Terrie E. Moffitt

An epigenetic speedometer to measure Pace of Aging: FraminghamPACE

Geroscience clinical trials need biomarker surrogate endpoints for healthspan. Leading candidates are omics-based composites developed from machine learning analysis of aging phenotypes including calendar age, survival, functional capacity, and Pace of Aging. Existing Pace of Aging biomarkers were developed in the Dunedin Longitudinal Study, limiting inference about the strengths and weaknesses of the method as distinct from the Study, a unique single-year birth cohort followed through midlife with near-perfect retention and uniform measurement of multi-organ-system function across two decades of follow-up. We adapted our Pace of Aging method for mixed-age cohorts with variable follow-up of organ-function measures and applied it to develop a novel DNA methylation biomarker of Pace of Aging in data from the Framingham Heart Study Offspring Cohort, FraminghamPACE. Validation analyses across four independent cohorts and one clinical trial establish advantages for the Pace of Aging method in developing biomarkers that are both predictive of healthspan and responsive to geroprotective intervention.

Diagnosis provision by young people’s mental health services: a comparison with epidemiological data

Background Little is known about the provision of diagnoses to young people with mental health disorders. We investigated diagnosis provision by NHS mental health services, focusing on 17-year-olds in South London between 2009-2024, and compared with estimated disorder prevalence. Methods To examine diagnosis provision in the population, we extracted diagnosis data from records of the NHS mental healthcare provider serving South London, using the Maudsley Biomedical Research Centre Clinical Record Interactive Search application; we then compared these data with the corresponding population size, obtained from the Office for National Statistics. To assess diagnosis provision in those with mental health disorders, we compared diagnosis data with the number of young people estimated to have met criteria for a disorder, derived from epidemiological interview data collected in the Environmental Risk (E-Risk) Longitudinal Twin Study and weighted according to characteristics of 17-year-old South Londoners. To assess diagnosis provision in those with mental health disorders within health services, we compared diagnosis data with the number estimated to have met criteria for a disorder and used any health service for their mental health, again derived from weighted E-Risk Study data. Findings Of 17-year-olds from South London in 2009-2024, 4.0% (n=8,958/223,404) had a diagnosis in mental health records during the previous year. This diagnosis provision covered <1 in 16 of those estimated to have had a mental health disorder, and <1 in 4 of those estimated to have also used health services. Diagnosis provision was lower in girls than boys and in young people with Black/Asian/Mixed/Other ethnicity than those with White ethnicity, in those estimated to have had a mental health disorder and used health services. Interpretation These findings demonstrate gaps and biases in mental health diagnosis provision for young people, including within health services, and reveal the imperative need to strengthen young people’s mental healthcare. Funding National Institute for Health Research, Medical Research Council, National Institute of Child Health and Development, Jacobs Foundation, National Society for Prevention of Cruelty to Children, Economic and Social Research Council, Prudence Trust, Wellcome Trust RESEARCH IN CONTEXT Evidence before this study Epidemiological research has found that less than half of young people with a mental health disorder report seeing a health professional for their symptoms and only a quarter to a third have seen a mental health specialist, and these findings are fairly consistent across high-income countries where this research has been conducted. For young people who see health professionals, there are likely to be barriers to the recognition and treatment of mental health disorders. We focused on the recognition of mental health disorders in young people, which is operationalised in clinical practice as provision of diagnoses. To identify studies examining mental health diagnosis provision in young people accessing health services, we searched MEDLINE with the terms “diagnos*” AND (“mental” OR “psychiatr*” OR [various terms for individual disorders]) AND (“young” OR “youth*” OR “child*” OR “adolescen*” OR “paedatric*” OR “pedatric*” OR “juvenile”) AND (“clinical” OR “healthcare” OR “health care” OR “service*”). This search was supplemented by reviewing reference lists and forward citations of relevant articles. We identified several studies that found diagnosis provision varied by sociodemographic characteristics and has increased over the past two decades in young people across multiple countries for several disorders, including depression, anxiety disorders, eating disorders, autism, and attention-deficit/hyperactivity disorder (ADHD). Only a small number of studies investigated diagnosis provision within young people who met criteria for a disorder. In the Avon Longitudinal Study of Parents and Children in the UK, of 18-year-olds who met criteria for depression, only 7.0% had a diagnosis of depression documented in their primary care records. In the Child and Adolescent Twin Study in Sweden, of 9-year-olds who met criteria for ADHD, only 18.5% of boys and 12.1% of girls had a diagnosis of ADHD noted in their health records. Within an Irish child and adolescent mental health service, of 12-15-year-olds who met criteria for depressive disorder, only 28.4% received a depressive disorder diagnosis after their usual clinical assessment. These studies suggest large gaps in diagnosis provision, including within health services, and highlight possible bias by sociodemographic characteristics. A better understanding of this topic is needed to enable more effective service planning, commissioning, and policymaking. Added value of this study This study investigated mental health diagnosis provision in 17-year-olds from South London. We examined diagnosis provision for several mental health disorders in NHS mental healthcare records. We compared these data with population and epidemiological data to calculate diagnosis provision rates in the general population, in those estimated to have met criteria for a disorder, and in those estimated to have also seen a health professional. We found that diagnosis provision substantially increased during our study period of 2009-2024, demonstrating an increase in the number of young people whose mental health needs were recognised in specialist services. However, we estimated that diagnoses were only provided to a small proportion of young people with a mental health disorder, including those within health services. Estimated diagnosis gaps were largest for those with generalised anxiety disorder and multiple disorders. We also found evidence of biases in diagnosis provision, based on gender, neighbourhood deprivation, and ethnicity. Implications of all the available evidence Barriers to mental healthcare access for young people should be reduced by policymakers and commissioners, including through investment in adequately staffed services with skilled clinicians, enabling more young people with mental health disorders to receive cost-effective evidence-based healthcare that has long-term benefits. Greater awareness among clinicians of the under-diagnosis and bias in diagnosis of young people’s mental health disorders, alongside strategies to address these problems, could improve young people’s mental healthcare. Innovative scalable interventions that can reach many more young people need to be developed, evaluated, and implemented by researchers. Prevention strategies are also required, including addressing risk factors for young people’s mental health disorders, and intervening early for those with symptoms before disorders develop, to reduce the future burden of mental health disorders in young people.

The role of mothers' speech for children's education beyond the early years

Tests mothers' speech effects on children's educational outcomes, suggesting modest influence.

Longer Residence in Disadvantaged Neighborhoods Predicts Both a Syndrome of Despair and Deaths of Despair: Complementary Evidence From Nationwide Register and Birth-Cohort Studies

Deaths of despair have been difficult to predict by focusing solely on individual-level factors. In two complementary studies, we tested whether individuals living in disadvantaged neighborhoods in a country with robust social safety nets (New Zealand) were at greater risk for a despair-related death (suicides, drug overdoses, alcohol poisonings, and liver disease, Study 1) or a “premorbid” midlife syndrome of despair-related maladies (suicidality, substance misuse, sleep problems, and chronic pain, Study 2). In 2 decades of observation, New Zealanders residing in disadvantaged neighborhoods across adulthood were at greater risk for a despair-related death ( N = 2.4 million; analytic sample using nationwide administrative data, population risk ratio per quintile increase in cumulative disadvantage = 1.27, 95% confidence interval [CI] = 1.23, 1.30) and a more severe premorbid syndrome of despair-related maladies ( N = 907; analytic sample using a population-representative birth cohort, β = 0.24, 95% CI = 0.17, 0.31). Findings held after adjustment for individual-level socioeconomic status and in Study 2, adjustment for childhood antecedents and adult difficulties that could provoke despair. Neighborhoods could be intervention targets to reduce despair-related deaths.

What does psychopathology research have to gain by studying all mental disorders at the same time?

Commentaries explore transdiagnostic research in mental disorders, suggesting new research directions.

Early-life blood pressure and midlife brain and cognitive health: tests in two birth cohorts

Plasma pTau181 is associated with subjective cognitive concerns but not objective cognitive decline or structural brain integrity measures in midlife

Flourishing in Early Adulthood Among Victimized Children: A Longitudinal Cohort Study

Longitudinal study shows flourishing in early adulthood among victimized children, suggesting interventions can help.

Shared genetic architecture of brain age gap across 30 cohorts worldwide

Deviations from normative brain ageing trajectories are linked to a wide range of adverse health outcomes. A number of brain age prediction models have been developed, based on various neuroimaging modalities, machine learning algorithms, training samples, and age ranges. However, it remains unknown whether these models converge on a shared genetic liability, and whether capturing this shared signal could provide a more sensitive marker of brain health than any single model alone. We first conducted a new brain age gap (BAG) GWAS in a sample of 60,735 individuals across 29 cohorts worldwide, and then applied genomic structural equation modelling to examine the shared genetic variance between five prior BAG GWASs and our new analysis, using a single latent BAG factor (30 cohorts overall). All six BAG GWASs loaded onto a single factor, explaining 63% of the total genetic variance. We identified 19 independent SNPs associated with the BAG factor, including four novel associations. Genetically, the BAG factor was positively correlated with multiple traits, with blood pressure, smoking, longevity, autism, and sleep showing putatively causal effects. A polygenic score (PGS) for the BAG factor showed associations with phenotypic BAGs already in childhood, with stronger links observed in adulthood. Phenome-wide association analyses indicated that BAG factor PGS captured associations with more health traits than individual BAG PGSs. Our findings underscore the importance of considering the shared variance across different BAG constructs to identify robust correlates of poor brain health.

Mental health conditions are associated with increased risk of subsequent self-harm, assault and unintentional injuries in two nations

Mental health conditions are associated with an increased risk of chronic physical diseases, but their implications for other physical health outcomes, including injuries, are less established. In this prospective cohort study, we tested whether mental health conditions antedate unintentional as well as self-harm and assault injuries, using administrative data from Norway ( N = 2,753,646) and New Zealand ( N = 2,238,813). In Norway, after accounting for pre-existing injuries, individuals with a primary care encounter for a mental health condition had an elevated risk of subsequent primary care-recorded injury. In New Zealand, as expected, individuals with a mental health-related inpatient hospital admission had an elevated risk of subsequent inpatient hospital-recorded self-harm injury, as well as assault injury. However, they also had an elevated risk of unintentional injuries. Associations extended to injury insurance claims. Associations were evident across mental health conditions, sex, age and after accounting for indicators of socioeconomic status. Risk was particularly increased for brain and head injuries. Patients with mental health conditions are an important group for injury prevention.

Quantifying the impact of early life growth adversity on later life health

BACKGROUND: Early-life growth adversity is important to later-life health, but precision assessment in adulthood is challenging. We evaluated whether the difference between attained and genotype-predicted adult height ("height-GaP") would associate with prospectively ascertained early-life growth adversity and later-life all-cause and cardiovascular mortality. METHODS: Data were first analyzed from the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 4582; 56/43% female/male) and UKBiobank (n = 483,385; 54/46% female/male). Genotype-predicted height was calculated using a multi-ancestry polygenic height score. Height-GaP was calculated as the difference between measured and genotype-predicted adult height. Early-life growth conditions were ascertained prospectively via standardized procedures (ALSPAC) and mortality via death register (UKBiobank). Regression models examined: (i) adult height-GaP as the outcome with early-life growth conditions as predictors; and (ii) mortality as the outcome with adult height-GaP as predictor. All models were adjusted for age, sex, genotype-predicted height and genetic ancestry. Analyses were replicated in the Dunedin Multidisciplinary Health and Development Study (DMHDS; n = 855; 49/51% female/male) and the Multi-Ethnic Study of Atherosclerosis (MESA; n = 6352; 52/48% female/male). RESULTS: Here we show that among ALSPAC participants (median [IQR] age: 24 [18-25] years at height-GaP assessment), lower gestational age at birth, greater pre- and post-natal deprivation indices, tobacco smoke exposure and less breastfeeding are associated with larger adult height-GaP deficit (p < 0.01). Among UKBiobank participants (mean ± SD age: 56 ± 8 years at height-GaP assessment), height-GaP deficit is associated with death from all-causes (adjusted hazard ratio comparing highest-to-lowest height-GaP deficit quartile [aHR]: 1.25 95%CI: 1.21-1.29), atherosclerotic cardiovascular disease (aHR: 1.32 95%CI: 1.23-1.42) and coronary heart disease (aHR: 1.64 95%CI: 1.49-1.81). Early- and later-life height-GaP associations replicate in DMHDS and MESA. CONCLUSIONS: This study introduces a precision index of early-life growth adversity deployable in adulthood to investigate the developmental origins of longevity and improve health equity across the life course.

Children's Sensitivity to Facial Emotional Expressions: The Mediating Roles of Maternal Warmth and Home Environment

Analysis shows children's ability to identify emotions relates to socioeconomic status and maternal warmth.

A methylome-wide association study of major depression with out-of-sample case–control classification and trans-ancestry comparison

Meta-analysis uncovers DNA methylation markers and immune links to major depression across diverse ancestries, highlighting potential epigenetic and inflammatory mechanisms.

Parental income and psychiatric disorders from age 10 to 40: a genetically informative population study

Population study analyzes psychiatric disorders relative to parental income, revealing significant social causation effects.

The nature of the relation between mental wellbeing and illbeing

This review uncovers the complexities of mental health, highlighting the intertwined nature of illbeing and wellbeing.

Maternal expressions of warmth and negativity and adolescent mental health: using longitudinal monozygotic twin‐difference analyses to approach causal inference

Longitudinal twin study reveals maternal warmth and negativity affect mental health outcomes in adolescents, suggesting intervention opportunities.

Are Wednesday's Children Full of Woe? Children's Differences in Personality Are Independent of Day of Birth

INTRODUCTION: Nursery rhymes, which are rich in literary devices, benefit children's language learning. Less is known about the influence that nursery rhymes' messages may have on children's development. We focused on "Monday's Child," a popular nursery rhyme that alleges children's day of the week of birth forecasts their differences in personality and physical traits. METHODS: Data came from E-Risk, a UK population representative, longitudinal cohort study of 2232 same-sex twin children (with 93% retention). We used linear regression models to test whether the day of the week of birth predicted personality and physical traits at ages 5-18 years. RESULTS: Being born on Monday through Saturday did not predict children's personality and physical traits as implied by the "Monday's Child" rhyme. Being born on Sunday was also not associated with children's traits across measures. These results were unchanged after covariate adjustment (i.e., children's sex, birthweight, and socioeconomic status). CONCLUSION: We showed that children's differences in personality and physical traits are independent of their day of the week of birth. These findings suggest that nursery rhymes' messages are unlikely to influence children's development, at least those conveyed by "Monday's Child".

DunedinPACNI estimates the longitudinal Pace of Aging from a single brain image to track health and disease

To understand how aging affects functional decline and increases disease risk, it is necessary to develop measures of how fast a person is aging. Using data from the Dunedin Study, we introduce an accurate and reliable measure for the rate of longitudinal aging derived from cross-sectional brain magnetic resonance imaging, that is, the Dunedin Pace of Aging Calculated from NeuroImaging (DunedinPACNI). Exporting this measure to the Alzheimer's Disease Neuroimaging Initiative, UK Biobank and BrainLat datasets revealed that faster DunedinPACNI predicted cognitive impairment, accelerated brain atrophy and conversion to diagnosed dementia. Faster DunedinPACNI also predicted physical frailty, poor health, future chronic diseases and mortality in older adults. When compared to brain age gap, DunedinPACNI was similarly or more strongly related to clinical outcomes. DunedinPACNI is a next-generation brain magnetic resonance imaging biomarker that can help researchers explore aging effects on health outcomes and evaluate the effectiveness of antiaging strategies.

DNA methylation profiles of long-term cannabis users in midlife: a comprehensive evaluation of published cannabis-associated methylation markers in a representative cohort

Epigenetic responses to cannabis use could link cannabis use to health problems. We examined the DNA-methylation profiles of long-term cannabis users in midlife, re-evaluating a set of 246 cannabis-associated methylation markers that were previously identified in other studies. Data were from the Dunedin Study, a five-decade longitudinal study of a birth cohort (analytic n = 787). Peripheral whole blood was drawn when the cohort was age 45, and DNA methylation was assayed using the EPIC 850 K BeadChip. Analyses compared long-term cannabis users with non-users and, for a benchmark comparison, long-term tobacco users. Results showed that long-term cannabis use was associated with sixteen of the previously published 246 cannabis-related methylation markers. Methylation markers that were associated with long-term cannabis use were also associated with long-term tobacco use. However, after adjusting for long-term tobacco use and other covariates, long-term cannabis use was robustly associated with hypomethylation of nine markers: cg05575921, cg21566642, cg03636183, cg21161138, cg01940273, cg17739917, cg05086879, cg02978227, cg23079012. Cannabis-related hypomethylation was associated with higher gene expression in the Dunedin Cohort, suggesting meaningful biological associations. A comparison of long-term cannabis users with cannabis quitters revealed that quitters showed less extreme DNA hypomethylation. Long-term cannabis use could affect the epigenome similarly to tobacco use, possibly at least partly though smoke inhalation. Cannabis cessation, like tobacco cessation, may reverse altered DNA methylation.

Cognitive Abilities and Educational Attainment as Antecedents of Mental Disorders: A Total Population Study of Males

The positive relation between mental health and educational attainment is well established, yet the extent to which cognitive abilities influence this gradient or independently predict mental health outcomes remains unclear. In this study, we investigated the association between adolescent cognitive abilities, educational attainment, and adult mental health. Cognitive ability was ascertained in Norwegian military conscript test data ( N = 272,351; mean age 17.8 years; males only), whereas mental disorders were ascertained using the Norwegian register of primary care diagnoses received between the age of 36–40. Higher cognitive abilities were associated with a monotonically decreasing risk of developing all the studied mental disorders except bipolar disorder. The association held even when comparing the cognitive abilities of brothers raised in the same family, attesting that cognitive ability and mental disorders are not associated because both arise from the same family background circumstances. Similarly, individuals with higher educational attainment had fewer mental health disorders. The association between low cognitive abilities and the risk of mental disorders was notably stronger in males with low educational attainment, compared to those with high educational attainment. These individuals may be an underutilized target group for mental-disorder prevention.