Publications (19) View all
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Article: The interaction between child maltreatment, adult stressful life events and the 5-HTTLPR in major depression.
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ABSTRACT: Both childhood maltreatment and adult stressful life events are established risk factors for the onset of depression in adulthood. However, the interaction between them can be viewed through two conflicting frameworks. Under a mismatch hypothesis stressful childhoods allow 'adaptive programming' for a stressful adulthood and so can be protective. Only when childhood and adulthood do not match is there a risk of behavioural problems. Alternatively, under the cumulative stress hypothesis we expect increased risk with each additional stressor. It has also been suggested that an individual's genetic background may determine the extent they undergo adaptive programming, and so which of these two hypotheses is relevant. In this study we test for an interaction between exposure to childhood maltreatment and adult stressful life events in a retrospective sample of 455 individuals, using major depression as the outcome. We also test whether this interaction differs by genotype at the 5-HTTLPR, a candidate for an individual's plasticity to adaptive programming. Early maltreatment and stressful life events in adulthood interacted to produce increased risk for depression over each individually (p = 0.055). This supports the cumulative stress hypothesis over the mismatch hypothesis, at least with respect to severe environmental risk factors. This effect was not altered by 5-HTTLPR allele, suggesting there was no difference by genotype in adaptive programming to these events. We suggest that the apparent additional vulnerability to stressful events of those who have experienced maltreatment has clinical relevance, highlighting the importance of providing support beyond the immediate aftermath of maltreatment into adulthood.Journal of psychiatric research 04/2013; · 3.72 Impact Factor -
Article: The Relationship Between Delusions and Violence: Findings From the East London First Episode Psychosis Study.
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ABSTRACT: IMPORTANCE Psychotic persons who are violent often explain their violence as being due to delusions. However, research has failed to confirm associations between delusions and violent behavior. OBJECTIVES To investigate which delusional beliefs and characteristics are associated with violent behavior during a first episode of psychosis and whether these associations are mediated by affect due to delusions. DESIGN Population-based epidemiological survey of first-episode psychosis during a 2-year study period. SETTING Three inner-city boroughs in East London, England. PARTICIPANTS A total of 458 patients with first-episode psychosis who were 18 to 64 years of age. INTERVENTIONS Patients were clinically assessed (using the Schedules for Clinical Assessment in Neuropsychiatry and the Maudsley Assessment of Delusions Schedule) and interviewed about their displaying violent behavior while experiencing psychotic symptoms during the 12-month period prior to interview. MAIN OUTCOME MEASURES Violence was classified at 2 levels of severity: minor and serious violence. RESULTS The prevalence of violence was 38% during the 12-month period, and 12% of the sample engaged in serious violence. Distinct sets of demographic and comorbid risk factors were associated with minor and serious violence. These were adjusted for in subsequent analyses. Anger was the only affect due to delusions that was positively associated with violence. The population-attributable risk percentage was 30.8% for minor violence and 55.9% for serious violence. A small number of uncommon delusional beliefs demonstrated direct pathways leading to minor violence. Three highly prevalent delusions demonstrated pathways to serious violence mediated by anger due to delusional beliefs: persecution (z = 3.09, P = .002), being spied on (z = 3.03, P = .002), and conspiracy (z = 2.98, P = .002). CONCLUSIONS AND RELEVANCE Anger due to delusions is a key factor that explains the relationship between violence and acute psychosis. A subset of delusional beliefs may be causally linked to violence, and certain uncommon beliefs demonstrated a direct association with minor violence. Highly prevalent delusional beliefs implying threat were associated with serious violence, but they were mediated by anger.JAMA psychiatry (Chicago, Ill.). 03/2013; -
Article: Estimating the heritability of reporting stressful life events captured by common genetic variants.
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ABSTRACT: BACKGROUND: Although usually thought of as external environmental stressors, a significant heritable component has been reported for measures of stressful life events (SLEs) in twin studies. Method We examined the variance in SLEs captured by common genetic variants from a genome-wide association study (GWAS) of 2578 individuals. Genome-wide complex trait analysis (GCTA) was used to estimate the phenotypic variance tagged by single nucleotide polymorphisms (SNPs). We also performed a GWAS on the number of SLEs, and looked at correlations between siblings. RESULTS: A significant proportion of variance in SLEs was captured by SNPs (30%, p = 0.04). When events were divided into those considered to be dependent or independent, an equal amount of variance was explained for both. This 'heritability' was in part confounded by personality measures of neuroticism and psychoticism. A GWAS for the total number of SLEs revealed one SNP that reached genome-wide significance (p = 4 × 10-8), although this association was not replicated in separate samples. Using available sibling data for 744 individuals, we also found a significant positive correlation of R 2 = 0.08 in SLEs (p = 0.03). CONCLUSIONS: These results provide independent validation from molecular data for the heritability of reporting environmental measures, and show that this heritability is in part due to both common variants and the confounding effect of personality.Psychological Medicine 12/2012; · 6.16 Impact Factor -
Article: Antidepressant-dependent mRNA changes in mouse associated with hippocampal neurogenesis in a mouse model of depression.
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ABSTRACT: Monoaminergic imbalances play a role in the pathogenesis of depression and most common antidepressant drugs act on monoamine neurotransmitters. However, the lag time between restoring neurochemical balance and symptom improvement suggests that the response to drugs involves complex biological events downstream of primary targets that have not yet been fully characterized. Here, we report a mouse mRNA expression study to evaluate the effect of escitalopram (a serotonergic antidepressant) and nortriptyline (a noradrenergic antidepressant) on genes that are involved in the pathogenesis of depression and to assess the similarities and differences between two drugs on gene expression levels. Genome-wide RNA expression data from the hippocampal tissues of four inbred mouse strains (129S1/SvlmJ, C57LB/6J, DBA/2J and FVB/NJ) were treated with varying doses of either nortriptyline (NRI) or escitalopram (SSRI) and subjected to two different depressogenic protocols. Following robust multichip average normalization, we applied the nonparametric RankProd approach to identify differentially expressed genes in response to drugs across the four strains. Pathway analysis was subsequently carried out on top-ranking genes to gain further biological insights. A total of 371 genes were significantly differentially expressed in response to nortriptyline, whereas 383 were altered by escitalopram. Genes involved in the pathways of integrin signalling (Fnlb, Mapk1, Mapk8), synaptic transmission (Cacnb1, Dnajc5, Kcnma1, Slc1a2) or Huntington disease (Crebbp, Dlg4, Ncor1) were altered by both nortriptyline and escitalopram. Several biological processes and pathways were identified, which could explain the divergence between the molecular mechanisms of nortriptyline and escitalopram. From a large-scale animal study, we obtain gene sets comprised of commonly and differentially expressed genes in response to different antidepressant drug treatments. The results may help to characterize the response to antidepressant treatment, shed further light on the neurobiology of depressive disorders and inform future animal and human studies. Finally, the top-ranking pathways from Ingenuity provide further evidence for the hippocampal neurogenesis hypothesis of major depressive disorders.Pharmacogenetics and Genomics 09/2012; 22(11):765-76. · 3.48 Impact Factor -
Article: Dissecting the genetic heterogeneity of depression through age at onset.
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ABSTRACT: Genome-wide studies in major depression have identified few replicated associations, potentially due to heterogeneity within the disorder. Several studies have suggested that age at onset (AAO) can distinguish sub-types of depression with specific heritable components. This paper investigates the role of AAO in the genetic susceptibility for depression using genome-wide association data on 2,746 cases and 1,594 screened controls from the RADIANT studies, with replication performed in 1,471 cases and 1,403 controls from two Munich studies. Three methods were used to analyze AAO: First a time-to-event analysis with controls censored, secondly comparing controls to case-subsets defined using AAO cut-offs, and lastly analyzing AAO as a quantitative trait. In the time-to-event analysis three SNPs reached suggestive significance (P < 5E-06), overlapping with the original case-control analysis of this study. In a case-control analysis using AAO thresholds, SNPs in 10 genomic regions showed suggestive association though again none reached genome-wide significance. Lastly, case-only analysis of AAO as a quantitative trait resulted in 5 SNPs reaching suggestive significance. Sex specific analysis was performed as a secondary analysis, yielding one SNP reaching genome-wide significance in early-onset males. No SNPs achieved significance in the replication study after correction for multiple testing. Analysis of AAO as a quantitative trait did suggest that, across all SNPs, common genetic variants explained a large proportion of the variance (51%, P = 0.04). This study provides the first focussed analysis of the genetic contribution to AAO in depression, and establishes a statistical framework that can be applied to a quantitative trait underlying any disorder. © 2012 Wiley Periodicals, Inc.American Journal of Medical Genetics Part B Neuropsychiatric Genetics 08/2012; 159B(7):859-68. · 3.70 Impact Factor
