Biomedical subjects

Avshalom Caspi

Publications and source records attributed to Avshalom Caspi.

At least 19 recordsLinked to original sources

PubMed2025

An Updated Polygenic Index Repository: Expanded Phenotypes, New Cohorts, and Improved Causal Inference.

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.

Journal Article↗

PubMed2025

Measures of retinal health successfully capture risk for Alzheimer's disease and related dementias at midlife.

BackgroundIdentification of at-risk individuals who would benefit from early intervention for Alzheimer's disease and related dementias (ADRD) is critical as new treatments are developed. Measures of retinal health could offer accessible and low-cost indication of pre-morbid disease risk, but their association with ADRD risk is unknown.ObjectiveTo determine whether midlife retinal neuronal and microvascular measures are associated with ADRD risk-index scores and individual domains of ADRD risk.MethodsData were from the Dunedin Multidisciplinary Health and Development Study, a population-representative longitudinal New Zealand-based birth cohort study. 94.1% (N = 938) of living Study members were seen at age 45 (2017-2019). Retinal neuronal (retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GC-IPL)) and microvascular (arterioles and venules) measures were used as predictors. Outcome measures were four top ADRD risk indexes (CAIDE, LIBRA, Lancet, and ADU-ADRI), and a comprehensive midlife ADRD risk index, the DunedinARB.ResultsPoorer retinal microvascular health (narrower arterioles and wider venules) was associated with greater ADRD risk (βs = 0.16-0.31; ps < 0.001). Thinner RNFL was modestly associated with higher ADRD risk (βs = 0.05-0.08; ps = 0.02-0.13). Follow-up tests of distinct domains of ADRD risk indicated that while RNFL associations reflected cardiometabolic risk only, microvascular measures were associated with diverse ADRD risk factors.ConclusionsMeasures of retinal health, particularly microvascular measures, successfully capture ADRD risk across several domains of known risk factors, even at the young midlife age of 45 years. Retinal microvascular imaging may be an accessible, scalable, and relatively low-cost method of assessing ADRD risk among middle-aged adults.

Humans↗

PubMed2024

Characterizing midlife-onset alcohol dependence: Implications for etiology, prevention, and healthy aging.

We evaluated the developmental epidemiology of midlife-onset alcohol dependence (AD) in the Dunedin Study (N=1,037), a population-representative cohort followed across five decades. At ages 18, 21, 26, 32, 38, and 45, past-year AD prevalence was 11.0%, 18.4%, 13.6%, 8.1%, 9.6%, and 11.3%, respectively. As expected, relative to never-diagnosed individuals, those with early-onset AD (first diagnosis: age-18 or age-21, prevalence=22.9%) were distinguished by a range of early-life and adult correlates. Individuals with midlife-onset AD (first diagnosis: age-38 or age-45, prevalence=5.6%) were distinguished by fewer early-life correlates, but exhibited a family history of AD, and adolescent dysregulation and marijuana-use. They were characterized by an array of adult correlates, including internalizing disorders, mental-health treatment-contact, criminal-behavior, perceived-stress, coping-by-drinking, lower likelihood of marriage and parenthood, and reduced preparedness for old age. They also experienced more adult alcohol-related impairment than the early-onset group. Results can guide efforts to reduce midlife alcohol-related problems and support healthy aging.

Journal Article↗

PubMed2022

Improving risk indexes for Alzheimer's disease and related dementias for use in midlife.

Knowledge of a person's risk for Alzheimer's disease and related dementias (ADRDs) is required to triage candidates for preventive interventions, surveillance, and treatment trials. ADRD risk indexes exist for this purpose, but each includes only a subset of known risk factors. Information missing from published indexes could improve risk prediction. In the Dunedin Study of a population-representative New Zealand-based birth cohort followed to midlife (N = 938, 49.5% female), we compared associations of four leading risk indexes with midlife antecedents of ADRD against a novel benchmark index comprised of nearly all known ADRD risk factors, the Dunedin ADRD Risk Benchmark (DunedinARB). Existing indexes included the Cardiovascular Risk Factors, Aging, and Dementia index (CAIDE), LIfestyle for BRAin health index (LIBRA), Australian National University Alzheimer's Disease Risk Index (ANU-ADRI), and risks selected by the Lancet Commission on Dementia. The Dunedin benchmark was comprised of 48 separate indicators of risk organized into 10 conceptually distinct risk domains. Midlife antecedents of ADRD treated as outcome measures included age-45 measures of brain structural integrity [magnetic resonance imaging-assessed: (i) machine-learning-algorithm-estimated brain age, (ii) log-transformed volume of white matter hyperintensities, and (iii) mean grey matter volume of the hippocampus] and measures of brain functional integrity [(i) objective cognitive function assessed via the Wechsler Adult Intelligence Scale-IV, (ii) subjective problems in everyday cognitive function, and (iii) objective cognitive decline measured as residualized change in cognitive scores from childhood to midlife on matched Weschler Intelligence scales]. All indexes were quantitatively distributed and proved informative about midlife antecedents of ADRD, including algorithm-estimated brain age (β's from 0.16 to 0.22), white matter hyperintensities volume (β's from 0.16 to 0.19), hippocampal volume (β's from -0.08 to -0.11), tested cognitive deficits (β's from -0.36 to -0.49), everyday cognitive problems (β's from 0.14 to 0.38), and longitudinal cognitive decline (β's from -0.18 to -0.26). Existing indexes compared favourably to the comprehensive benchmark in their association with the brain structural integrity measures but were outperformed in their association with the functional integrity measures, particularly subjective cognitive problems and tested cognitive decline. Results indicated that existing indexes could be improved with targeted additions, particularly of measures assessing socioeconomic status, physical and sensory function, epigenetic aging, and subjective overall health. Existing premorbid ADRD risk indexes perform well in identifying linear gradients of risk among members of the general population at midlife, even when they include only a small subset of potential risk factors. They could be improved, however, with targeted additions to more holistically capture the different facets of risk for this multiply determined, age-related disease.

Alzheimer’s disease↗

PubMed2007

Childhood maltreatment predicts adult inflammation in a life-course study.

Stress in early life has been associated with insufficient glucocorticoid signaling in adulthood, possibly affecting inflammation processes. Childhood maltreatment has been linked to increased risk of adult disease with potential inflammatory origin. However, the impact of early life stress on adult inflammation is not known in humans. We tested the life-course association between childhood maltreatment and adult inflammation in a birth cohort followed to age 32 years as part of the Dunedin Multidisciplinary Health and Development Study. Regression models were used to estimate the effect of maltreatment on inflammation, adjusting for co-occurring risk factors and potential mediating variables. Maltreated children showed a significant and graded increase in the risk for clinically relevant C-reactive protein levels 20 years later, in adulthood [risk ratio (RR)=1.80, 95% confidence interval (CI)=1.26-2.58]. The effect of childhood maltreatment on adult inflammation was independent of the influence of co-occurring early life risks (RR=1.58, 95% CI=1.08-2.31), stress in adulthood (RR=1.64, 95% CI=1.12-2.39), and adult health and health behavior (RR=1.76, 95% CI=1.23-2.51). More than 10% of cases of low-grade inflammation in the population, as indexed by high C-reactive protein, may be attributable to childhood maltreatment. The association between maltreatment and adult inflammation also generalizes to fibrinogen and white blood cell count. Childhood maltreatment is a previously undescribed, independent, and preventable risk factor for inflammation in adulthood. Inflammation may be an important developmental mediator linking adverse experiences in early life to poor adult health.

Adult↗

PubMed2007

Generalized anxiety disorder and depression: childhood risk factors in a birth cohort followed to age 32.

BACKGROUND: The close association between generalized anxiety disorder (GAD) and major depressive disorder (MDD) prompts questions about how to characterize them in future diagnostic systems. We tested whether risk factors for MDD and GAD are similar or different. METHOD: The representative 1972-73 Dunedin birth cohort of 1037 males and females was followed to age 32 with 96% retention. Adult GAD and MDD were diagnosed at ages 18, 21, 26, and 32 years, and juvenile anxiety/depression were also taken into account. Thirteen prospective risk measures indexed domains of family history, adverse family environment, childhood behavior, and adolescent self-esteem and personality traits. RESULTS: Co-morbid MDD+GAD was antedated by highly elevated risk factors broadly across all domains. MDD+GAD was further characterized by the earliest onset, most recurrence, and greatest use of mental health services and medication. Pure GAD had levels of risk factors similar to the elevated levels for co-morbid MDD+GAD; generally, pure MDD did not. Pure GAD had risks during childhood not shared by pure MDD, in domains of adverse family environment (low SES, somewhat more maltreatment) and childhood behavior (internalizing problems, conduct problems, somewhat more inhibited temperament). Pure MDD had risks not shared by pure GAD, in domains of family history (of depression) and personality (low positive emotionality). CONCLUSIONS: Specific antecedent risk factors for pure adult MDD versus GAD may suggest partly different etiological pathways. That GAD and co-morbid MDD+GAD share many risk markers suggests that the presence of GAD may signal a pathway toward relatively more severe internalizing disorder.

Adolescent↗

PubMed2006

Early childhood factors associated with the development of post-traumatic stress disorder: results from a longitudinal birth cohort.

BACKGROUND: Childhood factors have been associated with increased risk of developing post-traumatic stress disorder (PTSD). Previous studies assessed only a limited number of childhood factors retrospectively. We examined the association between childhood neurodevelopmental, temperamental, behavioral and family environmental characteristics assessed before age 11 years and the development of PTSD up to age 32 years in a birth cohort. METHOD: Members of a 1972-73 New Zealand birth cohort (n=1037) who were assessed at ages 26 and 32 years for PTSD as defined by DSM-IV. RESULTS: We identified two sets of childhood risk factors. The first set of risk factors was associated both with increased risk of trauma exposure and with PTSD assessed at age 26. These included childhood externalizing characteristics and family environmental stressors, specifically maternal distress and loss of a parent. The second set of risk factors affected risk for PTSD only and included low IQ and chronic environmental adversity. The effect of cumulative childhood factors on risk of PTSD at age 26 was substantial; over 58% of cohort members in the highest risk quartile for three developmental factors had PTSD as compared to only 25% of those not at high risk on any factors. Low IQ at age 5, antisocial behavior, and poverty before age 11 continued to predict PTSD related to traumatic events that occurred between the ages of 26 and 32. CONCLUSIONS: Developmental capacities and conditions of early childhood may increase both risk of trauma exposure and the risk that individuals will respond adversely to traumatic exposures. Rather than being solely a response to trauma, PTSD may have developmental origins.

Adolescent↗

PubMed2006

Evidence for monozygotic twin (MZ) discordance in methylation level at two CpG sites in the promoter region of the catechol-O-methyltransferase (COMT) gene.

Monozygotic (MZ) twin concordance for a range of psychiatric conditions is rarely 100%. It has been suggested that epigenetic factors, such as DNA methylation, may account for a proportion of the variation in behavioral traits observed between these genetically identical individuals. In this study we have quantitatively assessed the methylation status of two CpG sites in the promoter region of the COMT gene in 12 MZ twins-pairs discordant for birth weight, but otherwise clinically unaffected. DNA was obtained at age 5-years using buccal swabs, and modified using sodium-bisulfite treatment. Methylation profiles were assessed using Pyrosequencing, a technology enabling the precise degree of methylation to be assessed at any CpG site. We found that the degree of methylation at the two CpG sites was highly correlated, but there was considerable variation in the concordance of methylation levels between MZ twin-pairs. Some MZ twin-pairs showed a high degree of methylation concordance, whereas others differed markedly in their methylation profiles. Such epigenetic variation between genetically identical individuals may play a key role in the etiology of psychopathology, and explain the incomplete phenotypic concordance observed in MZ twins.

Binding Sites↗

PubMed2006

Socially isolated children 20 years later: risk of cardiovascular disease.

OBJECTIVE: To test the hypothesis that children who occupy peripheral or isolated roles in their peer groups (isolated children) are at risk of poor adult health. DESIGN: Longitudinal study of an entire birth cohort. SETTING: Dunedin, New Zealand. PARTICIPANTS: A total of 1037 children who were followed up from birth to age 26 years. INTERVENTIONS: Measurement of social isolation in childhood, adolescence, and adulthood. MAIN OUTCOME MEASURES: When study members were 26 years old, we measured adult cardiovascular multifactorial risk status (overweight, elevated blood pressure, elevated total cholesterol level, low high-density lipoprotein level, elevated glycated hemoglobin concentration, and low maximum oxygen consumption). RESULTS: Socially isolated children were at significant risk of poor adult health compared with nonisolated children (risk ratio, 1.37; 95% confidence interval, 1.17-1.61). This association was independent of other well-established childhood risk factors for poor adult health (low childhood socioeconomic status, low childhood IQ, childhood overweight), was not accounted for by health-damaging behaviors (lack of exercise, smoking, alcohol misuse), and was not attributable to greater exposure to stressful life events. In addition, longitudinal findings showed that chronic social isolation across multiple developmental periods had a cumulative, dose-response relationship to poor adult health (risk ratio, 2.58; 95% confidence interval, 1.46-4.56). CONCLUSIONS: Longitudinal findings about children followed up to adulthood suggest that social isolation has persistent and cumulative detrimental effects on adult health. The findings underscore the usefulness of a life-course approach to health research, by focusing attention on the effect of the timing of psychosocial risk factors in relation to adult health.

Adolescent↗

PubMed2006

Prediction of heterogeneity in intelligence and adult prognosis by genetic polymorphisms in the dopamine system among children with attention-deficit/hyperactivity disorder: evidence from 2 birth cohorts.

CONTEXT: The study and treatment of psychiatric disorders is made difficult by the fact that patients with identical symptoms often differ markedly in their clinical features and presumably in their etiology. A principal aim of genetic research is to provide new information that can resolve such clinical heterogeneity and that can be incorporated into diagnostic practice. OBJECTIVE: To test the hypothesis that the DRD4 seven-repeat allele and DAT1 ten-repeat allele would prove useful in identifying a subset of children with attention-deficit/hyperactivity disorder (ADHD) who have compromised intellectual functions. DESIGN: Longitudinal epidemiologic investigation of 2 independent birth cohorts. SETTING: Britain and New Zealand. PARTICIPANTS: The first cohort was born in Britain in 1994-1995 and includes 2232 children; the second cohort was born in New Zealand in 1972-1973 and includes 1037 children. MAIN OUTCOME MEASURES: Evaluation of ADHD, IQ, and adult psychosocial adjustment. RESULTS: We present replicated evidence that polymorphisms in the DRD4 and DAT1 genes were associated with variation in intellectual functioning among children diagnosed as having ADHD, apart from severity of their symptoms. We further show longitudinal evidence that these polymorphisms predicted which children with ADHD were at greatest risk for poor adult prognosis. CONCLUSION: The findings indicate that genetic information of this nature may prove useful for etiology-based psychiatric nosologies.

Adolescent↗

PubMed2006

Low self-esteem during adolescence predicts poor health, criminal behavior, and limited economic prospects during adulthood.

Using prospective data from the Dunedin Multidisciplinary Health and Development Study birth cohort, the authors found that adolescents with low self-esteem had poorer mental and physical health, worse economic prospects, and higher levels of criminal behavior during adulthood, compared with adolescents with high self-esteem. The long-term consequences of self-esteem could not be explained by adolescent depression, gender, or socioeconomic status. Moreover, the findings held when the outcome variables were assessed using objective measures and informant reports; therefore, the findings cannot be explained by shared method variance in self-report data. The findings suggest that low self-esteem during adolescence predicts negative real-world consequences during adulthood.

Adolescent↗

PubMed2006

When parents have a history of conduct disorder: how is the caregiving environment affected?

Individuals with early-emerging conduct problems are likely to become parents who expose their children to considerable adversity. The current study tested the specificity of and alternative explanations for this trajectory. The sample included 246 members of a prospective, 30-year cohort study and their 3-year-old children. Parents who had a history of conduct disorder were specifically at elevated risk for socioeconomic disadvantage and relationship violence, but suboptimal parenting and offspring temperament problems were common to parents with any history of disorder. Recurrent disorder, comorbidity, and adversity in the family of origin did not fully account for these findings. The cumulative consequences of early-onset conduct disorder and assortative mating for antisocial behavior may explain the long-term effects of conduct disorder on young adult functioning.

Adolescent↗

PubMed2006

Genetic influences on the overlap between low IQ and antisocial behavior in young children.

The well-documented relation between the phenotypes of low IQ and childhood antisocial behavior could be explained by either common genetic influences or environmental influences. These competing explanations were examined through use of the Environmental Risk Longitudinal Twin Study 1994-1995 cohort (Moffitt & the E-Risk Study Team, 2002) of 1,116 twin pairs and their families. Children's IQ was assessed via individual testing at age 5 years. Mothers and teachers reported on children's antisocial behavior at ages 5 and 7 years. Low IQ was related to antisocial behavior at age 5 years and predicted relatively higher antisocial behavior scores at age 7 years when antisocial behavior at age 5 years was controlled. This association was significantly stronger among boys than among girls. Genetic influences common to both phenotypes explained 100% of the low IQ-antisocial behavior relation in boys. Findings suggest that specific candidate genes and neurobiological processes should be tested in relation to both phenotypes.

Adolescent↗

PubMed2006

Gene-environment interactions in psychiatry: joining forces with neuroscience.

Gene-environment interaction research in psychiatry is new, and is a natural ally of neuroscience. Mental disorders have known environmental causes, but there is heterogeneity in the response to each causal factor, which gene-environment findings attribute to genetic differences at the DNA sequence level. Such findings come from epidemiology, an ideal branch of science for showing that a gene-environment interactions exist in nature and affect a significant fraction of disease cases. The complementary discipline of epidemiology, experimental neuroscience, fuels gene-environment hypotheses and investigates underlying neural mechanisms. This article discusses opportunities and challenges in the collaboration between psychiatry, epidemiology and neuroscience in studying gene-environment interactions.

Animals↗

PubMed2006

Family conflict in childhood: a predictor of later insomnia.

STUDY OBJECTIVES: To examine the association between childhood exposure to family conflict and insomnia at 18 years of age. DESIGN: Longitudinal prospective data on an entire birth cohort were obtained. Parents completed the Conflict subscale of the Moos Family Environment Scale when the study members were 7, 9, 13, and 15 years of age. Insomnia was examined in a standardized interview when the participants were aged 18 years. SETTING: Participants were born in Dunedin, New Zealand, and were interviewed at this location. PATIENTS OR PARTICIPANTS: One thousand thirty-seven children born between April 1, 1972, and March 31, 1973, enrolled in the study (52% male). At age 18 years, 993 (97% of living cohort members) provided data. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: The mean level of family conflict at age 7 to 15 years predicted insomnia at 18 years after controlling for sex, socioeconomic status, sleep problems at 9 years, and self-reported health (odds ratio [95% confidence interval] = 1.42 [1.17-1.73], p < .001). There was a dose-response relationship, whereby the more assessments at which families scored in the top 25% for conflict, the greater the young person's likelihood of developing insomnia at age 18 years. This association was present even after controlling for depression at 18 years. CONCLUSIONS: This study demonstrates a modest but robust longitudinal link between family conflict during childhood and insomnia experienced at 18 years of age. Future work needs to replicate this finding in different populations and to elucidate the mechanisms underlying this association.

Adolescent↗

PubMed2006

Is domestic violence followed by an increased risk of psychiatric disorders among women but not among men? A longitudinal cohort study.

OBJECTIVE: The association between violence between intimate partners and psychiatric disorders is assumed to reflect a causal link. This assumption is now questioned because several longitudinal studies have documented that adolescents with psychiatric disorders grow up to be overrepresented among adults involved in partner violence. METHOD: The study followed a representative birth cohort prospectively. Adolescent mental disorders were diagnosed at age 18 years. Between ages 24 and 26 years, the authors identified individuals involved in nonabusive relationships versus those involved in clinically abusive relationships (i.e., resulting in injury and/or official intervention). At age 26 years, mental disorders were again diagnosed. RESULTS: Male and female adolescents with psychiatric disorders were at greatest risk of becoming involved in abusive adult relationships. After the authors controlled for earlier psychiatric history, women who were involved in abusive relationships, but not men, had an increased risk of adult psychiatric morbidity. CONCLUSIONS: 1) Psychiatric disorders pose risk for involvement in abusive relationships for both sexes; 2) partner abuse is a contributing source of psychiatric disorders among women but not among men.

Adolescent↗

PubMed2006

The caregiving environments provided to children by depressed mothers with or without an antisocial history.

OBJECTIVE: Many depressed women have a history of antisocial behavior, but research into maternal depression has not ascertained if this has implications for children of depressed mothers. This study compared the developmental outcomes in and caregiving environments provided to children by depressed mothers with or without an antisocial history. METHOD: In the Environmental Risk Longitudinal Twin Study, a nationally representative study of 1,106 families, mothers were administered the Diagnostic Interview Schedule for Major Depressive Disorder and interviewed about their lifetime history of antisocial personality disorder symptoms. Mothers and teachers provided information regarding the children's behavior problems at 5 and 7 years of age. The authors assessed the quality of the caregiving environment through maternal reports and interviewer observations. RESULTS: Compared with children of mothers with depression only, the children of depressed and antisocial mothers had significantly higher levels of antisocial behavior and rates of DSM-IV conduct disorder, even after the authors controlled for numbers of symptoms and chronicity of maternal major depressive disorder. The children of depressed and antisocial mothers were at an elevated risk of experiencing multiple caregiving abuses, including physical maltreatment, high levels of maternal hostility, and exposure to domestic violence. CONCLUSIONS: If one ignores the common co-occurrence of an antisocial history in depressed mothers, it may obscure the significantly elevated risks in children's development. Clinicians treating women's depression should be aware that children of depressed and antisocial mothers constitute a group at extremely high risk for early-onset psychopathology.

Adult↗

PubMed2006

Neuropsychological performance at the age of 13 years and adult schizophreniform disorder: prospective birth cohort study.

We examined neuropsychological functioning at age 13 years in adolescents who later developed schizophreniform disorder, compared with healthy controls and with adolescents diagnosed as having had a manic episode or depression or anxiety disorder. Participants were from an unselected birth cohort. Attentional, executive and motor impairments at age 13 were found in those who later fulfilled diagnostic criteria for schizophreniform disorder, suggesting that these impairments may be the earliest emerging neuropsychological impairments in schizophrenia-related disorders.

Adolescent↗