Sensitive periods for the effect of childhood adversity on DNA methylation: Results from a prospective, longitudinal study

Background: Exposure to "early life" adversity is known to predict DNA methylation (DNAm) patterns that may be related to psychiatric risk. However, few studies have investigated whether adversity has time-dependent effects based on the age at exposure.Methods: Using a two-stage structured life course modeling approach (SLCMA), we tested the hypothesis that there are sensitive periods when adversity induced greater DNAm changes. We tested this hypothesis in relation to two alternatives: an accumulation hypothesis, in which the effect of adversity increases with the number of occasions exposed, regardless of timing, and a recency model, in which the effect of adversity is stronger for more proximal events. Data came from the Accessible Resource for Integrated Epigenomics Studies (ARIES), a subsample of mother-child pairs from the Avon Longitudinal Study of Parents and Children (ALSPAC; n=691-774).Results: After covariate adjustment and multiple testing correction, we identified 38 CpG sites that were differentially methylated at age 7 following exposure to adversity. Most loci (n=35) were predicted by the timing of adversity, namely exposures before age 3. Neither theaccumulation nor recency of the adversity explained considerable variability in DNAm. A standard EWAS of lifetime exposure (vs. no exposure) failed to detect these associations.Conclusions: The developmental timing of adversity explains more variability in DNAm than the accumulation or recency of exposure. Very early childhood appears to be a sensitive period when exposure to adversity predicts differential DNAm patterns. Classification of individuals as exposed vs. unexposed to “early life” adversity may dilute observed effects

What life course theoretical models best explain the relationship between exposure to childhood adversity and psychopathology symptoms: Recency, accumulation, or sensitive periods?

Copyright © Cambridge University Press 2018Â. Background Although childhood adversity is a potent determinant of psychopathology, relatively little is known about how the characteristics of adversity exposure, including its developmental timing or duration, influence subsequent mental health outcomes. This study compared three models from life course theory (recency, accumulation, sensitive period) to determine which one(s) best explained this relationship.Methods Prospective data came from the Avon Longitudinal Study of Parents and Children (n = 7476). Four adversities commonly linked to psychopathology (caregiver physical/emotional abuse; sexual/physical abuse; financial stress; parent legal problems) were measured repeatedly from birth to age 8. Using a statistical modeling approach grounded in least angle regression, we determined the theoretical model(s) explaining the most variability (r2) in psychopathology symptoms measured at age 8 using the Strengths and Difficulties Questionnaire and evaluated the magnitude of each association.Results Recency was the best fitting theoretical model for the effect of physical/sexual abuse (girls r2 = 2.35%; boys r2 = 1.68%). Both recency (girls r2 = 1.55%) and accumulation (boys r2 = 1.71%) were the best fitting models for caregiver physical/emotional abuse. Sensitive period models were chosen alone (parent legal problems in boys r2 = 0.29%) and with accumulation (financial stress in girls r2 = 3.08%) more rarely. Substantial effect sizes were observed (standardized mean differences = 0.22-1.18).Conclusions Child psychopathology symptoms are primarily explained by recency and accumulation models. Evidence for sensitive periods did not emerge strongly in these data. These findings underscore the need to measure the characteristics of adversity, which can aid in understanding disease mechanisms and determining how best to reduce the consequences of exposure to adversity

Dopamine Genetic Risk Score Predicts Depressive Symptoms in Healthy Adults and Adults with Depression

Background: Depression is a common source of human disability for which etiologic insights remain limited. Although abnormalities of monoamine neurotransmission, including dopamine, are theorized to contribute to the pathophysiology of depression, evidence linking dopamine-related genes to depression has been mixed. The current study sought to address this knowledge-gap by examining whether the combined effect of dopamine polymorphisms was associated with depressive symptomatology in both healthy individuals and individuals with depression. Methods: Data were drawn from three independent samples: (1) a discovery sample of healthy adult participants (n = 273); (2) a replication sample of adults with depression (n = 1,267); and (3) a replication sample of healthy adult participants (n = 382). A genetic risk score was created by combining functional polymorphisms from five genes involved in synaptic dopamine availability (COMT and DAT) and dopamine receptor binding (DRD1, DRD2, DRD3). Results: In the discovery sample, the genetic risk score was associated with depressive symptomatology (β = −0.80, p = 0.003), with lower dopamine genetic risk scores (indicating lower dopaminergic neurotransmission) predicting higher levels of depression. This result was replicated with a similar genetic risk score based on imputed genetic data from adults with depression (β = −0.51, p = 0.04). Results were of similar magnitude and in the expected direction in a cohort of healthy adult participants (β = −0.86, p = 0.15). Conclusions: Sequence variation in multiple genes regulating dopamine neurotransmission may influence depressive symptoms, in a manner that appears to be additive. Further studies are required to confirm the role of genetic variation in dopamine metabolism and depression

Exposure to early childhood maltreatment and its effect over time on social cognition

Social cognitive deficits can have many negative consequences, spanning social withdrawal to psychopathology. Prior work has shown that child maltreatment may associate with poorer social cognitive skills in later life. However, no studies have examined this association from early childhood into adolescence. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 4,438), we examined the association between maltreatment (caregiver physical or emotional abuse; sexual or physical abuse), assessed repeatedly (every 1-3 years) from birth to age 9, and social cognitive skills at ages 7.5, 10.5, and 14 years. We evaluated the role of both the developmental timing (defined by age at exposure) and accumulation of maltreatment (defined as the number of occasions exposed) using a least angle regression variable selection procedure, followed by structural equation modeling. Among females, accumulation of maltreatment explained the most variation in social cognitive skills. For males, no significant associations were found. These findings underscore the importance of early intervention to minimize the accumulation of maltreatment and showcase the importance of prospective studies to understand the development of social cognition over time

Genome-wide association study of generalized anxiety symptoms in the Hispanic Community Health Study/Study of Latinos

Although generalized anxiety disorder (GAD) is heritable and aggregates in families, no genomic loci associated with GAD have been reported. We aimed to discover potential loci by conducting a genome-wide analysis of GAD symptoms in a large, population-based sample of Hispanic/Latino adults. Data came from 12,282 participants (aged 18–74) in the Hispanic Community Health Study/Study of Latinos. Using a shorted Spielberger Trait Anxiety measure, we analyzed: (1) a total trait anxiety score based on summing responses to all ten items; and (2) a GAD symptoms score restricted to the three items tapping diagnostic features of GAD as defined by DSM-V. We first calculated the heritability due to common variants (h2SNP) and then conducted a genome-wide association study (GWAS) of GAD symptoms. Replication was attempted in three independent Hispanic cohorts (Multi-Ethnic Study of Atherosclerosis, Women’s Health Initiative, Army STARRS). The GAD symptoms score showed evidence of modest heritability (7.2%; p=0.03), while the total trait anxiety score did not (4.97%; p=0.20). One genotyped SNP (rs78602344) intronic to Thrombospondin 2 (THBS2) was nominally associated (p=4.18×10−8) in the primary analysis adjusting for psychiatric medication use and significantly associated with the GAD symptoms score in the analysis excluding medication users (p=4.18×10−8). However, meta-analysis of the replication samples did not support this association. Although GWAS revealed a genome-wide significant locus in this sample, we were unable to replicate this finding. Evidence for heritability was also only detected for GAD symptoms, and not the trait anxiety measure, suggesting differential genetic influences within the domain of trait anxiety

Parental Smoking Modifies the Relation between Genetic Variation in Tumor Necrosis Factor-α (TNF) and Childhood Asthma

BACKGROUND: Polymorphisms in the proinflammatory cytokine genes tumor necrosis factor-α (TNF) and lymphotoxin-α (LTA, also called TNF-β) have been associated with asthma and atopy in some studies. Parental smoking is a consistent risk factor for childhood asthma. Secondhand smoke and ozone both stimulate TNF production. OBJECTIVES: Our goal was to investigate whether genetic variation in TNF and LTA is associated with asthma and atopy and whether the association is modified by parental smoking in a Mexican population with high ozone exposure. METHODS: We genotyped six tagging single nucleotide polymorphisms (SNPs) in TNF and LTA, including functional variants, in 596 nuclear families consisting of asthmatics 4–17 years of age and their parents in Mexico City. Atopy was determined by skin prick tests. RESULTS: The A allele of the TNF-308 SNP was associated with increased risk of asthma [relative risk (RR) = 1.54; 95% confidence interval (CI), 1.04–2.28], especially among children of non-smoking parents (RR = 2.06; 95% CI, 1.19–3.55; p for interaction = 0.09). Similarly, the A allele of the TNF-238 SNP was associated with increased asthma risk among children of nonsmoking parents (RR = 2.21; 95% CI, 1.14–4.30; p for interaction = 0.01). LTA SNPs were not associated with asthma. Haplotype analyses reflected the single SNP findings in magnitude and direction. TNF and LTA SNPs were not associated with the degree of atopy. CONCLUSIONS: Our results suggest that genetic variation in TNF may contribute to childhood asthma and that associations may be modified by parental smoking

Preserving the Chesapeake: Law, Ecology, and the Bay

This event was co-sponsored by the Merhige Center for Environmental Studies, the Allen Chair of Law, the Virginia State Bar, and the Miller Center of Public Affairs. The “Historical Background” session, held from 9:30 - 10:30 a.m., was presented by the Hon. Governor Gerald L. Baliles, Director of the Miller Center of Public Affairs and 65th Governor of the Commonwealth of Virginia; Gerald McCarthy, Executive Director of the Virginia Environmental Endowment; and Russell W. Baxter, Deputy Director of the Virginia Department of Conservation and Recreation. Rodney A. Smolla, Dean of the University of Richmond School of Law, served as moderator. The “Current State of the Bay” session, held on Friday, October 20, 2006 from 10:45 - 11:45 a.m., was presented by Jonathan Z. Cannon, Director of the Center for Environmental and Land Use Law at the University of Virginia School of Law; Erin Ryan, of the Marshall-Wythe School of Law at the College of William and Mary; and Richard Batiuk, Associate Director for Science of the Chesapeake Bay Program Office, United States Environmental Protection Agency. Joel Eisen, University of Richmond School of Law, served as moderator. The Keynote was given from 11:45 a.m. - 1:15 p.m. by L. Preston Bryant, Secretary of Natural Resources of the Commonwealth of Virginia. The “Regulatory Efforts” session, held 1:15-2:15 p.m., was presented by Kathy R. Frahm, Director of the Division of Policy at the Virginia Department of Environmental Quality; Joseph J. Tannery, Virginia Staff Attorney for the Chesapeake Bay Foundation; David E. Evans, Partner at McGuireWoods LLP; and Mark Smith, Environmental Scientist with the Water Protection Division, U.S. Environmental Protection Agency. The “Future and Solutions” session, held from 2:30-3:45 p.m., was presented by Nikki Rovner, Deputy Secretary of Natural Resources for the Commonwealth of Virginia; Timothy G. Hayes, Partner at Hunton & Williams LLP; Clyde Wilbur, Principal of Greeley & Hanson; and Alexandra Dunn, General Counsel for the National Association of Clean Water Agencies. Carl W. Tobias, Williams Professor of Law University of Richmond School of Law, served as moderator

An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype

AbstractBackgroundThe genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder.MethodsWe analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures.ResultsThe SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 × 10–9) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 × 10–9).ConclusionsThis large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression