Richie Poulton

Environmental exposures influence the risk of psychiatric disorders, yet the biological mechanisms by which such experiences become embedded in brain structure remain poorly understood. The human cerebral cortex is crucial for cognition and emotional regulation, and variation in cortical thickness (CT) and surface area (SA) is linked to various behavioural and psychiatric traits. Here, we present a large-scale epigenome-wide association study that combines peripheral blood DNA methylation (DNAm) with MRI-derived cortical measures in over 7,400 individuals across 20 cohorts within the ENIGMA consortium. We identify mostly non-overlapping DNAm signatures associated with CT and SA, consistent with their distinct developmental and regulatory architectures. CT-associated CpGs are replicated across independent cohorts and are enriched for environmentally responsive regulatory elements and pathways associated with stress, metabolism, and immune signalling. In contrast, SA-associated CpGs cluster within chromatin-regulatory regions involved in early cortical development. Phenome-wide and Mendelian randomisation analyses reveal pleiotropic associations between DNAm, cortical structure, and psychiatric and cognitive traits. These findings suggest that peripheral DNAm captures environmentally sensitive biological processes that link exposure, cortical organisation, and behavioural vulnerability.

Polygenic indexes (PGIs) — DNA-based predictors of individual phenotypes — have become essential tools across biomedical and social sciences. We introduce Version 2 of the Polygenic Index Repository, which expands phenotype coverage from 47 to 61, increases the number of participating datasets from 11 to 20, and adopts a more consistent and improved methodology for PGI construction. For 16 phenotypes, we leverage summary statistics from an updated GWAS meta-analysis with greater statistical power compared to the original release, thereby improving the PGI’s predictive power. To improve power for family-based analyses, we provide imputed parental PGIs in all datasets with first-degree relatives and offer a framework for interpreting results from analyses that control for parental PGIs. We illustrate the utility of parental PGIs using two applications: (1) comparing PGI associations with and without parental PGI controls for all phenotypes in two Repository datasets with family data, and (2) for BMI and diastolic blood pressure, exploring the contribution of causal versus non-causal components of PGI associations to the imperfect portability of PGIs across subgroups within a genetic ancestry. Collectively, the updates enhance predictive performance, broaden the Repository’s scope, and introduce novel resources that reduce confounding bias and improve interpretability.

INTRODUCTION Although plasma pTau181 has been shown to accurately discriminate patients with Alzheimer’s disease from healthy older adults, its utility as a preclinical biomarker in middle-aged community-based cohorts is unclear. METHODS Participants were members of the Dunedin Multidisciplinary Health and Development Study, a longitudinal study of 1037 people born in New Zealand in 1972-1973. Plasma pTau181, MRI-based brain structure, and DunedinPACE (an epigenetic biomarker of biological ageing) were measured at age 45; cognition was measured in childhood and age 45. RESULTS We observed a wide range of pTau181 concentrations in our same-aged sample (n=856; M=13.6pg/mL, SD=9.1pg/mL). Males had significantly higher pTau181 concentrations than females. No statistically significant associations were observed with cognitive decline, lower structural brain integrity, or accelerated biological ageing. DISCUSSION In this midlife cohort, wide variation in pTau181 concentrations was present by age 45, but was not associated with patterns of AD-risk in cognition, brain structure, or biological ageing. Systematic review Authors reviewed the literature using PubMed and Web of Science databases. While research on plasma biomarkers of AD has largely focused on older people with mild cognitive impairment or AD, there are few studies of plasma biomarkers among general middle-aged populations. Given the potential utility of plasma biomarkers of AD such as pTau181 in early screening for disease risk, examining the concentrations of pTau181 among a younger cohort free of dementia is important for possible future clinical implementation. Interpretation Plasma pTau181 concentrations varied widely among our same-aged sample, yet higher pTau181 was not associated with cognitive decline, lower MRI-estimated structural brain integrity, or accelerated biological ageing. These findings indicate that variability in pTau181 exists in middle-age, but independently of other AD risk factors. Future directions Understanding how variability in pTau181 concentrations in midlife may predict later AD and to what extent this is distinct from other risk factors is important for shaping the translational pathway from lab to clinic.

Background: Wait times for mental health treatment are long. This protocol describes a trial to test whether engaging in a self-directed online cognitive behavioural therapy tool (called ‘Just a Thought’) while waiting for psychological therapy is an acceptable and effective intervention for help-seeking patients. The trial will be conducted within the context of a large psychological service in Auckland, New Zealand. Methods: In this parallel group, pragmatic randomised controlled trial, consenting patients with at least five weeks to wait for their first therapy appointment will be randomly assigned to receive Just a Thought (intervention) or waitlist-as-usual conditions plus generic wellbeing information (control) while they wait. Mental health, general health and wellbeing, and treatment satisfaction will be measured across the first ten weeks of the trial, and at 8 months. Outcomes: The primary outcomes are the acceptability and effectiveness of Just a Thought as an initial treatment. Acceptability will be assessed as participants’ satisfaction, and effectiveness as change in psychological distress over time (relative to control). We hypothesise that participants will be more satisfied with Just a Thought than generic wellbeing information and that those who engage in Just a Thought will show greater reductions in psychological distress than those in the waiting-as-usual group. Conclusions: Online cognitive behavioural therapy is efficacious and has the potential to provide people experiencing psychological distress with fast access to evidence-based psychological treatment. This study will provide insight into its potential as an acceptable and effective pre-treatment for people seeking psychological help.

Genetic inheritance is not the only way parents’ genes may affect children. It is also possible that parents’ genes are associated with investments into children’s development. We examined evidence for links between parental genetics and parental investments, from the prenatal period through to adulthood, using data from six population-based cohorts in the UK, US and New Zealand, together totalling 36,566 parents. Our findings revealed associations between parental genetics—summarized in a genome-wide polygenic score—and parental behaviour across development, from smoking in pregnancy, breastfeeding in infancy, parenting in childhood and adolescence, to leaving a wealth inheritance to adult children. Effect sizes tended to be small at any given time point, ranging from RR = 1.12 (95% confidence interval (95%CI) 1.09, 1.15) to RR = 0.76 (95%CI 0.72, 0.80) during the prenatal period and infancy; β = 0.07 (95%CI 0.04, 0.11) to β = 0.29 (95%CI 0.27, 0.32) in childhood and adolescence, and RR = 1.04 (95%CI 1.01, 1.06) to RR = 1.11 (95%CI 1.07, 1.15) in adulthood. There was evidence for accumulating effects across development, ranging from β = 0.15 (95%CI 0.11, 0.18) to β = 0.23 (95%CI 0.16, 0.29) depending on cohort. Our findings are consistent with the interpretation that parents pass on advantages to offspring not only via direct genetic transmission or purely environmental paths, but also via genetic associations with parental investment from conception to wealth inheritance.

Background: The field of epigenomics holds great promise in understanding and treating disease with advances in machine learning (ML) and artificial intelligence being vitally important in this pursuit. Increasingly, research now utilises DNA methylation measures at cytosine–guanine dinucleotides (CpG) to detect disease and estimate biological traits such as aging. Given the challenge of high dimensionality of DNA methylation data, feature-selection techniques are commonly employed to reduce dimensionality and identify the most important subset of features. In this study, our aim was to test and compare a range of feature-selection methods and ML algorithms in the development of a novel DNA methylation-based telomere length (TL) estimator. We utilised both nested cross-validation and two independent test sets for the comparisons.Results: We found that principal component analysis in advance of elastic net regression led to the overall best performing estimator when evaluated using a nested cross-validation analysis and two independent test cohorts. This approach achieved a correlation between estimated and actual TL of 0.295 (83.4% CI [0.201, 0.384]) on the EXTEND test data set. Contrastingly, the baseline model of elastic net regression with no prior feature reduction stage performed less well in general—suggesting a prior feature-selection stage may have important utility. A previously developed TL estimator, DNAmTL, achieved a correlation of 0.216 (83.4% CI [0.118, 0.310]) on the EXTEND data. Additionally, we observed that different DNA methylation-based TL estimators, which have few common CpGs, are associated with many of the same biological entities.Conclusions: The variance in performance across tested approaches shows that estimators are sensitive to data set heterogeneity and the development of an optimal DNA methylation-based estimator should benefit from the robust methodological approach used in this study. Moreover, our methodology which utilises a range of feature-selection approaches and ML algorithms could be applied to other biological markers and disease phenotypes, to examine their relationship with DNA methylation and predictive value.

Objective: We investigated whether childhood social isolation was associated with retinal neural layer changes in adulthood, and whether this association was independent of other childhood or adulthood risk factors, including adult social isolation. Methods: Participants were members of the Dunedin Multidisciplinary Health and Development Study, a longitudinal population-based birth cohort from Aotearoa New Zealand (n = 1037), born 1972 to 1973 and followed until age 45 years, with 94% of the living cohort still participating. Social isolation was recorded prospectively at ages 5, 7, 9, and 11 years, from teacher and parent report. Retinal nerve fiber layer (RNFL) and ganglion cell–inner plexiform layer thicknesses were measured via optical coherence tomography at age 45 years. Results: Childhood social isolation was associated with thinner average RNFL (B = −0.739, p = .02), nasal RNFL (B = −1.118, p = .005), and inferior RNFL (B = −1.524, p = .007), although only nasal RNFL remained significant after adjustment. These associations were not fully explained by other psychosocial or physical health risk factors in childhood or adulthood, nor were they mediated by adult loneliness or social support. Conclusions: Childhood social isolation was an independent predictor of RNFL thickness in middle age. Highlighting prospective links between childhood psychosocial adversity and retinal neuronal measures will help to inform future research into the utility of retinal neuronal thickness as a biomarker for neurodegeneration.

Prior research shows that individuals who have exhibited antisocial behavior are in poorer health than their same-aged peers. A major driver of poor health is aging itself, yet research has not investigated relationships between offending trajectories and biological aging. We tested the hypothesis that individuals following a life-course persistent (LCP) antisocial trajectory show accelerated aging in midlife. Trajectories of antisocial behavior from age 7 to 26 years were studied in the Dunedin Multidisciplinary Health and Development Study, a population-representative birth cohort (N = 1037). Signs of aging were assessed at age 45 years using previously validated measures including biomarkers, clinical tests, and self-reports. First, we tested whether the association between antisocial behavior trajectories and midlife signs of faster aging represented a decline from initial childhood health. We then tested whether decline was attributable to tobacco smoking, antipsychotic medication use, debilitating illnesses in adulthood, adverse exposures in childhood (maltreatment, socioeconomic disadvantage) and adulthood (incarceration), and to childhood self-control difficulties. Study members with a history of antisocial behavior had a significantly faster pace of biological aging by midlife, and this was most evident among individuals following the LCP trajectory (β, 0.22, 95%CI, 0.14, 0.28, p ≤ 0.001). This amounted to 4.3 extra years of biological aging between ages 25–45 years for Study members following the LCP trajectory compared to low-antisocial trajectory individuals. LCP offenders also experienced more midlife difficulties with hearing (β, −0.14, 95%CI, −0.21, −0.08, p ≤ 0.001), balance (β, −0.13, 95%CI, −0.18, −0.06, p ≤ 0.001), gait speed (β, −0.18, 95%CI, −0.24, −0.10, p ≤ 0.001), and cognitive functioning (β, −0.25, 95%CI, −0.31, −0.18, p ≤ 0.001). Associations represented a decline from childhood health. Associations persisted after controlling individually for tobacco smoking, antipsychotic medication use, midlife illnesses, maltreatment, socioeconomic status, incarceration, and childhood self-control difficulties. However, the cumulative effect of these lifestyle characteristics together explained why LCP offenders have a faster Pace of Aging than their peers. While older adults typically age-out of crime, LCP offenders will likely age-into the healthcare system earlier than their chronologically same-aged peers. Preventing young people from offending is likely to have substantial benefits for health, and people engaging in a LCP trajectory of antisocial behaviors might be the most in need of health promotion programs. We offer prevention and intervention strategies to reduce the financial burden of offenders on healthcare systems and improve their wellbeing.