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Cannabinoid receptor genotype moderation of the effects of childhood physical abuse on anhedonia and depression.

ABSTRACT: 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.

SUBMITTER: Agrawal A

PROVIDER: S-EPMC3706194 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Cannabinoid receptor genotype moderation of the effects of childhood physical abuse on anhedonia and depression.

Agrawal Arpana A Nelson Elliot C EC Littlefield Andrew K AK Bucholz Kathleen K KK Degenhardt Louisa L Henders Anjali K AK Madden Pamela A F PA Martin Nicholas G NG Montgomery Grant W GW Pergadia Michele L ML Sher Kenneth J KJ Heath Andrew C AC Lynskey Michael T MT

Archives of general psychiatry 20120701 7

<h4>Context</h4>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.<h4>Objectives</h4>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 interactio ...[more]

PMID: 22393204

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Project description:ContextGenetic inheritance and developmental life stress both contribute to major depressive disorder in adults. Child abuse and trauma alter the endogenous stress response, principally corticotropin-releasing hormone and its downstream effectors, suggesting that a gene x environment interaction at this locus may be important in depression.ObjectiveTo examine whether the effects of child abuse on adult depressive symptoms are moderated by genetic polymorphisms within the corticotropin-releasing hormone type 1 receptor (CRHR1) gene.DesignAssociation study examining gene x environment interactions between genetic polymorphisms at the CRHR1 locus and measures of child abuse on adult depressive symptoms.SettingGeneral medical clinics of a large, public, urban hospital and Emory University, Atlanta, Georgia.ParticipantsThe primary participant population was 97.4% African American, of low socioeconomic status, and with high rates of lifetime trauma (n = 422). A supportive independent sample (n = 199) was distinct both ethnically (87.7% Caucasian) and socioeconomically (less impoverished).Main outcome measuresBeck Depression Inventory scores and history of major depressive disorder by the Structured Clinical Interview for DSM-IV Axis I Disorders.ResultsFifteen single-nucleotide polymorphisms spanning 57 kilobases of the CRHR1 gene were examined. We found significant gene x environment interactions with multiple individual single-nucleotide polymorphisms (eg, rs110402, P = .008) as well as with a common haplotype spanning intron 1 (P < .001). Specific CRHR1 polymorphisms appeared to moderate the effect of child abuse on the risk for adult depressive symptoms. These protective effects were supported with similar findings in a second independent sample (n = 199).ConclusionsThese data support the corticotropin-releasing hormone hypothesis of depression and suggest that a gene x environment interaction is important for the expression of depressive symptoms in adults with CRHR1 risk or protective alleles who have a history of child abuse.

Dataset Information

Cannabinoid receptor genotype moderation of the effects of childhood physical abuse on anhedonia and depression.

Publications

Cannabinoid receptor genotype moderation of the effects of childhood physical abuse on anhedonia and depression.

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