, our understanding of the relationship across different settings and ancestries is limited. Here, we test the relationship between body composition and depression in people of East Asian ancestry. METHODS: Multiple Mendelian randomisation (MR) methods were used to test the relationship between (a) BMI and (b) waist-hip ratio (WHR) with depression. Firstly, we performed two-sample MR using genetic summary statistics from a recent genome-wide association study (GWAS) of depression (with 15,771 cases and 178,777 controls) in people of East Asian ancestry. We selected 838 single nucleotide polymorphisms (SNPs) correlated with BMI and 263 SNPs correlated with WHR as genetic instrumental variables to estimate the causal effect of BMI and WHR on depression using the inverse-variance weighted (IVW) method. We repeated these analyses stratifying by home location status: China versus UK or USA. Secondly, we performed one-sample MR in the China Kadoorie Biobank (CKB) in 100,377 participants. This allowed us to test the relationship separately in (a) males and females and (b) urban and rural dwellers. We also examined (c) the linearity of the BMI-depression relationship. RESULTS: Both MR analyses provided evidence that higher BMI was associated with lower odds of depression. For example, a genetically-instrumented 1-SD higher BMI in the CKB was associated with lower odds of depressive symptoms [OR: 0.77, 95% CI: 0.63, 0.95]. There was evidence of differences according to place of residence. Using the IVW method, higher BMI was associated with lower odds of depression in people of East Asian ancestry living in China but there was no evidence for an association in people of East Asian ancestry living in the USA or UK. Furthermore, higher genetic BMI was associated with differential effects in urban and rural dwellers within China. CONCLUSIONS: This study provides the first MR evidence for an inverse relationship between BMI and depression in people of East Asian ancestry. This contrasts with previous findings in European populations and therefore the public health response to obesity and depression is likely to need to differ based on sociocultural factors for example, ancestry and place of residence. This highlights the importance of setting-specific causality when using genetic causal inference approaches and data from diverse populations to test hypotheses. This is especially important when the relationship tested is not purely biological and may involve sociocultural factors.

Social mobility across the lifecourse and DNA methylation age acceleration in adults in the UK.

Disadvantaged socio-economic position (SEP) is associated with greater biological age, relative to chronological age, measured by DNA methylation (positive 'age acceleration', AA). Social mobility has been proposed to ameliorate health inequalities. This study aimed to understand the association of social mobility with positive AA. Diagonal reference modelling and ordinary least square regression techniques were applied to explore social mobility and four measures of age acceleration (first-generation: 'Horvath', 'Hannum' and second-generation: 'Phenoage', DunedinPoAm) in n = 3140 participants of the UK Household Longitudinal Study. Disadvantaged SEP in early life is associated with positive AA for three (Hannum, Phenoage and DunedinPoAm) of the four measures examined while the second generation biomarkers are associated with SEP in adulthood (p < 0.01). Social mobility was associated with AA measured with Hannum only such that compared to no mobility, upward mobility was associated with greater age independently of origin and destination SEP. Compared to continuously advantaged groups, downward mobility was associated with positive Phenoage (1.06y [- 0.03, 2.14]) and DunedinPoAm assessed AA (0.96y [0.24, 1.68]). For these two measures, upward mobility was associated with negative AA (Phenoage, - 0.65y [- 1.30, - 0.002]; DunedinPoAm, - 0.96y [- 1.47, - 0.46]) compared to continually disadvantaged groups. While we find some support for three models of lifecourse epidemiology with early life as a sensitive period, SEP across the lifecourse and social mobility for age acceleration measured with DNA methylation, our findings suggest that disadvantaged SEP across the lifecourse is most consistently associated with positive AA.

Body mass index and childhood symptoms of depression, anxiety, and attention-deficit hyperactivity disorder: A within-family Mendelian randomization study.

Background: Higher BMI in childhood is associated with emotional and behavioural problems, but these associations may not be causal. Results of previous genetic studies imply causal effects but may reflect influence of demography and the family environment. Methods: This study used data on 40,949 8-year-old children and their parents from the Norwegian Mother, Father and Child Cohort Study (MoBa) and Medical Birth Registry of Norway (MBRN). We investigated the impact of BMI on symptoms of depression, anxiety, and attention-deficit hyperactivity disorder (ADHD) at age 8. We applied within-family Mendelian randomization, which accounts for familial effects by controlling for parental genotype. Results: Within-family Mendelian randomization estimates using genetic variants associated with BMI in adults suggested that a child's own BMI increased their depressive symptoms (per 5 kg/m2 increase in BMI, beta = 0.26 S.D., CI = -0.01,0.52, p=0.06) and ADHD symptoms (beta = 0.38 S.D., CI = 0.09,0.63, p=0.009). These estimates also suggested maternal BMI, or related factors, may independently affect a child's depressive symptoms (per 5 kg/m2 increase in maternal BMI, beta = 0.11 S.D., CI:0.02,0.09, p=0.01). However, within-family Mendelian randomization using genetic variants associated with retrospectively-reported childhood body size did not support an impact of BMI on these outcomes. There was little evidence from any estimate that the parents' BMI affected the child's ADHD symptoms, or that the child's or parents' BMI affected the child's anxiety symptoms. Conclusions: We found inconsistent evidence that a child's BMI affected their depressive and ADHD symptoms, and little evidence that a child's BMI affected their anxiety symptoms. There was limited evidence of an influence of parents' BMI. Genetic studies in samples of unrelated individuals, or using genetic variants associated with adult BMI, may have overestimated the causal effects of a child's own BMI. Funding: This research was funded by the Health Foundation. It is part of the HARVEST collaboration, supported by the Research Council of Norway. Individual co-author funding: the European Research Council, the South-Eastern Norway Regional Health Authority, the Research Council of Norway, Helse Vest, the Novo Nordisk Foundation, the University of Bergen, the South-Eastern Norway Regional Health Authority, the Trond Mohn Foundation, the Western Norway Regional Health Authority, the Norwegian Diabetes Association, the UK Medical Research Council. The Medical Research Council (MRC) and the University of Bristol support the MRC Integrative Epidemiology Unit.

Some studies show that children with obesity are more likely to receive a diagnosis of depression, anxiety, or attention-deficit hyperactivity disorder (ADHD). But this does not necessarily mean obesity causes these conditions. Depression, anxiety, or ADHD could cause obesity. A child's environment, including family income or their parents' mental health, could also affect a child's weight and mental health. Understanding the nature of these relationships could help scientists develop better interventions for both obesity and mental health conditions. Genetic studies may help scientists better understand the role of the environment in these conditions, but it's important to consider both the child's and their parents' genetics in these analyses. This is because parents and children share not only genes, but also environmental conditions. For example, families that carry genetic variants associated with higher body weight might also have lower incomes, if parents have been affected by biases against heavier people in society and the workplace. Children in these families could have worse mental health because of effects of their parent's weight, rather than their own weight. Looking at both child and adult genetics can help disentangle these processes. Hughes et al. show that a child's own body mass index, a ratio of weight and height, is not strongly associated with the child's mental health symptoms. They analysed genetic, weight, and health survey data from about 41,000 8-year-old children and their parents. The results suggest that a child's own BMI does not have a large effect on their anxiety symptoms. There was also no clear evidence that a child's BMI affected their symptoms of depression or ADHD. These results contradict previous studies, which did not account for parental genetics. Hughes et al. suggest that, at least for eight-year-olds, factors linked with adult weight and which differ between families may be more critical to a child's mental health than a child's own weight. For older children and adolescents, this may not be the case, and the individual's own weight may be more important. As a result, policies designed to reduce obesity in mid-childhood are unlikely to greatly improve the mental health of children. On the other hand, policies targeting the environmental or societal factors contributing to higher body weights, bias against people with higher weights, and poor child mental health directly may be more beneficial.

Socioeconomic position and adverse childhood experiences as risk factors for health-related behaviour change and employment adversity during the COVID-19 pandemic: insights from a prospective cohort study in the UK.

BACKGROUND: Non-pharmaceutical interventions to reduce the spread of COVID-19 may have disproportionately affected already disadvantaged populations. METHODS: We analysed data from 2710 young adult participants of the Avon Longitudinal Study of Parents and Children. We assessed the associations of socioeconomic position (SEP) and Adverse Childhood Experiences (ACEs, e.g. abuse, neglect, measures of family dysfunction) with changes to health-related behaviours (meals, snacks, exercise, sleep, alcohol and smoking/vaping), and to financial and employment status during the first UK lockdown between March-June 2020. RESULTS: Experiencing 4+ ACEs was associated with reporting decreased sleep quantity during lockdown (OR 1.53, 95% CI: 1.07-2.18) and increased smoking and/or vaping (OR 1.85, 95% CI: 0.99-3.43); no other associations were seen between ACEs or SEP and health-related behaviour changes. Adverse financial and employment changes were more likely for people with low SEP and for people who had experienced multiple ACEs; e.g. a history of 4+ ACEs was associated with being furloughed or on other leave during lockdown (OR 1.92, 95% CI: 1.35-2.74). CONCLUSIONS: In this sample of young adults, there was little evidence that lockdown worsened inequalities in health-related behaviours. However, adverse financial and employment consequences of lockdown were more likely to be experienced by people who have already experienced socioeconomic deprivation or childhood adversity, thereby widening social inequalities and demonstrating the need for support into adulthood for those with a history of ACEs.

Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects.

Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.

Transcriptional neighborhoods regulate transcript isoform lengths and expression levels.

Sequence features of genes and their flanking regulatory regions are determinants of RNA transcript isoform expression and have been used as context-independent plug-and-play modules in synthetic biology. However, genetic context-including the adjacent transcriptional environment-also influences transcript isoform expression levels and boundaries. We used synthetic yeast strains with stochastically repositioned genes to systematically disentangle the effects of sequence and context. Profiling 120 million full-length transcript molecules across 612 genomic perturbations, we observed sequence-independent alterations to gene expression levels and transcript isoform boundaries that were influenced by neighboring transcription. We identified features of transcriptional context that could predict these alterations and used these features to engineer a synthetic circuit where transcript length was controlled by neighboring transcription. This demonstrates how positional context can be leveraged in synthetic genome engineering.