CNR1 Gene is Associated with High Neuroticism and Low Agreeableness and Interacts with Recent Negative Life Events to Predict Current Depressive Symptoms

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DOI: 10.1038/npp.2009.19 · Source: PubMed
Cannabinoid receptor 1 (CB1) gene (CNR1) knockout mice are prone to develop anhedonic and helpless behavior after chronic mild stress. In humans, the CB1 antagonist rimonabant increases the risk of depressed mood disorders and anxiety. These studies suggest the hypothesis that genetic variation in CB1 receptor function influences the risk of depression in humans in response to stressful life events. In a population sample (n=1269), we obtained questionnaire measures of personality (Big Five Inventory), depression and anxiety (Brief Symptom Inventory), and life events. The CNR1 gene was covered by 10 SNPs located throughout the gene to determine haplotypic association. Variations in the CNR1 gene were significantly associated with a high neuroticism and low agreeableness phenotype (explained variance 1.5 and 2.5%, respectively). Epistasis analysis of the SNPs showed that the previously reported functional 5' end of the CNR1 gene significantly interacts with the 3' end in these phenotypes. Furthermore, current depression scores significantly associated with CNR1 haplotypes but this effect diminished after covariation for recent life events, suggesting a gene x environment interaction. Indeed, rs7766029 showed highly significant interaction between recent negative life events and depression scores. The results represent the first evidence in humans that the CNR1 gene is a risk factor for depression--and probably also for co-morbid psychiatric conditions such as substance use disorders--through a high neuroticism and low agreeableness phenotype. This study also suggests that the CNR1 gene influences vulnerability to recent psychosocial adversity to produce current symptoms of depression.
CNR1 Gene is Associated with High Neuroticism and Low
Agreeableness and Interacts with Recent Negative Life Events
to Predict Current Depressive Symptoms
Gabriella Juhasz*
, Diana Chase
, Emma Pegg
, Darragh Downey
, Zoltan G Toth
, Kathryn Stones
Hazel Platt
, Krisztina Mekli
, Antony Payton
, Rebecca Elliott
, Ian M Anderson
and JF William Deakin
Neuroscience and Psychiatry Unit, School of Community Based Medicine, Faculty of Medical and Human Sciences, University of Manchester,
Manchester, UK;
Faculty of Life Sciences, University of Manchester, Manchester, UK;
Centre for Integrated Genomic Medical Research, School
of Translational Medicine, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK;
Department of Pharmacology
and Pharmacotherapy, Semmelweis University, Budapest, Hungary
Cannabinoid receptor 1 (CB1) gene (CNR1) knockout mice are prone to develop anhedonic and helpless behavior after chronic mild
stress. In humans, the CB1 antagonist rimonabant increases the risk of depressed mood disorders and anxiety. These studies suggest the
hypothesis that genetic variation in CB1 receptor function influences the risk of depression in humans in response to stressful life events.
In a population sample (n ¼ 1269), we obtained questionnaire measures of personality (Big Five Inventory), depression and anxiety (Brief
Symptom Inventory), and life events. The CNR1 gene was covered by 10 SNPs located throughout the gene to determine haplotypic
association. Variations in the CNR1 gene were significantly associated with a high neuroticism and low agreeableness phenotype
(explained variance 1.5 and 2.5%, respectively). Epistasis analysis of the SNPs showed that the previously reported functional 5
end of
the CNR1 gene significantly interacts with the 3
end in these phenotypes. Furthermore, current depression scores significantly associated
with CNR1 haplotypes but this effect diminished after covariation for recent life events, suggesting a gene environment interaction.
Indeed, rs7766029 showed highly significant interaction between recent negative life events and depression scores. The results represent
the first evidence in humans that the CNR1 gene is a risk factor for depression––and probably also for co-morbid psychiatric conditions
such as substance use disorders––through a high neuroticism and low agreeableness phenotype. This study also suggests that the CNR1
gene influences vulnerability to recent psychosocial adversity to produce current symptoms of depression.
Neuropsychopharmacology (2009) 34, 2019–2027; doi:10.1038/npp.2009.19; published online 25 February 2009
Keywords: CNR1; haplotype; personality; depression; epistasis; gene environment interaction
Accumulating evidence suggests that the endocannabinoid
(eCB) system plays an important role in the etiology of
depression through control of emotional behavior (Martin
et al, 2002; Hill and Gorzalka, 2005a; Vinod and Hungund,
2006; Serra and Fratta, 2007). In humans, the acute effects of
cannabis include euphoria and relaxation, but early and
chronic use has been associated with increased risk of
psychotic illness and deterioration of bipolar disorder (Hall
and Solowij, 1998; Ashton et al, 2005). Rimonabant, a
cannabinoid receptor 1 (CB1) antagonist, administered to
humans as a weight-loss drug, has been shown to increase
the risk of depressed mood disorder, and anxiety even
though depressed mood in the history was an exclusion
criteria in these trials (Christensen et al, 2007). In animal
studies, anxiogenic-like or anxiolytic effects of cannabi-
noids depend on the strain, the behavioral test used, and
the drug dosage (Martin et al, 2002; Haller et al, 2004a).
Rimonabant produces antidepressant-like effects in differ-
ent species and models (Witkin et al, 2005) but an eCB
uptake inhibitor (AM404) and a potent CB1 receptor
agonist (HU-210) also elicit antidepressant-like effects
in the forced swim test in rats (Hill and Gorzalka,
2005b). Animals with genetic deletion of the CB1 receptor
(CB1/) exhibit anxiogenic-like responses in different
behavioral models (Haller et al, 2004a) and a tendency to
develop a depressive-like state (anhedonia) during the
exposure to the chronic unpredictable mild stress paradigm
(Martin et al, 2002; Valverde et al, 2005). Thus, taken as a
whole, the current evidence supports the theory that
reduction in CB1 receptor signaling induces increased
anxiety and depression-like behavior (Hill and Gorzalka,
Received 25 November 2008; revised 12 January 2009; accepted 27
January 2009
*Correspondence: Dr G Juhasz, Neuroscience and Psychiatry Unit,
School of Community Based Medicine, Faculty of Medical and Human
Sciences, University of Manchester, Stopford Building, Oxford Road,
Manchester M13 9PT, UK, E-mail:
Neuropsychopharmacology (2009) 34, 20192027
2009 Nature Publishing Group All rights reserved 0893-133X/09
The human CB1 receptor gene (CNR1) is located at
chromosome 6q14F15, but the exact structure of the gene
and its effect on the CB1 receptor function are still unclear
(Zhang et al, 2004). This genetic region has been linked to
schizophrenia (Levinson et al, 2000; Leroy et al, 2001), but
this has not been replicated, although recently the CNR1
gene has been associated with specific symptoms or with
non-responder status for antipsychotic drugs rather than
with schizophrenia as a disorder (Chavarria-Siles et al,
2008; Hamdani et al, 2008). There are more convincing
results on the association of the CNR1 gene and substance
abuse disorders (Zhang et al, 2004; Zuo et al, 2007; Chen
et al, 2008), although there is a negative replication study
(Herman et al, 2006). Regarding depression, two studies
with significantly smaller sample sizes failed to find any
association with depression using the (AAT)
ism (Barrero et al, 2005; Tsai et al, 2001), although the
former found that a significant association emerged when
only the depressed patients with Parkinson’s disease were
considered (Barrero et al, 2005).
Given that the CNR1 gene has been implicated in a broad
spectrum of psychiatric disorders, it is plausible that it affects
dimensions of psychopathology (eg, specific personality
factors) that are risk factors for these disorders (Widiger
and Sankis, 2000; Khan et al, 2005). Twin studies have
demonstrated that personality factors are highly influenced by
genes. Using measures of Big Five-factor models of person-
ality, the heritability has been estimated as follows: extraver-
sion 0.54, agreeableness 0.42–0.52, conscientiousness 0.40–
0.49, neuroticism 0.48–0.58, and openness 0.52–0.57 (Bou-
chard and McGue, 2003). Furthermore, twin studies have also
suggested that the correlations between personality factors
and psychiatric disorders are mainly due to shared genetic
factors (Kendler et al, 2006; Fanous and Kendler, 2005).
However, we could not find a systematic investigation of the
association between the CNR1 gene and different personality
factors. Impulsivity, which is one facet of neuroticism, has
been associated with polymorphisms in the region of the
CNR1 gene in an Indian population (Ehlers et al, 2007).
Furthermore, two recent studies demonstrated association
between striatal response to happy faces and variations of the
CNR1 gene and suggested that this gene represents a risk
factor for depression through subcortical hypo-responsive-
ness to social reward stimuli (Chakrabarti et al, 2006;
Domschke et al, 2008).
We hypothesized that the CNR1 gene influences person-
ality factors that predispose to specific psychiatric condi-
tions, especially anxiety and depressive symptoms. Most of
the animal studies suggest that stress plays crucial role in
the effects of the eCB system, so we also investigated the
role of adverse life events. We used a population study
design with independent individuals and applied haplotypic
association analysis to investigate the effect of the CNR1
gene on these phenotypes.
Subjects aged 18–60 years predominantly from Greater
Manchester, UK, were recruited through general practices
and the NewMood website (
Almost 4500 packs were sent out to individuals on two GP
practice lists in the Manchester area, 30% of people
responded, and about half of these agreed to participate.
The NewMood website was launched in August 2005 and
almost 2000 information/questionnaire packs were sent out
to people enquiring about the study through the website
and over 50% of those participated. Altogether more than
2000 people completed and returned the NewMood ques-
tionnaire (39% through general practices and 61% through
NewMood website). Of the sample, 92% were white, 68%
were women (which reflects the gender ratio of people with
depression), 48% had a history of depression (28% in the
last year), 40% had had antidepressant treatment in the
past, 35% had a family history of depression, and 84% were
willing to give DNA.
Participants who returned the signed consent form to
provide DNA (n ¼ 1679) were then sent a genetic sampling
kit. Of these subjects, n ¼ 1520 returned the kit (35% from
general practices and 65% from NewMood website).
Women (78 vs 71% of men; p ¼ 0.001) and those who had
a history of depression (55 vs 42% of those who reported no
depression in the past; po0.001) were more likely to send a
DNA sample.
We excluded those reporting manic or hypomanic
episodes, psychotic symptoms, obsessive-compulsive dis-
order and those of non-Caucasian origin, but we did not
exclude those with a self-reported history of depression or
any other anxiety disorder, or substance misuse (all
information based on background questionnaire data); thus
1269 participants were included in the analysis. Population
details are shown in Table 1.
This study was approved by the local ethics committees
and was carried out in accordance with the Declaration of
Helsinki. All participants provided written informed con-
We used brief standard questionnaires that were easy for
participants to complete and return to us by post. The
booklet included questions covering background informa-
tion (age, ethnicity, and family circumstances), personal
and family psychiatric history, and questionnaires covering
current mood and anxiety, personality, life events, and
childhood trauma.
To assess personality, we used the Big Five Inventory
(BFI-44) (John and Srivastava, 1999). For analysis, BFI
factor scores were calculated using a continuous weighted
dimension score (sum of items scored divided by the
number of items completed). Although the NEO PI-R (Costa
and McCrae, 1992) is the best validated Big Five ques-
tionnaire battery, the BFI-44 Inventory has the advantage of
being short, easy to understand, and shows a high cross-
instrument convergent validity correlations with other five-
factor personality questionnaires (eg with NEO, mean
r ¼ 0.73) (John and Srivastava, 1999). In total, 142 of our
participants filled out both the NEO PI-R and BFI-44
questionnaires for validation purposes and the results
showed highly significant (po0.001) correlations between
the two instruments (Pearson’s correlation: extraversion
R ¼ 0.79; agreeableness R ¼ 0.59; conscientiousness
R ¼ 0.75; neuroticism R ¼ 0.81; and openness R ¼ 0.66).
CNR1 and depression
G Juhasz et al
Depressive symptoms were measured using the depres-
sion subscale plus additional items, and anxiety symptoms
using the anxiety subscale from the 53-item Brief Symptom
Inventory (BSI) (Derogatis, 1993). A continuous weighted
dimension score (sum of item scores on the dimension
divided by the number of items completed) was calculated.
Mood and anxiety symptoms of 140 participants were also
rated by independent trained investigators using the
Montgomery Asberg Depression Rating Scale (Montgomery
and Asberg, 1979) and the Clinical Anxiety Scale (Snaith
et al, 1982). The results showed highly significant
(po0.001) correlations between the self-reported symptom
scores and the independent ratings (Pearson’s correlation:
depression R ¼ 0.79; anxiety R ¼ 0.80) in our population.
The recent negative life events questionnaire was adapted
from the list of life threatening experiences (Brugha et al,
1985) and asked participants to identify negative life events
related to intimate relationships, financial difficulties,
illnesses/injuries, and network problems occurring in the
last year. The sum of life event items was used in the
Childhood adversity questions related to emotional and
physical abuse, and emotional and physical neglect were
derived from the Childhood Trauma Questionnaire (Bern-
stein et al, 1994). An additional question asked about
parental loss during childhood. The sum of item scores was
used in the analysis.
Buccal mucosa cells were collected using cytology brush
(Cytobrush plus C0012; Durbin PLC) and 15-ml plastic tube
containing 2.0 ml of collection buffer. Genomic DNA was
extracted according to a protocol suggested by Freeman
et al (2003).
HaploView software package (
personal/jcbarret/haploview/) was employed to identify
haplotype tag SNPs (htSNP; minimum pairwise correlation
) to select htSNPs was 0.8) (Barrett et al, 2005; Gabriel
et al, 2002) based on the AFD_EUR_PANEL (AFD_EUR_18-
MAY-2004) population data of PERLEGEN (http://genome. (Hinds et al, 2005) and the CEPH popula-
tion data of the International HapMap Project (http://; Phase I. June 2005). Previously identified
possibly functional htSNPs in the 5
direction from the
CNR1 gene were also examined (Zhang et al, 2004).
The chosen SNPs were genotyped using the Sequenom
MassARRAY technology (Sequenom, San Diego). The
assay was followed according to the manufacturer’s
instructions ( using 25 ng of
DNA. Genotyping was blinded with regard to phenotype.
All laboratory work was performed under the ISO 9001:2000
quality management requirements.
Statistical Analysis
PLINK v1.04 (
was used for testing the association of different genetic
models (dominant, recessive, and additive; linear regression
model covariation with age and sex), interactions between
htSNPs (epistasis, linear regression model based on allele
dosage for tested SNPs), and with life events (linear
regression model, covariation with age and sex). Quanto
1.2 version ( was employed to
calculate the power of the recruited populations. Hardy–
Weinberg and haplotype analyses were performed using
HelixTreet 6.4.1 (Golden Helix, USA).
For haplotypic association analysis, we used haplotype
trend regression. Only haplotypes with a frequency greater
than 5% were used in the analysis. In all cases, data were
adjusted for age and sex. We used linear regression in
HelixTree to identify variance in the dependent variable
explained by age and sex (the ‘reduced model’). We then
determined whether adding haplotype frequencies to the
model (now the ‘full model’) explained significantly more
variance than the reduced model using a variance ratio
F-test. To remove the influence of multiple testing, we used
a permutation test, randomly grouping the sample 10 000
times. The permutated p-values were the fraction of
permutated tests that gave an improved p-value.
Bonferroni correction assumes independent outcome
variables and this assumption is not true of personality
factors and symptoms (depression and anxiety); therefore,
Table 1 Population Details for Those who Fulfilled the Inclusion
Criteria for the Study (n ¼ 1269)
Women 883 (70%)
Men 386 (30%)
Age (years) (mean
SEM) 34.04
Personal psychiatric history
Reported depression 676 (53%)
Single episode 181 (14%)
Recurrent episodes 495 (39%)
Reported suicide 190 (15%)
Reported anxiety 368 (29%)
Reported substance use disorder 85 (7%)
Family psychiatric history
Reported depression in immediate blood relatives 449 (35%)
Personality scores (range 1–5)
BFI extraversion (mean
SEM) 3.22
BFI agreeableness (mean
SEM) 3.78
BFI conscientiousness (mean
SEM) 3.66
BFI neuroticism (mean
SEM) 3.31
BFI openness (mean
SEM) 3.63
Symptom scores (range 0–4)
BSI depression (mean
SEM) 1.03
BSI anxiety (mean
SEM) 0.94
Recent negative life events (mean
SEM) 1.29
Childhood adversity (mean
SEM) 3.53
BFI, Big Five Inventory; BSI, Brief Symptom Inventory.
CNR1 and depression
G Juhasz et al
this method unnecessarily increases stringency (Westfall
and Young, 1993). Thus, we used false discovery rate (FDR)
calculation at a level of 5% (Qvalue: http://genomics. to adjust p-values accord-
ing to the number of hypothesis tested (Storey and
Tibshirani, 2003). We report q-value, which is a measure
of significance of each test of many tests performed
The CNR1 gene identified from the current National Center
for Biotechnology Information (NCBI, March 2007) data-
base was covered by seven htSNPs; in addition, we
genotyped three reported SNPs located 5
from the gene
(see Figure 1). The latter SNPs have a possible effect on the
mRNA expression of this gene (Zhang et al, 2004). All of the
genotyped SNPs were in Hardy–Weinberg equilibrium.
Allele and genotype frequencies can be seen in Supplemen-
tary Table S1. On the basis of the method published by
Gabriel et al (2002), we identified two blocks of linkage
disequilibrium (LD; haploblock 1: rs806379, rs1535255, and
rs2023239; haploblock 2: rs806369, rs1049353, rs4707436,
rs12720071, rs806368, and rs806366), whereas rs7766029
just partially belonged to the second haploblock (for LD
data, see Supplementary Table S2). This haplotype structure
is in close agreement with the results previously reported on
the European American population (Zuo et al, 2007).
Single Marker Association with Personality and
Detailed single marker association data (additive (add),
dominant (dom), and recessive (rec) model) can be seen in
Supplementary Table S3. In summary, rs1535255 G allele
¼ 0.023), rs2023239 C allele (p
¼ 0.046), and rs806366
C allele (p
¼ 0.024 and p
¼ 0.009) showed significant
positive association with agreeableness; rs4707436 A allele
negatively associated with conscientiousness (p
¼ 0.043);
neuroticism positively associated with rs1049353 A allele
¼ 0.042 and p
¼ 0.039) and negatively associated
with rs806366 C allele (p
¼ 0.017 and p
¼ 0.038); and
openness negatively associated with rs806368 C allele
¼ 0.044) as did rs7766029 T allele (p
¼ 0.040).
Finally, rs806369 T allele showed negative association with
depression (p
¼ 0.038) and positive association with
anxiety (p
¼ 0.019), as did rs7766029 T allele
¼ 0.038). All of the reported p-values are nominal
significance values and none of them survived correction
for multiple testing.
For a continuous trait such as neuroticism, using an
independent individual study design and assuming a linear
model relating the phenotype to genotype, we would require
1045 individuals to detect a polymorphism (with an allele
frequency 410%) that explained 1% of the variance of the
trait at the 5% two-tailed significance level with 90% power.
As we included 1269 participants, our study was adequately
Haplotypic Association with Personality
Haplotype trend regression showed significant association
with neuroticism (p ¼ 0.0043) and agreeableness
(p ¼ 0.00003; see Table 2). This association remained
significant after permutation and FDR correction (neuroti-
cism: q ¼ 0.0025 and agreeableness: q ¼ 0.0002). The varia-
tions in the CNR1 gene explained 2.5% variance in
agreeableness and 1.5% variance in neuroticism.
SNP SNP Interaction (Epistasis) in Relation to
Neuroticism and Agreeableness
Previously, Zhang et al (2004) showed that haplotypic
combination of rs806379, rs1535255, and rs2023239 influ-
enced the expression of CNR1 mRNA. In our study, we
tested the hypothesis that the effects of SNPs in the 5
haploblock 1 can be modified by the SNPs in the haploblock
2. Indeed, in our study, rs806379 showed significant
epistasis with several SNPs on both neuroticism and
agreeableness after covariation for age and sex, whereas
rs1535255 and rs2023239 showed significant epistasis on
agreeableness (Figure 1). Results where po0.04 remained
significant after FDR correction for multiple testing.
Haplotypic Association with Depressive and Anxiety
Using haplotypic trend regression, with age and sex as
covariates, depressive symptoms were significantly asso-
ciated with CNR1 haplotypes (explained variance 1.1%,
p ¼ 0.037, permutated p ¼ 0.039, FDR q ¼ 0.018; Table 3).
Figure 2 shows significant haplotypic effects on depression
scores, neuroticism, and agreeableness. There was no
significant haplotypic association with anxiety symptoms
(explained variance 0.7%, p ¼ 0.281; Table 3).
Exon 1 Exon 2 Exon 3 Exon 1 / Exon 4Splicing
Figure 1 Schematic figure of the CNR1 gene and the position of the
genotyped SNPs. Exon numbers in gray are proposed by Zhang et al
(2004). The black bar represents the exonic region according to the
National Center for Biotechnology Information (NCBI, March 2007) and
the University of California at Santa Cruz Browser. The gray region within
the black bar corresponds to the coding region and the splicing site is in
white. Dashed lines above the rs numbers refer to the significant epistasis
between the two haploblocks; p-values represented raw p data without
correction for multiple testing. (p
: significant epistasis p-values on
agreeableness; p
: significant epistasis p-values on neuroticism; ~: relevant
SNP pairs in the epistasis calculation that showed significant p-values on
both phenotypes; K: relevant SNP pairs in the epistasis calculation that
showed significant p-values only on agreeableness).
CNR1 and depression
G Juhasz et al
The magnitude of the haplotypic effect on depression
scores remained unchanged after excluding subjects with
reported substance use disorder (explained variance 1.3%,
p ¼ 0.026, permutated p ¼ 0.027) and with reported suicide
attempt (explained variance 1.3%, p ¼ 0.047, permutated
p ¼ 0.053).
CNR1 Environment Interaction in Relation to
Depression Scores
The significant CNR1 haplotype association with depressive
symptoms became nonsignificant (explained variance 0.9%,
p ¼ 0.071, permutated p ¼ 0.074; Table 3) after controlling
for recent negative life events scores. It is possible that the
CNR1 gene might have an effect either on experiencing
repeated negative life events through personality-dependent
life choices or through modifying the interpretation of a
specific life event (McGue and Bouchard, 1998; Bouchard
and McGue, 2003).
Indeed, rs7766029 showed highly significant interaction
with recent negative life events on depression scores
¼ 0.0004, p
¼ 0.0007), which remained significant
after FDR correction for multiple testing (q
¼ 0.004,
¼ 0.004; age, sex, and recent negative life events were
covariates in the analysis; Figure 3). Two other SNPs also
showed tendencies to interact with recent negative life
events on depression scores (rs806369 p
¼ 0.028;
rs1049353 p
¼ 0.052), but these associations did not
Table 2 Haplotypic Trend Regression Results for Personality Factors Measured by the Big Five Inventory (BFI)
Haplotypes Frequency (%)
Extraversion Agreeableness Conscientiousness Neuroticism Openness
Beta p Beta p Beta p Beta p Beta p
A,T,T,T,G,G,A,T,C,T 18.34 0.078 0.625 0.144 0.169 0.069 0.562 0.343 0.0193 0.040 0.705
A,T,T,C,A,A,A,T,T,C 15.27 0.454 0.0145 0.486 o0.0001 0.238 0.087 0.530 0.0019 0.054 0.661
T,T,T,C,G,G,A,T,C,C 8.30 0.012 0.982 0.589 0.089 0.059 0.881 0.895 0.065 0.047 0.893
T,T,T,T,G,G,A,T,C,T 8.10 0.057 0.839 0.378 0.0394 0.355 0.090 0.353 0.168 0.047 0.801
T,G,C,C,A,A,A,T,T,C 7.31 0.173 0.641 0.634 0.0094 0.060 0.829 0.210 0.538 0.133 0.587
A,T,T,C,G,G,A,C,T,T 7.06 0.434 0.276 0.352 0.187 0.172 0.572 0.253 0.498 0.082 0.761
T,T,T,C,A,A,A,T,T,C 5.38 0.578 0.185 0.225 0.434 0.165 0.614 0.600 0.135 0.296 0.291
Rare haplotypes 30.23
Full vs reduced model p 0.342 o0.0001 0.413 0.0043 0.938
Permutated p 0.337 0.0001 0.409 0.0028 0.939
FDR q 0.088 0.0002 0.092 0.0025 0.190
FDR q, false discovery rate significance value.
Age and sex were covariates in all calculations and the order of the htSNPs in the haplotypes corresponds to the SNP order in Figure 1.
Bold values indicate significant results (po0.05), italic values indicate trends (0.05opo0.01).
Table 3 Haplotypic Trend Regression Results for Symptom Scores Measured by the Brief Symptom Inventory (BSI)
Haplotypes Frequency (%)
Anxiety Depression Depression
Beta p Beta p Beta p Beta p
A,T,T,T,G,G,A,T,C,T 18.34 0.324 0.039 0.421 0.011 0.352 0.029 0.354 0.020
A,T,T,C,A,A,A,T,T,C 15.27 0.250 0.169 0.403 0.037 0.339 0.071 0.456 0.010
T,T,T,C,G,G,A,T,C,C 8.30 0.781 0.131 0.398 0.467 0.365 0.493 0.321 0.525
T,T,T,T,G,G,A,T,C,T 8.10 0.210 0.444 0.259 0.373 0.261 0.355 0.174 0.515
T,G,C,C,A,A,A,T,T,C 7.31 0.066 0.857 0.661 0.086 0.727 0.052 0.774 0.029
A,T,T,C,G,G,A,C,T,T 7.06 0.058 0.884 0.129 0.761 0.208 0.612 0.011 0.977
T,T,T,C,A,A,A,T,T,C 5.38 0.234 0.585 0.366 0.419 0.286 0.516 0.153 0.713
Rare haplotypes 30.23
Full vs reduced model p 0.281 0.037 0.071 0.012
Permutated p 0.278 0.039 0.074 0.012
FDR q 0.084 0.018 0.027 0.007
FDR q, false discovery rate significance value.
After covariation for recent negative life events (po0.001).
After covariation for childhood adversity (po0.001).
Age and sex were covariates in all calculations and the order of the htSNPs in the haplotypes corresponds to the SNP order in Figure 1.
Bold values indicate significant results (po0.05), italic values indicate trends (0.05opo0.01).
CNR1 and depression
G Juhasz et al
survive FDR correction (for detailed results, see Supple-
mentary Table S4).
Finally, we used childhood adversity scores as covariates
in the haplotypic trend regression. Haplotypic association
between the CNR1 gene and depression scores became
more significant (explained variance 1.1%, p ¼ 0.012,
permutated p ¼ 0.012, FDR q ¼ 0.007; Table 3), suggesting
that childhood adversity acts independently from the
CNR1 gene. This model remained significant after reintro-
ducing recent negative life events scores into it (explained
variance 1.0%, p ¼ 0.035, permutated p ¼ 0.029, FDR
q ¼ 0.013). Failure to include childhood adversity in
variance models could be an important confounding
variable in association studies of CNR1 and possibly other
genes in depression.
This is the first study to demonstrate a significant
association between the CNR1 gene and a high neuroti-
cism/low agreeableness phenotype. Haplotype had a statis-
tically significant effect on neuroticism and agreeableness,
although single markers showed only weak associations.
This observation directed our interests toward interactions
between SNPs. Using epistasis calculations on agreeableness
and neuroticism, we observed interaction between SNPs
located at the 5
end and SNPs in the second haploblock.
Previously, Zhang et al (2004) demonstrated that combina-
tions of rs806379, rs1535255, and rs2023239 influenced the
transcription of the CNR1 gene. Furthermore, in our study,
we found that the same haploblock 1 variation (ATT in
haplotypes 1 and 2) showed an opposite effect on
agreeableness, neuroticism, and depression depending on
the variation in haploblock 2 (haplotype 1: TGGATCT and
haplotype 2: CAAATTC).
Our data emphasize the point that although separate
SNPs probably explain less than 1% variance in these
phenotypes (Flint et al, 2008; Shifman et al, 2008), genetic
risk factors can be revealed in gene gene or gen-
e environment interactions. Shifman et al (2008) in a
recent whole genome association study failed to find a
susceptibility locus for neuroticism in the CNR1 genetic
region but they had only a 50% power to detect loci
accounting for 1% of the variance. Furthermore, based on
HapMap CEU data set, the SNPs covering this region using
Affymetrix 500K mapping arrays are in low LD with the
SNPs in our study (we found only one common SNP:
Depression symptom scores showed significant associa-
tion with the CNR1 gene after controlling for the effect of
childhood adversity. This observation suggests that the
CNR1 gene does not modify the influence of early trauma
on current levels of depression. In contrast, the CNR1 gene
significantly interacted with negative life events over the
past 12 months in explaining depression scores. On the
basis of this result, we propose that the CNR1 gene modifies
the depressive effect of experienced negative life events in
humans, which parallels the finding that CB1/ mice are
more sensitive than wild-type controls to 4 weeks of chronic
mild unpredictable stress in triggering learned helplessness
and anhedonia (Martin et al, 2002; Valverde et al, 2005;
Gorzalka et al, 2008).
Neuroticism can be defined as the ease with which
emotions are aroused. It is a well-known predictor for
lifetime depression and acts by magnifying the triggering
effect of life events on the onset of depression (Kendler et al,
2004). About 50% of the genetic vulnerability to depression
is shared with genetic risk factors for neuroticism (Kendler
et al, 2006). Hitherto, the main identified genetic influence
is the short-long polymorphism in the promoter region of
the serotonin transporter gene (5HTTLPR) (Lesch, 2004).
The less active short allele of the 5HTTLPR is associated
with higher neuroticism (Greenberg et al, 2000) and it
affects both the structure and function of an endopheno-
typic corticolimbic circuit underpinning emotion regulation
(Hariri et al, 2006). Although the 5HTTLPR polymorphism
accounts for only a few percent of the variation in
neuroticism, it nevertheless shares the characteristic of
Z-scores ± SEM
Figure 2 Effects of haplotype 1 (A,T,T,T,G,G,A,T,C,T; population
frequency: 18.34%) and haplotype 2 (A,T,T,C,A,A,A,T,T,C; population
frequency: 15.27%) on depression, neuroticism, and agreeableness scores.
Z-scores were calculated as follows: (haplotype mean scoretotal
population mean)/SD of haplotype mean. SEM: standard error of mean.
Significant haplotypic effects: *po0.05, **po0.005, ***po0.0001.
0 or 1 2 3 or more
Number of recent negative life events
BSI Depression score ± SEM
Figure 3 Significant interaction between rs7766029 and recent negative
life events on depression scores (p
¼ 0.0004, p
¼ 0.0007, after false
discovery rate (FDR) correction for multiple testing q
¼ 0.004,
¼ 0.004). Age, sex, and recent negative life events were covariates in
this calculation. T allele carriers are more vulnerable to negative life events
than CC genotype carriers (numbers in subgroups according to negative life
events and genotype: 0 or 1: TT ¼ 174, CT ¼ 387, CC ¼ 207; 2: TT ¼ 54,
CT ¼ 96, CC ¼ 72; and 3 or more: TT ¼ 37, CT ¼ 97, CC ¼ 60.).
CNR1 and depression
G Juhasz et al
increasing sensitivity to life events in triggering depression
(Caspi et al, 2003; Jacobs et al, 2006; Uher and McGuffin,
2008; Lazary et al, 2008). The fact that CNR1 variants are
not only associated with neuroticism but also interact with
recent life events to predict current depressive symptoms
suggests the variants act on the core endophenotypic
emotion regulation processes of neuroticism.
Neuroticism has been shown to be a strong risk factor
also for anxiety (Bienvenu et al, 2004; Kendler et al, 2007).
In our study, we could not demonstrate significant effect of
the CNR1 gene on anxiety symptoms, although both human
(Christensen et al, 2007) and animal (Haller et al, 2004a, b)
data suggest that impaired CB1 receptor signaling induces
anxiety. This negative result raises the possibility that
interaction with other genes or environmental factors is
necessary for the anxiogenic effect of the CB1 gene. Indeed,
CB1/ animals showed state-dependent increase of
anxiety: they behaved similarly to the wild-type animals in
non-/mildly stressful paradigms in contrast to the acute
highly stressful paradigms where anxiety symptoms mark-
edly increased compared with wild-type animals (Haller
et al, 2004a). Further studies are needed to test CNR1
gene gene and CNR1 gene environment interactions in
Much less is known about the role of agreeableness in
depression. In general, people who score highly for
agreeableness (reflecting a prosocial cooperative nature)
are more likely to cope by seeking support and using less
confrontation (O’Brien and DeLongis, 1996). Most studies
investigating the role of personality in depression have not
reported any major effects of agreeableness (Bienvenu et al,
2004; Kendler et al, 2006). However, indirect evidence
suggests that lower agreeableness predicts the development
of depression in various patient groups including adoles-
cents who suffered severe burns in early childhood (Liber
et al, 2008), adults undergoing interferon-alpha treatment
for hepatitis C (Lotrich et al, 2007), and patients with
chronic kidney disease (Hoth et al, 2007). Finch and
Graziano (2001) demonstrated that agreeableness exerts its
effects on depression exclusively through social exchange
such as social support and social conflict. In CB1/
animals, social contacts were reduced in the social
interaction test (Haller et al, 2004a) and this is usually
taken as an index of anxiety, but could indicate a lack of
response to social reinforcement that might underpin the
association between agreeableness and CNR1 gene varia-
tions. Furthermore, although infrequently cited, the
5HTTLPR short allele has also been associated with lower
agreeableness (Greenberg et al, 2000). Therefore, it is
possible that a high neuroticism/low agreeableness pheno-
type has a stronger predictive value for genetic vulnerability
to depression than neuroticism alone. Further studies are
needed to explore this hypothesis.
High neuroticism and low agreeableness are also risk
factors for several other psychiatric conditions that are
frequently co-morbid with depression. Independent of the
clusters, high neuroticism and low agreeableness were
consistent dimensional characteristics of personality dis-
orders in young adults (Moran et al, 2006). Substance use
disorders, especially smoking (Terracciano and Costa,
2004), alcohol (Malouff et al, 2007), marijuana (Terracciano
et al, 2008), and polysubstance abuse (McCormick et al,
1998) have also been associated with a high neuroticism/low
agreeableness phenotype. The CNR1 gene has been
associated with substance use disorders (Zhang et al,
2004; Zuo et al, 2007) and this association might be driven
by the common personality structure influenced by this
gene, as we have demonstrated in this study. Another study
did not find association between substance use and CNR1
gene, but they investigated only a limited part of the CNR1
gene (Herman et al, 2006). We found a significant
interaction to exist between the two haploblocks of this
gene (epistasis), and this may have an impact on the
expression of CB1 receptor (Zhang et al, 2004). Schizo-
phrenia has also been associated with the CNR1 gene,
although with conflicting results (Levinson et al, 2000;
Leroy et al, 2001; Zhang et al, 2004; Chavarria-Siles et al,
2008; Hamdani et al, 2008). It is important to note that
schizophrenic patients compared with depressed subjects,
score just as high for neuroticism but even lower for
agreeableness (Bagby et al, 1997), particularly if they have
co-morbid substance abuse disorder (Reno, 2004).
In conclusion, our results provide evidence that CNR1
gene is implicated in determining a personality phenotype
(high neuroticism and low agreeableness), which has been
associated with, and may be a vulnerability factor for, a
variety of psychiatric conditions, including major depres-
sion and substance misuse. In addition, our finding that
current depressive symptoms can be partly explained by an
interaction between recent life events and variation in the
CNR1 gene is further support for the eCB system playing a
role in the development of depressive symptoms. Further
studies are needed to evaluate the mechanism by which
CNR1 gene expression and translation are controlled.
We are grateful to Heaton Mersey Medical Practice and
Cheadle Medical Practice for their assistance in the
recruitment. This study was supported by the Sixth
Framework Program of the EU, NewMood, LSHM-CT-
The authors declare that, except for income received from
their primary employer, no financial support or compensa-
tion has been received from any individual or corporate
entity over the past 3 years for research or professional
service and there are no personal financial holdings that
could be perceived as constituting a potential conflict of
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Supplementary Information accompanies the paper on the Neuropsychopharmacology website (
CNR1 and depression
G Juhasz et al
    • "Participants provided genetic sample and completed a questionnaire pack. The subjects' ethnicity, socio-economic background, medical and psychiatric anamnesis was assed using a background questionnaire developed and validated for that study (Juhasz et al., 2009Juhasz et al., , 2011 Lazary et al., 2008 ). Reported medical or psychiatric conditions were not exclusion criteria, since we aimed to investigate a general population sample. "
    [Show abstract] [Hide abstract] ABSTRACT: Interleukin-1β is one of the main mediators in the cross-talk between the immune system and the central nervous system. Higher interleukin-1β levels are found in mood spectrum disorders, and the stress-induced expression rate of the interleukin-1β gene (IL1B) is altered by polymorphisms in the region. Therefore we examined the effects of rs16944 and rs1143643 single nucleotide polymorphisms (SNPs) within the IL1B gene on depressive and anxiety symptoms, as measured by the Brief Symptom Inventory, in a Hungarian population sample of 1053 persons. Distal and proximal environmental stress factors were also included in our analysis, namely childhood adversity and recent negative life-events. We found that rs16944 minor (A) allele specifically interacted with childhood adversity increasing depressive and anxiety symptoms, while rs1143643's minor (A) allele showed protective effect against depressive symptoms after recent life stress. The genetic main effects of the two SNPs were not significant in the main analysis, but the interaction effects remained significant after correction for multiple testing. In addition, the effect of rs16944 A allele was reversed in a subsample with low-exposure to life stress, suggesting a protective effect against depressive symptoms, in the post-hoc analysis. In summary, both of the two IL1B SNPs showed specific environmental stressor-dependent effects on mood disorder symptoms. We also demonstrated that the presence of exposure to childhood adversity changed the direction of the rs16944 effect on depression phenotype. Therefore our results suggest that it is advisable to include environmental factors in genetic association studies when examining the effect of the IL1B gene.
    Full-text · Article · Feb 2016
    • "The most studied gene is the one encoding the CB1r, the CNR1 gene. Different studies have now provided evidence for a role of this gene per se or in combination with life events or other genes in the development of depression (Mitjans et al. 2013; Bagdy et al. 2012; Agrawal et al. 2012; Monteleone et al. 2010; Juhasz et al. 2009; Domschke et al. 2008 ). Few studies have explored the consequences of polymorphic changes in the FAAH gene; nonetheless the data that have been obtained point toward the importance of this gene in stress reactivity and thus susceptibility to mood disorders (Monteleone et al. 2010; Gunduz-Cinar et al. 2013b). "
    [Show abstract] [Hide abstract] ABSTRACT: Preclinical and clinical data fully support the involvement of the endocannabinoid system in the etiopathogenesis of several mental diseases. In this review we will briefly summarize the most common alterations in the endocannabinoid system, in terms of cannabinoid receptors and endocannabinoid levels, present in mood disorders (anxiety, posttraumatic stress disorder, depression, bipolar disorder, and suicidality) as well as psychosis (schizophrenia) and autism. The arising picture for each pathology is not always straightforward; however, both animal and human studies seem to suggest that pharmacological modulation of this system might represent a novel approach for treatment.
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    • "Acute administration of a CB1 receptor agonist (Kruk-Slomka et al., 2015), CB2 receptor agonist (Bahi et al., 2014; Kruk-Slomka et al., 2015) or antagonist (Kruk-Slomka et al., 2015) also causes antidepressant-like effect in mice. In humans, variation in the endocannabinoid genes is found to (1) be related to depression (Onaivi et al., 2008 ), (2) moderate the effects of childhood physical abuse (Agrawal et al., 2012) and recent life events (Juhasz et al., 2009) on anhedonia and depression, and (3) affect the pallidum reactivity to happy faces and responsiveness to antidepressant treatment (Domschke et al., 2008. See reviews by Vinod and Hungund, 2006; Hill et al., 2009; Gorzalka and Hill, 2011 for research on endocannabinoid and depression). "
    [Show abstract] [Hide abstract] ABSTRACT: Despite being considered primarily a mood disorder, major depressive disorder (MDD) is characterized by cognitive and decision making deficits. Recent research has employed computational models of reinforcement learning (RL) to address these deficits. The computational approach has the advantage in making explicit predictions about learning and behavior, specifying the process parameters of RL, differentiating between model-free and model-based RL, and the computational model-based functional magnetic resonance imaging and electroencephalography. With these merits there has been an emerging field of computational psychiatry and here we review specific studies that focused on MDD. Considerable evidence suggests that MDD is associated with impaired brain signals of reward prediction error and expected value (‘wanting’), decreased reward sensitivity (‘liking’) and/or learning (be it model-free or model-based), etc., although the causality remains unclear. These parameters may serve as valuable intermediate phenotypes of MDD, linking general clinical symptoms to underlying molecular dysfunctions. We believe future computational research at clinical, systems, and cellular/molecular/genetic levels will propel us towards a better understanding of the disease.
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