Cannabinoid Receptor Genotype Moderation of the Effects of Childhood Physical Abuse on Anhedonia and Depression

Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Archives of general psychiatry (Impact Factor: 14.48). 03/2012; 69(7):732-40. DOI: 10.1001/archgenpsychiatry.2011.2273
Source: PubMed


The endocannabinoid system has been implicated in stress adaptation and the regulation of mood in rodent studies, but few human association studies have examined these links and replications are limited.
To examine whether a synonymous polymorphism, rs1049353, in exon 4 of the gene encoding the human endocannabinoid receptor (CNR1) moderates the effect of self-reported childhood physical abuse on lifetime anhedonia and depression and to replicate this interaction in an independent sample.
Genetic association study in 1041 young US women with replication in an independent Australian sample of 1428 heroin-dependent individuals as cases and 506 participants as neighborhood controls.
Self-reported anhedonia and depression (with anhedonia).
In both samples, individuals who experienced childhood physical abuse were considerably more likely to report lifetime anhedonia. However, in those with 1 or more copies of the minor allele of rs1049353, this pathogenic effect of childhood physical abuse was attenuated. Thus, in participants reporting childhood physical abuse, although 57.1% of those homozygous for the major allele reported anhedonia, only 28.6% of those who were carriers of the minor allele reported it (P=.01). The rs1049353 polymorphism also buffered the effects of childhood physical abuse on major depressive disorder; however, this influence was largely attributable to anhedonic depression. These effects were also noted in an independent sample, in which minor allele carriers were at decreased risk for anhedonia even when exposed to physical abuse.
Consistent with preclinical findings, a synonymous CNR1 polymorphism, rs1049353, is linked to the effects of stress attributable to childhood physical abuse on anhedonia and anhedonic depression. This polymorphism reportedly resides in the neighborhood of an exon splice enhancer; hence, future studies should carefully examine its effect on expression and conformational variation in CNR1, particularly in relation to stress adaptation.

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    • "Because all samples are Australian and were either ascertained based on selfreport of childhood trauma exposure, or for genetic studies of substance dependence (populations with high prevalence of childhood trauma compared to general population samples), these results are not necessarily generalizable to population-based samples. We are encouraged by our finding (Agrawal et al. 2012) of a significant interaction in CAT Study data involving the CPA factor and an endocannabinoid receptor (CNR1) polymorphism (rs1049353) associated with anhedonia and anhedonic depression that replicated a similar interaction involving a binary measure of CPA and rs1049353 genotype in a general population Missouri twin sample. However, additional research will be necessary to demonstrate generalizability. "
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    ABSTRACT: Introduction: Forms of childhood trauma tend to co-occur and are associated with increased risk for psychiatric and substance use disorders. Commonly used binary measures of trauma exposure have substantial limitations. Methods: We performed multigroup confirmatory factor analysis (CFA), separately by sex, using data from the Childhood Trauma (CT) Study's sample of twins and siblings (N = 2594) to derive three first-order factors (childhood physical abuse, childhood sexual abuse, and parental partner abuse) and, as hypothesized, one higher order, childhood trauma factor (CTF) representing a measure of their common variance. Results: CFA produced a good-fitting model in the CT Study; we replicated the model in the Comorbidity and Trauma (CAT) Study's sample (N = 1981) of opioid-dependent cases and controls. In both samples, first-order factors are moderately correlated (indicating they measure largely unique, but related constructs) and their loadings on the CTF suggest it provides a reasonable measure of their common variance. We examined the association of CTF score with risk for psychiatric and substance use disorders in these samples and the OZ-ALC GWAS sample (N = 1538) in which CT Study factor loadings were applied. We found that CTF scores are strongly associated with liability for psychiatric and substance use disorders in all three samples; estimates of risk are extremely consistent across samples. Conclusions: The CTF is a continuous, robust measure that captures the common variance across forms of childhood trauma and provides a means to estimate shared liability while avoiding multicollinearity.
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    • "have been associated with heavy cannabis use in humans. For example, the endocannabinoid system has been proposed to play a role in the pathogenesis of schizophrenia (although, as noted earlier, the evidence to support this hypothesis has been mixed; Ferretjans et al., 2012), while two recent studies have provided evidence that variation in the CNRI gene moderates the effect of stressful life events on depressive symptoms (Juhasz et al., 2009; Agrawal et al., 2012). While a detailed discussion of the interaction between multiple risk factors is beyond the scope of this review, these studies provide insight into how processes associated with the development of the endocannabinoid system may impact variability in risk within adolescent populations, as well as making the developing brain vulnerable to the effects of cannabis more generally. "
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    ABSTRACT: Heavy cannabis use has been frequently associated with increased rates of mental illness and cognitive impairment, particularly amongst adolescent users. However, the neurobiological processes that underlie these associations are still not well understood. In this review, we discuss the findings of studies examining the acute and chronic effects of cannabis use on the brain, with a particular focus on the impact of commencing use during adolescence. Accumulating evidence from both animal and human studies suggests that regular heavy use during this period is associated with more severe and persistent negative outcomes than use during adulthood, suggesting that the adolescent brain may be particularly vulnerable to the effects of cannabis exposure. As the endocannabinoid system plays an important role in brain development, it is plausible that prolonged use during adolescence results in a disruption in the normative neuromaturational processes that occur during this period. We identify synaptic pruning and white matter development as two processes that may be adversely impacted by cannabis exposure during adolescence. Potentially, alterations in these processes may underlie the cognitive and emotional deficits that have been associated with regular use commencing during adolescence.
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    • "Endocannabinoid receptor 1 receptor knockout in mice modulates the effects of chronic unpredictable stress on the development of anhedonia in mice (50). In a recent study Agrawal et al. (51) evaluated the role of a polymorphism in the human endocannabinoid receptor (CNR1), rs1049353, in moderating the association between childhood physical abuse and anhedonia or MDD in young adult US women. Those women who carried two copies of the minor allele (G/G) exhibited less anhedonia when exposed to childhood physical abuse compared to carriers of the A allele (A/A or A/G). "
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    ABSTRACT: This review focuses on current research developments in the study of gene by early life stress (ELS) interactions and depression. ELS refers to aversive experiences during childhood and adolescence such as sexual, physical or emotional abuse, emotional or physical neglect as well as parental loss. Previous research has focused on investigating and characterizing the specific role of ELS within the pathogenesis of depression and linking these findings to neurobiological changes of the brain, especially the stress response system. The latest findings highlight the role of genetic factors that increase vulnerability or, likewise, promote resilience to depression after childhood trauma. Considering intermediate phenotypes has further increased our understanding of the complex relationship between early trauma and depression. Recent findings with regard to epigenetic changes resulting from adverse environmental events during childhood promote current endeavors to identify specific target areas for prevention and treatment schemes regarding the long-term impact of ELS. Taken together, the latest research findings have underscored the essential role of genotypes and epigenetic processes within the development of depression after childhood trauma, thereby building the basis for future research and clinical interventions.
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