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

Abstract

Context: 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.

Objectives: 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.

Design, setting, and participants: 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.

Main outcome measures: Self-reported anhedonia and depression (with anhedonia).

Results: 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.

Conclusions: 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.

Fig. 1. Interaction between rs1049353 (CNR1) and childhood physical abuse and its association with anehdonia in two independent samples

The association between childhood physical abuse and anhedonia as a function of rs1049353. Dark red lines represent exposure to childhood physical abuse, dashed blue lines represent no exposure to physical abuse. The dotted green line in the replication sample represents intermediate exposure to abuse whereas the solid red line is high exposure and the dashed blue line is low exposure. Numbers are color-coded to represent the total (black) as well as those with each type of genotype, stratified by childhood physical abuse.