Twin Research and Human Genetics

Childhood weight development, especially overweight and obesity, has been associated with mental health, but their dynamic, causal relationships, and whether these differ by sex, remain unclear. We applied causal discovery to data from the Danish National Birth Cohort (n=67,593) spanning six periods from pregnancy to late adolescence and considering 67 variables related to child and parental weight, mental health, lifestyle, and socio-economic factors. We found no statistically significant difference between the causal graphs for boys and girls (P=0.079). The data-driven models found causal influence of childhood weight on subsequent weight status. Mental health pathways were exclusively within or across adjacent periods and centered on early adolescent stress. We examined the interplay between a subset of mental health variables, containing information on externalizing and internalizing problems, and weight, and found no direct causal pathway between the two processes. These findings suggest that observed links between weight and these mental health measures may be attributable to confounding. Our findings demonstrate the value of data-driven causal discovery in large cohort studies and how to test for differences in causal mechanisms across subgroups. Results are available in an interactive application, enabling future research to further explore the interplay between weight and mental health.

C-Reactive Protein (hs-CRP) is a common marker for human inflammation, a response to perceived threat and precipitate to many compromising health conditions. Previous work demonstrated that in addition to other biological features that may be predictive and explanatory of variance in inflammation, psychosocial influences may play a role. The present work uses structural equation modeling to examine pathways including socioeconomic status (SES), psychological capital (PsyCap), and perceived discrimination (Discrim) -insofar as they explain variance in hs-CRP, potentially moderated by neurological lateralization (handedness). Body mass index (BMI), an indicator of body composition, stood as the strongest predictor of the obesity-related inflammatory marker (ORIM). On average, females are predicted to have higher hs- CRP scores than males. The psychosocial constructs were estimated to have little to no effect on inflammation (via hs-CRP) in the analysis sample (ADD Health Study) in either group (left and right-handers) although a small, statistically non-zero indirect path is found in the retained model for right-handed participants (given statistical power for estimation). With this finding, contextual effect estimates are provided with regard to the effect of perceived discrimination on hs-CRP given the range of SES and BMI.

Importance: In adolescence, attempts to lose weight are common, but their long-term impacts on mental and physical health are not known. Objective: To investigate the association between adolescent dieting and exercising to lose weight and adult trajectories of depressive symptoms and body mass index (BMI). Design: A longitudinal cohort study of children born between April 5 and 11, 1970, and followed up to age 51 years. Setting: Adolescents in the 1970 British Cohort Study in England, Wales and Scotland. Participants: A total of 4,650 adolescents with available exposure data. Exposures: Self-reported lifetime dieting or exercising for weight loss measured at age 16 years. Main Outcomes and Measures: Depressive symptoms measured with the nine-item Malaise Inventory, and BMI derived from self-reported height and weight, at ages 26, 30, 34, 42, 46, and 51 years. Results: Among 4,650 adolescents (56.7% girls, 97.7% White), 1,938 (41.7%) had dieted and 343 (7.4%) had exercised for weight loss by age 16 years. In fully adjusted analyses controlling for a wide range of child- and family-based confounders including prior BMI and emotional difficulties, there was evidence that adolescents who had dieted had higher adult depressive symptom trajectories (adjusted mean difference [aMD] 0.13, 95% CI 0.03-0.24, p=0.015) and higher and increasing adult BMI trajectories than those who had not dieted. There was also evidence that adolescents who exercised for weight loss had higher adult depressive symptom (aMD 0.18, 95% CI 0.02-0.34, p=0.031), and BMI trajectories (aMD 0.37, 95% CI -0.03, 0.78, p=0.071), though evidence of the latter was weak. Conclusions and Relevance: Behaviours aimed at weight loss occurring in adolescence might be a shared risk factor for depressive symptoms and high BMI in adulthood. If causal, these findings could suggest that reducing pressures to lose weight in adolescence may help prevent poor mental and physical health across the lifecourse.

Abstract Parental depression and early child neurodevelopment are closely interconnected, yet few population-based studies have examined both maternal and paternal depression in relation to early neurodevelopmental risk. This study aimed to examine the association between child neurodevelopmental risk and parental depression in the French national birth cohort Etude Longitudinale Francaise depuis l'Enfance (ELFE). We conducted a cross-sectional analysis of 12,953 children and their parents who participated in the 2-year follow-up. Child neurodevelopmental risk was assessed at age 2 years using the Modified Checklist for Autism in Toddlers and categorized as low, intermediate, or high risk. Parental depression was assessed using the Kessler Psychological Distress Scale and defined as maternal depression, paternal depression, or depression in at least one parent. Multivariable logistic regression models were adjusted for sociodemographic, pregnancy-related, and child characteristics. Compared with low child neurodevelopmental risk, intermediate risk was associated with higher odds of maternal depression and depression in at least one parent. High child neurodevelopmental risk was associated with substantially higher odds of maternal depression and depression in at least one parent. Associations with paternal depression were weaker and were no longer statistically significant after adjustment. These findings suggest that parental depression, particularly maternal depression, is associated with early child neurodevelopmental risk from the stage of initial developmental concerns. They support an integrated, family-centred approach combining early identification of child developmental vulnerability with attention to parental mental health.

Genetic literacy is an integral measure for examining societys interaction with genetics, but widely-used "genetic literacy" measures lack both knowledge comprehension measures and psychometric validation. To address these issues, we validated the Education and Assessment of Genetic Literacy measure (EAGL) in a sample of 2708 US participants, using both exploratory and confirmatory factor analysis. In addition to standard subjective and objective knowledge subscales, our measures distinct knowledge comprehension subscale focuses on autism as an example of a complex condition. Regression analyses showed a statistically significant interaction when looking at education and personal connection to autism in relation to knowledge comprehension (F=3.68, p=0.003). Separately, those in our sample with a connection to autism scored higher on the subjective knowledge section (F=19.52, p<0.001) only, concurring with previous demonstrations of a subjective-objective knowledge gap in science literacy. We explored geographic location as one potential factor in genetic literacy and found that metropolitan vs non-metropolitan status had no significant main effects on overall levels. After the validation process, we have two multi-domain measures which accurately capture the construct of genetic literacy and are available for wide use: the multi-faceted EAGL-long, which has previously been tested in thousands of participants, or the validated three-factor EAGL-short.

The etiology of autism is influenced by genetic and non-genetic factors, with observational studies suggesting associations between early maternal health diagnoses and offspring autism. However, these associations may partly reflect shared familial genetic liability rather than direct causal effects. Using comprehensive national health registers and individual-level genetic data from the iPSYCH cohort (N=117,542), we examined whether maternal health diagnoses are associated with offspring polygenic scores (PGS) for autism. Such associations between maternal health and offspring autism would indicate shared genetic factors and the possibility of genetic confounding in the observational associations. We also tested such associations with PGSs for other neuropsychiatric and neurodevelopmental conditions that are genetically correlated with autism, but with better-powered PGS (due to larger GWAS sample sizes and likely more polygenic genetic architecture), as well as height, a negative control. Several maternal diagnoses were nominally associated with autism PGS in the child, including, e.g., certain obstetric complications, asthma, and obesity. After adjustment for multiple testing, the only statistically significant results included those between maternal diagnoses, predominantly psychiatric, and other neuropsychiatric and neurodevelopmental PGSs in the child. Sensitivity analyses confirmed the robustness of our results across exposure windows, diagnostic settings, and socioeconomic adjustments. These findings indicate that maternal diagnoses associated with autism partially reflect shared genetic liabilities between mothers and their children. However, such genetic effects, as captured by child PGS do not fully explain the observed associations, suggesting additional factors, including e.g., non-genetic familial factors, rare variants, and indirect effects.

Early-life exposures are important to several late-life health outcomes. We sought to study the effect of an in utero nutritional environment and its interaction with Alzheimer's disease (AD) genetic risk on late-life cognitive function. We used a natural experiment created by the pellagra epidemic, a nutritional disease caused by a vitamin B3 deficiency, to evaluate the association between in utero pellagra epidemic exposure and late-life cognitive function in the Health and Retirement Study (N = 18,285). We also evaluated whether the in utero exposure could modify the AD polygenic score's (PGS) effect on cognition. In utero pellagra epidemic exposure was significantly associated with cognition ({beta} = -0.025). However, these effects were not isolated to the prenatal period as exposure during childhood periods also had an effect. The interaction between the in utero exposure and the AD PGS was significant, where the genetic effect on cognition was amplified with increasing (progressively worse) in utero exposure levels. These associations imply that the early-life nutritional environment affects late-life cognitive function and that these effects can modify genetic risk.

BackgroundFathers adolescent smoking and overweight affect respiratory health in offspring, suggesting that paternal puberty exposures may influence offspring biological ageing through preconception epigenetic mechanisms. MethodsWe analyzed epigenetic age acceleration using four validated epigenetic clocks derived from blood DNA methylation in 892 RHINESSA offspring (mean age 27 years), linked to parental data on smoking and body shapes from RHINE/ECRHS. Linear regression examined parental smoking initiation ([&le;]15 or >15 years) and overweight body shape (childhood/puberty or age 30) in relation to offspring epigenetic age acceleration, adjusting for offspring sex, age and parental socioeconomic status. Sensitivity analyses accounted for offspring smoking and BMI. ResultsPCHorvath ({beta} 1.53; 95% CI 0.02, 2.9), PCGrimAge (1.21; 0.03, 2.1), DunedinPACE (0.04; -0.001, 0.1) and PCPhenoAge (1.92; -0.3, 4.2) were accelerated in daughters of fathers who started smoking [&le;]15 years. Likewise, PCHorvath (2.25; 1.2, 3.3), PCGrimAge (1.36; -0.2, 2.9), DunedinPACE (0.07; 0.01, 0.1) and PCPhenoAge (3.11; 1.8, 4.4) were accelerated in daughters and sons of fathers who had been overweight in childhood and puberty. These results remained largely unchanged after additional adjustments or stratification in sensitivity analyses. No associations were found for maternal smoking or overweight in puberty. ConclusionsEpigenetic ageing is accelerated in offspring of fathers who smoked or were overweight in puberty, independent of offspring lifestyle. These findings suggest that adolescent boys environment and lifestyle may be critical for next-generation health. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/26352444v1_fig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1eea189org.highwire.dtl.DTLVardef@1af41f4org.highwire.dtl.DTLVardef@1132932org.highwire.dtl.DTLVardef@f5ba2c_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1.C_FLOATNO Graphical abstract Legend to graphical abstract Figure Fathers smoking or overweight during puberty was associated with accelerated epigenetic aging in offspring (n=892), independent of the offsprings own lifestyle. No such pattern was observed for maternal puberty exposures, or when paternal exposures occurred after puberty. Male puberty may be a critical window for next-generation health. C_FIG

Patients with amyotrophic lateral sclerosis (ALS) face critical decisions regarding life-sustaining treatments, such as invasive mechanical ventilation and percutaneous endoscopic gastrostomy. Advance care planning and shared decision-making are standard supportive frameworks but they often fail to account for structural pressures like progressive decline, shifting patient values, and fear of becoming a burden that may influence decision-making. This study explores how patients with ALS interpret ventilator and care options amid progressive physical decline, thereby reconsidering approaches to decision support. Using a qualitative descriptive design, the researcher (a nurse/sociologist) conducted 2-3 hour home interviews with five purposively sampled patients with ALS. Data, including eye-tracking-aided responses, were analysed via Sandelowskis framework. Rigour was ensured through team-based triangulation, independent coding by two researchers, and a reflexive audit trail. Subjective narratives were prioritised without medical record cross-referencing to capture patients experiences. Four categories emerged: (1) Rewriting clinical prognosis into a narrative of exploration via peer models, where meeting active ventilator users transformed future perceptions; (2) The conflict between securing care infrastructure and the burden on family, which greatly influenced the will to survive; (3) Existential fluctuation, where patients intentions shifted with daily fulfilment and family events; and (4) Governance of the body via pre-emptive technology use and training carers as physical extensions. Findings showed decision-making was a multi-layered process redefining lifes meaning within social resources. This necessitate shifting from independent to relational autonomy, where agency relies on care infrastructure, not physical ability. Treatment choice is a dynamic exploration requiring narrative companions to support existential fluctuations. Professionals must coordinate environments to reduce patient indebtedness. Limitations include the small, resource-advantaged sample (N = 5) and reliance on subjective narratives without medical record verification. Living with ALS means governing a new self through relational support and continuous dialogue.

Objective: ADHD has been associated with obesity indicators, including BMI, across the lifespan. A possible mechanism linking ADHD and BMI is binge eating. Previous research has found associations between ADHD, binge eating and BMI. However, the role of genetic and environmental influences on these associations remains unclear. Method: We utilized data from the Twins Early Development Study (TEDS), comprising 3,675 monozygotic and 7,063 dizygotic twin pairs. ADHD symptoms in childhood and adolescence were assessed using parent-reported questionnaires. Adult ADHD symptoms were measured using both self-report and parent-report questionnaires. Phenotypic mediation models examined whether binge eating mediated the association between ADHD and BMI, without controlling for genetic confounding. Subsequently, the etiological architecture underlying the associations among the three traits across childhood, adolescence, and adulthood were investigated by incorporating genetic and environmental influences into the models. Results: Binge eating significantly mediated the association between ADHD symptoms and BMI in both adolescence and adulthood. However, these mediation effects were no longer present once genetic and environmental influences were incorporated into the models. The best-fitting model in childhood, adolescence and adulthood was Cholesky decomposition models, where covariance between traits was explained by shared aetiology. Conclusions: This twin study reveals shared liability across ADHD, binge eating, and BMI. The mediating role of binge eating in the relationship between ADHD symptoms and BMI was largely confounded by shared genetic influences. Intervention strategies could focus more on common underlying behavioural and self-regulatory mechanisms across these traits, as well as placing more emphasis on symptom patterns within families.

IntroductionEating behaviors are consistently associated with weight-related traits, yet the biological factors contributing to individual differences in these behaviors remain poorly characterized. Plasma proteomics offers an opportunity to investigate the biological processes underlying eating behaviors. MethodsParticipants were 730 young adult twins from the FinnTwin12 cohort. Eating behaviors were measured through self-report questionnaires, including the Three-Factor Eating Questionnaire-R18 and four additional items on eating styles. Associations between plasma proteins and eating behaviors were examined using generalized estimating equation models adjusted for age and sex, with additional analyses adjusting for body mass index (BMI). Within-pair analyses were conducted in both monozygotic (MZ) and dizygotic twin pairs to assess whether associations were influenced by genetic or environmental factors. ResultsWe identified 51 significant protein-eating behavior associations involving 35 unique proteins (FDR <0.05). We observed 19 associations for the item "overeating when feeling down" and 12 for the TFEQ factor of emotional eating. The identified proteins were predominantly enriched in immune system pathways, including the complement cascade and adaptive immune signaling. After further adjustment for BMI, 12 associations persisted, most of which were associated with eating-style items, suggesting that BMI had a substantial influence on protein-eating behavior associations. Within-pair analyses of MZ pairs indicated that several associations persist after accounting for genetic effects. ConclusionOur study identifies plasma proteins associated with eating behaviors, largely involving immune-related pathways. While some associations attenuated in twin analyses, several persisted, suggesting environmental influences. These results highlight potential biomarker candidates and indicate that modifiable environmental factors may contribute to the proteomic profiles associated with eating behaviors, with possible implications for weight-related traits.

Background: Depression and anxiety symptoms emerge early in life. We examined developmental trajectories of emotional symptoms, starting from early childhood, in three UK birth-cohorts spanning successive generations and diverse socio-ethnic contexts. Methods: Using data from three longitudinal, population-based UK birth-cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC), Millenium Cohort Study (MCS), and Born in Bradford (BiB) we identified group-based trajectories of emotional symptoms using repeated Strengths and Difficulties Questionnaire, Emotional Subscale (SDQ-E) scores from ages 3-14y. Baseline samples comprised children with [&ge;]1 SDQ-E measure between age 3-14y (NALSPAC=11,025; NMCS=15,446; NBiB=6711). Participants were born three decades apart (ALSPAC: 1990-2, MCS: 2000-2, BiB: 2007-10) in distinct socioeconomic and ethnic contexts. We characterised group membership by: female sex, non-white ethnicity, maternal depression/anxiety and IMD quintile. In ALSPAC we modelled associations between trajectories and depression/anxiety diagnoses in early adulthood (24y and 30y). Results: In all cohorts 49% were female. ALSPAC had few non-white participants (4%) compared to MCS (17%) and BiB (66%). Each cohort had low-, mid- and high-level symptom trajectories. High-level trajectories comprised 6-7% of the population in each cohort. However, in younger cohorts, high-level symptom trajectories started high and persisted from age 3-5y but started low and increased in the oldest cohort. Female sex and maternal depression/anxiety were associated with higher odds of high-level or increasing symptom trajectories across all cohorts. Higher socioeconomic status and belonging to the ethnic majority was protective. Mid- and high-level symptom trajectories had higher odds of depression/anxiety diagnoses in early-adulthood in the older ALSPAC cohort. Conclusions: Developmental trajectories of emotional symptoms across childhood and adolescence are broadly similar across generations and diverse social contexts. However, children born more recently and in more diverse contexts may experience more persistent, severe emotional symptoms from a young age Key words: Longitudinal trajectories; emotional symptoms; SDQ, ALSPAC; MCS; Born in Bradford

Socioeconomic inequalities in health and well-being are a major public health concern, particularly in ageing populations. Education is a key determinant shaping multiple aspects of health outcomes. We used cross-sectional data from wave 9 of the German sample (n=4,148) of the Survey of Health, Ageing and Retirement in Europe (SHARE) to test whether formal education is associated with well-being in later adulthood, with health literacy, self-rated health, and preventive health behaviours as possible mediators. Our results showed that education was positively associated with greater well-being, but only via indirect pathways. Specifically, self-rated health, health literacy, and fruit and vegetable consumption mediated the relationship between education and well-being accounting for 54.7, 24.7, and 12.6 percent of the total effect, respectively. In addition, there were significant positive correlations between education and health literacy, as well as high-intensity physical activity, daily fruit and vegetable consumption, more preventive health check-ups, and less smoking. In contrast, alcohol consumption was more common among those with higher levels of education. All health behaviours and health literacy were correlated directly or indirectly (i.e., mediated by health) with well-being. These findings highlight the importance of examining indirect pathways linking education to well-being in later life. Interventions aimed at improving health literacy and promoting healthy behaviours may help reduce educational inequalities in quality of life among older adults. About the SHARE Working Paper SeriesThe SHARE Working Paper Series started in 2011 and collects pre-publication versions of papers or book chapters, technical and methodological reports as well as policy papers based on SHARE data. The working papers are not reviewed by the publisher (SHARE-ERIC), layout and editing are not standardized. The publisher takes no responsibility for the scientific content of the paper. Working Papers can be updated - a version number is indicated on the front page. Previous versions are available upon request.

Culture plays a crucial role in health; family, community, culture, and social conventions all have a significant impact on how an infant with jaundice is treated. Written or unwritten rules govern what parents and the community are allowed to do, which may have a detrimental effect on the neonates care. ObjectivesThe study explored how social expectations affect midwives management of neonatal jaundice at the St Patricks hospital in Maase-Offinso, in the Ashanti region of Ghana. MethodA total of seventeen midwives were sampled purposively using an exploratory descriptive design. Participants were engaged in interviews and focus group discussion after ethical approval was obtained. A semi-structured focus group discussion guide and interview guide was used to collect data. ResultsThe study discovered that the treatment of neonatal jaundice was adversely affected by social pressures, misconceptions, maternal choices, and spiritual views. Mothers and midwives socially approved sunbathing, and there were indications that grandmothers disapproved hospital care for their grandchildren. ConclusionCulture, family and social norms cannot be separated from health especially for the neonate whose means of identification is to belong to a family. Consequently, it is essential to respond to social influences, cultural conventions, and the various cultures of families with a culturally sensitive approach.

BackgroundLeukocyte telomere length (LTL) from cord blood is a marker of biological aging and long-term systemic health. Exposure to essential and toxic metals has been shown to influence LTL in a sexually dimorphic manner. However, little is known about the interplay between early-life longitudinal biodynamic patterns of these elements and cord blood LTL, as well as potential sex differences. MethodsFrom an ongoing longitudinal birth cohort study in Mexico City, we used available tooth samples from 231 children (129 males and 102 females) to generate 16 elemental weekly time series of direct fetal intensities from the second trimester through four to five months after birth. We analyzed the dentine growth rings using Inductively Coupled Plasma Mass Spectrometry to generate time-resolved elemental intensities. The elements included were Li, Mg, Ca, Mn, Co, Ni, Cu, Zn, As, Sr, Mo, Cd, Sn, Ba, Pb, and Bi. LTL was measured in cord blood using qPCR. We used cross-recurrence quantification analysis and entropy-complexity-based measures to generate time-resolved features that quantify the synchronization of elemental biodynamics. A stability-selection approach using five-fold cross-validation of regularized ridge regression was used for feature selection, and covariate-adjusted linear models were used to estimate associations with LTL. FindingsThe biodynamic interaction of Mg-Co and Mn-Sn was identified as the most stable feature among male and female children, respectively. In males, higher vertical entropy (i.e., a measure of higher variability) of Mg-Co temporal biodynamics was associated with shorter LTL ({beta}[95%CI]: -0.9[-0.14,-0.03]; p-value<0.01), but not in females ({beta}[95%CI]:-0.02[-0.10,0.06]; p-value=0.60); whereas higher recurrence rate (i.e., a measure of higher synchronicity) of Mn-Sn temporal biodynamics was associated with longer LTL ({beta}[95%CI]: 0.09[0.02,0.16]; p-value=0.01), in females but not in males ({beta}[95%CI], 0.03[-0.04, 0.09]; p-value=0.39). InterpretationWe demonstrate that time-varying multi-elemental synchronization of early-life elemental biodynamics, a potential marker of homeostatic balance, may be associated with cord blood-based telomere length in a sexual dimorphic manner.

Autism development involves multiple genetic and early-life environmental factors. Studying the placenta's gene expression profile may reveal key mechanistic pathways in autism development. Here, using a nested case-cohort design within an Australian population-derived prebirth cohort study (n=1074), we identified 1,644 differentially expressed genes (DEGs; FDR<0.05) in the placenta of children with autism diagnosis (n=43), compared to those without (n=120). The top enriched pathways related to mitochondrial translation, oxidative stress, RNA processing and transcription regulation. CYP1A1, the most important xenobiotic-metabolising enzyme of the placenta, was the top downregulated DEG in the placenta of children with autism, while immuno-regulatory human leukocyte antigen (HLA)-related genes were among the top upregulated DEGs. A machine learning-based approach predicted autism from the transcriptomic data with a median sensitivity of 0.57 (2.5th-97.5th centiles: 0.29, 0.76) and median specificity of 0.92 (2.5th-97.5th centiles: 0.78, 0.98). Weighted Gene Correlation Network Analysis identified eight affected placental gene modules, with the largest five modules being enriched primarily for mitochondrial bioenergetics, oxidative phosphorylation and RNA processing pathways. This placental transcriptomic signature of impaired mitochondrial function and gene transcription regulation among infants subsequently diagnosed with autism has profound implications for understanding both risk factors and prediction, suggesting the possibility of identifying modifiable prenatal pathways to improve autism outcomes.

Cultural engagement is associated longitudinally with better mental health and reduced depression incidence, but evidence has largely relied on self-reported symptoms and diagnoses, leaving uncertainty about clinically recorded disorders, and residual confounding remains a concern. Here, we examined whether cultural engagement (including going to cinemas, museums, galleries, exhibitions, theatre, concerts, or opera) predicts hospital-treated mental disorders in 8,274 adults aged 50 years or older from the English Longitudinal Study of Ageing. Participant records were linked to ICD-10 diagnoses in Hospital Episode Statistics and mortality records with follow-up of up to 20 years. In fully adjusted Cox models accounting for sociodemographic, lifestyle, and social factors and multiple testing, frequent cultural engagement was associated with lower risk of any mental disorders (HR 0.71, 95% CI 0.62-0.82, FDR adjusted P value<0.001), dementia (0.71, 0.56-0.89, FDR adjusted P value=0.010), substance misuse (0.75, 0.59-0.95,FDR adjusted P value=0.040), and mood disorders (0.73, 0.56-0.95, FDR adjusted P value=0.044), but not neurotic disorders. Associations persisted after excluding early incident cases and adjusting for baseline depressive symptoms and cognition, and showed robustness to unmeasured confounders. To further probe causality, eye disease, ear disease, and traumatic brain injury, which share similar socio-demographic profiles to mental disorders, were prespecified as negative control outcomes. Cultural engagement was not associated with any negative control outcomes. These findings provide triangulated statistical data to suggest that cultural engagement is associated with reduced risk of several clinically recorded mental disorders and support further testing of cultural engagement as a population mental health strategy.

Background Literature investigating mediation of the association between child abuse and dementia has largely considered composite adverse childhood experience scores rather than individual adverse experiences, despite evidence that different experiences have different impacts on dementia risk. Additionally, prior studies consider mediators in isolation, despite known associations between mediators which may impact indirect pathways from child abuse to dementia. Objectives To investigate whether potentially modifiable health and lifestyle factors mediate the association between child abuse and dementia. Methods We used data from the English Longitudinal Study of Ageing to investigate associations between child abuse and dementia (N:5,448). Indirect pathways through four mediator categories (education, health behaviours, mental health and cardiovascular health) were examined. We used regression modelling to estimate associations between child abuse, mediators and dementia, and causal mediation analysis using the g-formula to estimate the joint indirect effect through the mediators. Results Individuals who experienced child abuse had, on average, an 80% higher hazard of dementia, compared to those who did not (RTE HR:1.80, 95% CI:1.21-2.39). Mental health mediators showed strong associations with both child abuse and dementia. Evidence for other mediators was weaker. Education, health behaviours, mental health and cardiovascular health mediated approximately 18% of the association. Sensitivity analysis revealed that almost all this mediation occurred through mental health. Conclusions Child abuse was associated with higher risk of dementia. Joint mediation analysis suggested that education, health behaviours, cardiovascular health, and mental health accounted for a relatively small proportion of the observed association, with most mediation occurring through mental health. Future research must focus on other potential pathways from child abuse to dementia, including biological and social mechanisms.

Population fertility patterns are closely linked to socioeconomic inequality, with educational attainment (EA) being a key predictor of completed fertility. While EA is partially heritable, the extent to which EA-associated genetic variation relates to fertility independently of education remains unclear, particularly outside Western European and North American populations. Using data from [~]40,000 women and [~]10,000 men in the Estonian Biobank, we examine sex-specific associations between EA polygenic scores (PGSEA) and completed fertility. We extend prior work by distinguishing cognitive and non-cognitive EA components, accounting for age at first pregnancy (AFP), and applying within-family analyses to assess the role of direct genetic effects. Among women, PGSEA is negatively associated with fertility, with a significantly stronger association for the non-cognitive than the cognitive EA polygenic score. The association between PGSEAand fertility is moderated by EA and changes sign across AFP strata, from negative among women with earlier AFP to positive among those with later AFP. Importantly, this association is not attenuated in within-family models, consistent with a predominant role of direct genetic effects. Among men, associations are weak or slightly positive and stable across education groups. Overall, EA-related genetic variation is associated with fertility through pathways that appear largely independent of educational attainment, suggesting that shared genetic influences operate through multiple mechanisms that differ by sex and reproductive timing. SignificanceEducational attainment is closely linked to completed fertility, yet the mechanisms behind this relationship remain not fully understood. Using a population-based cohort from Estonia, we show that genetic variants associated with education relate to fertility in markedly different ways for women and men and that these associations cannot be explained by education level alone. Differences between cognitive and non-cognitive education-related genetic components further point to multiple life-course pathways linking genetics and reproduction. Family-based analyses suggest that these associations are largely consistent with direct genetic effects and not driven by correlated family environments. Together, our findings suggest that education-related genetic variation shapes fertility through multiple sex-specific and life-course-dependent pathways, rather than acting solely through educational attainment.

Mediation analysis quantifies how an exposure affects an outcome through an intermediate variable. We extend mediation analysis to capture the cumulative effects of longitudinal predictors on longitudinal outcomes. Our proposed model examines how mediators transmit the effects of the current and previous exposure on the current outcome. We construct a least-squared estimator for cumulative indirect effect (CIE) and used three approaches (exact form, delta method, and bootstrap procedure) to estimate its standard error (SE). The estimator of CIE is unbiased with no unmeasured confounding and independent model errors between mediator model and outcome model at all time points, as shown in statistical inference and in simulations. While three SE estimates are numerically similar, bootstrap procedure is recommended due to its simplicity in implementation. We apply this method to Framingham Heart Study offspring cohort to assess if DNA methylation mediates the association of alcohol consumption with systolic blood pressure over two time points. We identify two CpGs (cg05130679 and cg05465916) as mediators and construct a composite DNA methylation score from 11 CpGs, which mediates for 39% of the cumulative effect. In conclusion, we propose an unbiased estimator for CIE. Future studies will investigate the missingness in mediators and outcomes.