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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Arch Gen Psychiatry. Author manuscript; available in PMC 2013 July 9.
Published in final edited form as:
PMCID: PMC3706194

Cannabinoid receptor (CNR1) genotype moderates the effects of childhood physical abuse on anhedonia and depression



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 further, to replicate this interaction in an independent sample.


Genetic association study in 1041 young adult U.S. women with replication in an independent Australian sample of 1428 heroin dependent cases and 506 neighborhood controls.

Main outcome measure

Self-reported anhedonia and depression (with anhedonia).


In both samples, those who experienced childhood physical abuse were considerably more likely to report lifetime anhedonia. However, in those with one or more copies of the minor allele of rs1049353, this pathogenic effect of childhood physical abuse was attenuated. Thus, in those reporting childhood physical abuse, while 57% of those homozygous for the major allele reported anhedonia, only 29% of those who were carriers of the minor allele reported it (p < 0.02). rs1049353 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, where 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 and hence, future studies should carefully examine its impact on expression and conformational variation in CNR1, particularly in relation to stress adaptation.

Keywords: CNR1, endocannabinoid, physical abuse, rs1049353, GxE, anhedonia, major depression


Anhedonia, a core clinical feature of major depressive disorder1, reflects loss of ability to experience pleasure or joy from activities normally considered pleasurable, or alternatively, lack of reactivity to pleasurable stimuli. While anhedonia is not necessary for a diagnosis of depression, anhedonic depression, sometimes referred to as melancholic sub-type, has been identified as one of the more severe forms of major depressive disorder2;3.

Animal models suggest that chronic unpredictable stress blunts hedonic capacity4, consequently producing a depression-like phenotype5. Similarly, in human studies, perceived stress has been found to increase negative affect and anhedonia6 and to contribute to reduced reward responsiveness,7 even after controlling for depressed mood. Childhood exposure to physical abuse may be one such potent stressor. This form of stress, often perpetrated by a parent or caregiver, can be inescapable and have virulent short- and long-term effects on the physical and mental well-being of the child8;9. However, not all children exposed to childhood abuse and maltreatment develop problems. For instance, Caspi and colleagues10 found that carriers of the high activity allele of a polymorphism in the monoamine oxidase A (MAOA) gene were buffered from the pathogenic influence of severe childhood maltreatment on antisocial behavior and violence during early adulthood. Likewise, albeit controversially11;12, multiple studies have found that carriers of the short, putatively less functional, allele of the serotonin transporter gene (SLC6A4) are at greater risk for depression upon exposure to stress, particularly childhood maltreatment13. Studies such as this point to the existence of possible biological and environmental mechanisms for stress adaptation.

While the HPA (hypothalamic-pituitary-adrenal) axis is central to stress adaption, in rodents, the endocannabinoid signaling system (eCBS) has been implicated in this process as well, both independently and in concert with the HPA-axis14. Specifically, the eCBS, which consists of the endocannabinoid receptors (CB1 and CB2) and the endogenous cannabinoids (e.g. anandamide), is instrumental in moderating the effects of chronic unpredictable stress on anhedonia. Compared with wild-type, CB1 knock-out mice subjected to chronic unpredictable stress demonstrate decreased intake of sucrose-sweetened water15, an experimental paradigm for anhedonia in rodents. Administration of CB1 inverse agonist Rimonabant coupled with stress also produces similar effects16. These experiments, along with other studies that show the impact of eCBS on hedonic tone17;18 as well as modulations in eCBS attributable to stress19, have led preclinical researchers to posit that eCBS may be a vital contributor to the plasticity of the link between stress and depression-like phenotypes2021.

Despite this accumulating preclinical and emerging human association evidence2223, the moderating effects of eCBS on the link between chronic uncontrollable stress and anhedonia has only been infrequently examined and replicated. The goal of this study was to investigate whether rs1049353 in CNR1 is involved in stress adaption of this nature. We (a) examined whether carriers of the minor allele (AA/AG) of rs1049353 who were exposed to childhood physical abuse have a differential likelihood of self-reported lifetime anhedonia compared with those homozygous for the major allele (GG); (b) examined whether this effect extended to a diagnosis of major depressive disorder with anhedonia; (c) examined whether our results were specific to childhood physical abuse; and (d) replicated this finding in an independent sample.



Primary sample

The primary sample was drawn from a large prospective cohort study (the Missouri Adolescent Female Twin Study (MOAFTS)) of female same-sex twin pairs born between July 1st 1975 – June 30th 1985 who were identified from birth records24. Twins were eligible to participate if both members of the twin pair had survived past infancy, were not adopted and if their biological parents were Missouri residents at the time of the twins’ birth. Using a cohort-sequential sampling design, twins and at least one biological parent (typically the biological mother), were invited to participate in the baseline interviews during 1994–1999, when the twins were 13, 15, 17 or 19 years old. Recruitment of additional 13 year olds continued over a two-year period as twins became age-eligible. A telephone diagnostic interview was administered, first to the parents, and subsequently, after obtaining parental permission, to the twins (minors). Further details regarding sample recruitment and characteristics of this first wave of interview data, which are not utilized in the current study, are given elsewhere25. Subsequently, participants were invited to participate in several full-length and mini follow-up interviews and respond to mailed questionnaires.

During 2002–2005, the first full-length follow-up interview was completed, which included assessments of childhood experiences, including physical abuse, and mental health, including anhedonia and depression26. All eligible twins, including those who may not have completed a baseline assessment, were invited to participate in the follow-up, provided that they, or their parents, had not previously indicated an unwillingness to participate in future studies. A total of 3,787 twins (14% African-American) aged 18–29 years, completed follow-up interviews. Twins were also invited, during this period, to provide permission for future DNA collection for genomic studies27. In a subsequent effort, of those contacted, 1191 subjects, including one or both members of monozygotic and dizygotic twin pairs provided a sample – collection of samples from remaining subjects is ongoing and this study reports on genotyping efforts completed on 1,188 subjects (with 3 dropped due to genotyping problems). Genotyping was conducted using Golden Gate technology from Illumina Inc with an array of 1536 single nucleotide polymorphisms (SNPs) in genes implicated in the etiology of addictions28 and those for population admixture29. For this study, data from 1041 women of European-American descent (designated using birth record data) with both phenotypic and genetic data are used – as noted in a previous study, these women are representative of the larger cohort and do not vary on key socio-demographic or psychiatric assessments from the remainder of the cohort27.

Replication sample

We also utilized data from an independent sample for replication. The Comorbidity and Trauma Study (CATS)3034 recruited heroin dependent cases from opioid replacement therapy (ORT) clinics in the greater Sydney region in New South Wales, Australia. Inclusion criteria were age 18 years or over, an adequate understanding of English, and current or past participation in ORT for heroin dependence. Participants reporting recent suicidal intent or known to be currently experiencing psychosis were excluded. Neighborhood controls were recruited from geographic areas in proximity to ORT clinics. The use of opioids recreationally more than ten times lifetime was an exclusion criterion for controls; the inclusion and exclusion criteria, except for ORT participation, were otherwise identical to cases. Written informed consent was obtained from all participants. Genotyping was conducted using Illumina Golden Gate technology, however, the array was custom designed for this proposal. For the current analyses, phenotypic and genetic data were drawn for replication from 1428 cases and 506 neighborhood controls. Principal components (PCs) created in SmartPCA35 from all SNPs were used to control for ethnic admixture. For each outcome (anhedonia, depression, anhedonic depression) one PC was identified as significant (p-0.03–0.04) and consequently all logistic regression analyses included this PC as a covariate.

Participants provided informed consent as part of the individual studies, which received approval from institutional review boards.


Both studies used modified versions of the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA)36 for interview-based data collection. Reliability36 and validity37 for the SSAGA are good.


Anhedonia was coded using one or more self-report items querying inability to experience pleasure from daily activities, which is a component of the depression diagnosis. All participants were queried about anhedonia (i.e. no skip-outs). Specifically, in MOAFTS, subjects were asked if there had ever been a time when they were a lot less interested in most things or unable to enjoy the things they usually enjoyed, or felt unable to care about things or other people, most of the day and nearly every day for a period of two weeks or longer. In CATS, anhedonia was coded from an item asking about a time when, for at least one week, the respondent lost interest/enjoyment in almost everything or in things they usually enjoyed.

Major depressive disorder (MDD)

A lifetime diagnosis of MDD was coded using DSM-IV diagnostic criteria. Self-reported items were used to ascertain diagnostic criteria. MDD was further classified by presence or absence of anhedonia.

Childhood physical abuse

Assessed via self-report, exposure to childhood physical abuse in MOAFTS was coded dichotomously: an individual was coded as being exposed to childhood physical abuse if they reported either being “physically abused as a child” or “ever physically injured or hurt on purpose by any adult” or responded that they were often “hit with a belt or stick or something like that” or “physically punished so hard you hurt the next day” by a parent/parent figure. In CATS, 9 items assessing childhood physical abuse were drawn from a longitudinal cohort study from New Zealand.38 Items included being severely beaten, kicked, choked, throttled, burned with hot objects for punishment, or bruised, occurring prior to age 18, perpetrated by either parent. They were used to create a continuous factor which was used for analysis. In both studies, physical punishment, such as occasional spanking or slapping were excluded from the definition of abuse.


rs1049353 was coded dichotomously as carriers of the minor allele (AA/AG) and those homozygous for the major allele (GG). Secondary analyses compared AA and AG genotypes separately. We selected this SNP because it is (a) widely studied in the context of mood, (b) is exonic and (c) was typed in both samples with high quality. No other SNPs in CNR1 or any other gene were examined.

Statistical analyses

Analyses were conducted in SAS (v9)39, using logistic regression. The model used to test the statistical significance of b4 was:


Covariates were study-specific, and included age, sex and case-control or ascertainment status and a principal component reflecting ethnic variation. For MOAFTS, survey options that allow for adjustment of standard errors for familial clustering of twin data were used.


Sample characteristics

Table 1 shows the characteristics of the primary and replication samples. The primary (MOAFTS) sample consisted of young adult women aged 18–27 years from the general population. Rates of anhedonia (22%), MDD (18.4%) and abuse (9.4%) are representative of young female populations, and generalize to the full sample (including non-genotyped individuals). Not surprisingly, rates of anhedonia (cases: 63.9%, controls: 51.2%), MDD (cases: 59.9%, controls: 51.3%), and abuse (51.6% and 24% of cases and controls respectively endorsing at least one form of abuse) were considerably higher in CATS. Rates are high in the controls presumably because they were matched with the heroin dependent cases for neighborhood characteristics.

Table 1
Characteristics of the primary sample of the Missouri Adolescent Female Twin Study (MOAFTS) and the Australian heroin dependence replication sample.

Physical abuse and Anhedonia in MOAFTS

First, we conducted univariate analyses between anhedonia, rs1049353 and childhood physical abuse. Childhood physical abuse was strongly associated with anhedonia [O.R. 2.75, 95% C.I. 1.78–4.24] – 40.8% of those with a history of childhood physical abuse reported anhedonia compared with 20% of those without a history of abuse. Genotype (rs1049353) was not associated with anhedonia [O.R. 0.82, 95% C.I. 0.61–1.10] or with exposure to childhood physical abuse [O.R. 1.26, 95% C.I. 0.83–1.92].

Next, we examined the association between anhedonia and childhood physical abuse, stratified by genotype (coded AA/AG or GG). In GG individuals, there was a highly significant association between anhedonia and abuse [O.R. 5.09, 95% C.I. 2.66–9.77]. As shown in Table 2, 57.1% of GG individuals with a history of childhood physical abuse reported anhedonia compared with 20.7% of non-abuse GG individuals (also Figure 1). In contrast, in AA/AG individuals, there was no significant association between anhedonia and abuse [O.R. 1.66, 95% C.I. 0.89–3.09] with 28.6% and 19.4% of abused and non-abused subjects reporting anhedonia respectively. We also examined all three genotype groups separately (GG, AG, AA). However, given the small number of AA individuals exposed to abuse, estimates for AA and AG genotypes could be statistically equated, allowing us to combine AA and AG groups.

Fig. 1
Interaction between rs1049353 (CNR1) and childhood physical abuse and its association with anehdonia in two independent samples
Table 2
Rates of lifetime anhedonia [with N] stratified by rs1049353 genotype and lifetime exposure to childhood physical abuse.

To formally test the interaction effect, we conducted a logistic regression which included genotype (AA/AG versus GG), abuse (exposed/unexposed) and their interaction, as well as age. As shown in Table 3, the interaction odds-ratio [O.R.= 0.31, 95% C.I. 0.12–0.79] confirmed that in carriers of the minor allele (AA/AG) the effect of childhood physical abuse on anhedonia was attenuated.

Table 3
Association between rs1049353 genotype, childhood physical abuse and anhedonia as well as depression. Results are presented as odds-ratios with their 95% confidence limits.

Physical abuse and MDD in MOAFTS

Childhood physical abuse [O.R. 2.93, 95% C.I. 1.88–4.57], but not genotype [O.R. 0.91, 95% C.I. 0.67–1.25], was associated with a diagnosis of lifetime MDD. Genotype interacted with childhood physical abuse to predict lifetime MDD [Table 3, [interaction O.R. 0.34, 95% C.I. 0.14–0.85]]. However, the effect of the interaction was largely attributable to the presence of anhedonia in the context of depression. The interaction between rs1049353 and childhood physical abuse influenced anhedonic MDD in a manner similar to its effect on anhedonia alone, suggesting that the stress adaptive effects of rs1049353 on MDD is attributable to anhedonia (Table 3).


We successfully replicated the significant effects of the interaction between genotype and childhood physical abuse on both anhedonia and on anhedonic MDD in the CATS sample. The continuously distributed abuse factor [mean=0, SD=1] had a strong main effect on anhedonia resulting in 1.59 increased odds of anhedonia for every standard deviation increase in exposure. Next, we compared rates of anhedonia as a function of genotype and exposure to abuse. While childhood abuse was derived as a continuously distributed factor score, for ease of visualization, in Table 2 and Figure 1, the continuous physical abuse measure is shown as the top and bottom quartile and the mid-50%. As shown in Table 2 and Figure 1, rates of anhedonia, irrespective of genotype were highest in those in the top-quartile for exposure to abuse (70.8%). However, in carriers of the A allele (i.e. AA/AG individuals) rates of anhedonia (66.1%) were attenuated in those in the top-quartile for abuse exposure. Unlike MOAFTS, there was no evidence for an additive increase in buffering with increasing copies of the A allele. We also examined whether the continuously distributed measure of abuse was associated with anhedonia in GG versus AA/AG individuals. Unlike MOAFTS, the continuous abuse measure was associated with anhedonia in both GG [O.R. 1.65, 95% C.I. 1.44–1.89] and AA/AG [O.R. 1.31, 95% C.I. 1.13–1.51] individuals.

Table 3 shows the corresponding logistic regression results which were conducted using the continuously distributed measure of abuse. Consistent with the primary sample, even after controlling for sex, age and heroin dependence, the interaction between continuously distributed abuse and rs1049353 was significant [OR=0.79, 95% C.I. 0.65–0.96].

Next, we examined whether the interaction between rs1049353 and the continuous measure of childhood physical abuse was a significant predictor of MDD. Again, consistent with the primary sample, an interaction significant at the trend level (p=0.0558) was noted (Table 3).

Finally, we examined whether the buffering effect of rs1049353 on MDD was only observed in those with anhedonic depression. Consistent with the primary sample, rs1049353 interacted with the factor representing childhood physical abuse to predict anhedonic depression (Table 2, Figure 1, p-value=0.0077). Hence, the replication confirmed not only the stress-buffering effects of rs1049353 on the relationship between childhood physical abuse and anhedonia, but also attributed any effect of this interaction on MDD to presence of anhedonia.

Suicide attempts

Rates of suicide attempt were considerably elevated in those reporting both anhedonia and MDD. Showing remarkable across-study consistency, 20.4% of those reporting both anhedonia and MDD in MOAFTS and CATS reported suicide attempts. In those reporting anhedonia but not meeting criteria for MDD, suicide attempts were reported by 8.4% and 8.3% of MOAFTS and CATS respectively while in those meeting criteria for MDD without anhedonia, suicide attempts were reported by 6–7% (0–1.4% in those with neither anhedonia nor MDD). Overall, 65% and 95% of suicide attempts reported in MOAFTS and CATS respectively aggregated in those with both anhedonia and MDD.

Specificity analyses

To provide a framework for appropriate future replication, we examined whether this interaction would be captured when using other definitions of abuse. All analyses were conducted only in MOAFTS. (a) Childhood sexual abuse was associated with increased likelihood of reporting anhedonia [O.R. 2.41, 95% C.I. 1.52–3.83], but the interaction with rs1049353 was not significant [OR = 0.56, 95% C.I. 0.23–1.43]. (b) We modified our childhood physical abuse measure to include physical punishment such as sometimes/often being slapped by a parent. Not only did the association between abuse and anhedonia attenuate [O.R. 1.47, 95% C.I. 1.08–2.01] but the interaction was no longer significant [OR =0.86, 95% C.I. 0.46–1.62]. (c) An interaction with a dichotomous measures of adult exposure to adult (assaultive or non-assaultive) traumas was also not significant [OR=0.49, 95% C.I. 0.23–1.05]. This series of analyses indicate that replication analyses are likely to be successful only when examining childhood physical abuse.


We sought to examine whether a synonymous polymorphism in the gene encoding the human cannabinoid receptor (CNR1) was involved in stress adaptation for anhedonia and depression. Highly consistent with findings from rodent models, our study replicates the buffering effect of the minor allele of rs1049353 (CNR1) on the pathogenic effects of childhood physical abuse on anhedonia. Furthermore, the protective effect of rs1049353 on MDD was attributable to the presence of anhedonia. Individuals who carried one or more copies of the minor allele (AA/AG) who reported being exposed to physical abuse during childhood were not at increased risk for anhedonia or for MDD.

Anhedonia and Depression

Anhedonia is amongst the hallmark clinical features of MDD. However, a variety of epidemiological and human experimental research demonstrates that melancholic (or anhedonic) depression varies from other forms of depression. In addition to the DSM-IV definition of melancholic depression, which requires pervasive anhedonic features, both psychometric4044 and laboratory-based settings7 have been used to examine hedonic capacity. These studies conclude that anhedonia represents a unique and clinically important phenotype.

Anhedonia, Depression and Stress

A wealth of studies demonstrate the pathogenic influence of childhood stressors, particularly maltreatment on risk for depression9;45. In our study as well, individuals with a history of childhood physical abuse were at considerably increased odds of MDD. However, research indicates that anhedonia may be the “endophenotype” that connects childhood adversity to MDD. For instance, Pizzagalli and colleagues have demonstrated that both acute46 and perceived6 stress impact depression by impairing hedonic capacity.

Genotype and Stress Adaptation

Not all individuals exposed to childhood adversity develop depression and genotype may moderate the relationship between childhood adversity and mental health outcomes10;47. For instance, a polymorphism, rs1360780, in the FKBP5 gene (which regulates glucocorticoid regulator sensitivity) reportedly enhances risk for depression only in the presence of moderate/severe (but not mild) physical abuse48. Similarly, Cichetti et al found that maltreated individuals with the high activity genotype of the monoamine oxidase (MAOA) gene reported fewer depressive symptoms in the presence of self-coping strategies, indicating that the high activity allele produces a substrate, even in maltreated individuals, where receptivity to coping strategies is enhanced49. Our study demonstrates a similar stress-adaptive role for CNR1- this is important because the endogenous cannabinoid system, in rodent paradigms, has been found to afford stress buffering directly as well as indirectly, via modulation of HPA-axis activity.

Consistency with the Preclinical Endocannabinoid Literature

Both eCBS and chronic stress are independently associated with hedonic capacity4;17. However, the link between chronic stress, anhedonia and the endocannabinoid system is highly complex. Experimental manipulations of CB1 (via knock-out or administration of antagonist) produce phenotypes that mimic human melancholic depression21. For instance, studies find that CB1 is associated with impaired cognition and neurodegeneration21;50 and emotional processing (such as positive affective memory)51;52 which may be recruited in extinction of aversive memories53 and in the inability to process emotions, which are features of melancholic depression. In addition, exposure to chronic stress reduces hippocampal CB1 receptor expression54. Prolonged exposure to elevated glucocorticoid levels, such as those induced by chronic stress conditions, also significantly reduces hippocampal CB1 receptor binding site density55. In fact, a recent study suggests that CB1 receptor deficiency may mimic the effects of chronic stress on emotional behavior20. The most intriguing synergy of chronic stress and CB1 activity is its influence on anhedonia and depression56. Chronic stress also reduces anadamide (an endogenous cannabinoid) signaling in the corticolimbic circuit14.

The present study is remarkably consistent with these preclinical observations. We show, for the first time in humans, that CNR1 genotype plays a stress adaptive role in the etiology of anhedonia and depression. When coupled with the rodent literature, our study suggests the possibility of a significant therapeutic role of the endocannabinoid system in depression57;58. However, which elements of the endocannabinoid system will need to be targeted remains to be examined. For instance, our work, consistent with animal experiments, focuses attention on the gene encoding the CB1 receptor and a number of clinical studies of CB1 inverse agonist, Rimonabant (for weight loss), have shown serious side-effects of depression5963 and suicidality62;64 and thus, more research is required to understand the precise role of CNR1 and specifically rs1049353 in this domain. Whether the adverse effects of Rimonabant are moderated by rs1049353 or other CNR1 genotypes may also be of particular interest, particular in future drug development.

Consistency with emerging human association studies

The role of the eCBS in humans is beginning to garner considerable interest. Congruent with the preclinical observation that CB1 deficient rodents exhibit melancholic features21, and remarkably consistent with our findings, a study of depressed patients found that those with the rs1049353 AA genotype were more likely to respond well to antidepressant treatment22. Relatedly, GG individuals appeared resistant to treatment, particularly if they were female and had melancholic depression. Another study identified 2.46 increased odds of patients with MDD carrying the A allele65. Additionally, a study of FAAH (fatty acid amide hydrolase, encoding the enzyme involved in hydrolysis of anandamide, and also a component of the eCBS) and reward-related human brain function noted that 385A (reduced enzymatic activity) carriers show decreased threat-related amygdala reactivity and increased reward-related reactivity in the ventral striatum66 indicating its putative role in stress adaptation. One prior study has also explored the interaction between stress and CNR1 in the etiology of mood-related conditions - Juhasz et al23 found that a CNR1 haplotype, including rs1049353, was associated with neuroticism, agreeableness, and depressive symptoms. Exposure to recent negative life events interacted with rs7766029 – relative to carriers of the T allele, carriers of the CC genotype did not show an appreciable increase in vulnerability to depressive symptoms, even upon recent exposure to life events. Evidence for an interaction with rs1049353 was noted but not considered to be significant upon correction for multiple testing. The authors also reported a strong mediating influence of childhood adversity but interactions with it remained unexplored. Our study extends these prior efforts, via use of a fairly large sample and replication, adding further support for the role of the endocannabinoid system in regulation of human mood, particularly in the context of stress adaptation.

rs1049353 and CNR1

rs1049353 is exonic but synonymous, indicating that its impact on the activity of CNR1 is not attributable to a coding change. However, synonymous SNPs can induce widespread modification in protein formation and there is preliminary evidence that rs1049353 is in the region of an exon splice enhancer (ESE), responsible for recruiting spliceosomes and other machinery necessary for accurate splicing of exons during translation67. Future studies should also explore whether the A/A (and A/G) genotypes of rs1049353 are associated with change in endocannabinoid activity. Finally, rs1049353 is in high linkage disequilibrium (r2=0.94) with rs4707436 which resides in the 3′ untranslated region of CNR1, which could have potential regulatory effects. Similar other untyped causal variants may also exist.


Our results may be viewed with the following limitations in mind: (a) These analyses were conducted in samples of primarily European descent. This is an advantage in genetic studies where population stratification can confound association signals and there is allelic variation in the frequency of rs1049353 across populations. (b) Retrospective assessments of anhedonia and abuse were used which may be subject to recall bias. Additionally, our measures of anhedonia were drawn from interview sections designed to assess depression – currently, independent questionnaires or laboratory assessments of anhedonia in detail are not available. (c) A majority of the sample that met criteria for MDD reported lifetime anhedonia making the study of non-anhedonic MDD challenging. (d) While this is not a limitation, we used a dichotomous measure of childhood physical abuse in the primary sample and a continuous factor score in the replication sample. As rates of childhood physical abuse were higher in the CATS replication sample, and multiple indices of abuse were available, the factor score provides a more refined characterization of abuse exposure in that sample. It should be noted that replication with a dichotomous and continuously coded environmental exposure measure indicates the robustness of these findings68. (e) The replication sample included heroin-dependent cases and controls matched for neighborhood (i.e. high risk) exposure and rates of anhedonia and abuse in this population exceed the general population. Nonetheless, adjustment for case status did not influence our findings. However it is possible that the mechanisms underlying the relationship between genotype, anhedonia and physical abuse are different in this sample.

Two additional caveats regarding the replication are also worth noting. First, while the AA genotype appeared to have a stronger protective influence than the AG genotype in MOAFTS, this effect was not statistically significant nor replicated in CATS. Due to the smaller numbers in MOAFTS, it is not possible to discern whether this is an underpowered difference or a false-positive and future studies should contrast these genotypes (AA versus AG) before combining them. Second, while there was no association between abuse and anhedonia in AA/AG individuals, this association was significant in CATS. This is likely due to the higher rates of abuse in this sample and the power afforded by a continuous index of abuse. Nonetheless, future studies should examine the AA/AG subgroup carefully for these effects.


Despite widespread interest in the interface between biological contributors and environmental adversity11;13;6972, this is one of few replicated examples of genotype x environment interaction. That genotype confers resilience to the pathogenic effects of childhood physical abuse underscores the plasticity of biological and environmental underpinnings of mental health73. Importantly, this study reinforces the need to examine depression from a fine-grained phenotypic perspective, and highlights the role of anhedonia in depressive phenotypes. The role of anhedonia as a critical endophenotype is becoming increasingly apparent, particularly in genetic studies74. Hedonic capacity is heritable (46%) but the genetic correlation between anhedonia and depression is modest75. Thus, a composite measure such as MDD may attenuate genetic signals attributable to specific mechanisms underlying salient aspects of depression, such as anhedonia and this may have contributed to the general failure of genomewide association studies of depression76. Our study demonstrates that anhedonia may be the optimal target phenotype when examining the impact of childhood adversity on depression. The potential of this replicated finding will be further unveiled as future research identifies the precise mechanisms by which CNR1 confers stress adaptation in the etiology of anhedonia and depression.


Funding for this research was provided by the National Institutes of Health grants, DA23668 (AA), AA11998 (ACH, MTL, KJS), DA017305 (ECN), DA18267 (MTL), AA07728 & AA09022 (ACH), AA013526, AA013987, & AA007231 (KJS), DA12854 (PAFM); a Ruth L. Kirschstein National Research Service Award (AA19596) to AKL; and also from the National Drug and Alcohol Research Centre and the Australian National Health and Medical Research Council (to LD). AA also receives funding from ABMRF/The Foundation for Alcohol Research. Funding agencies were not involved in the design and conduct of the study, collection, management, analysis and interpretation of data and preparation, review or approval of the manuscript.


Dr. Agrawal had full access to all data in the study and takes responsibility for the integrity of the data and accuracy of data analysis. Drs. Agrawal and Nelson performed the statistical analyses.

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