European Neuropsychopharmacology (2016) 26, 150–155


Replication of the association between CHRNA4 rs1044396 and harm avoidance in a large population-based sample Katharina Beya,n, Leonhard Lennertza, Sebastian Markettb, Nadine Petrovskyb, Jürgen Gallinatc, Gerhard Gründerd, Katja N. Spreckelmeyere, Thomas F. Wienkerf, Arian Mobascherg, Norbert Dahmeng, Norbert Thueraufh, Johannes Kornhuberh, Falk Kieferi, Mohammad R. Toliatj, Peter Nürnbergj, Georg Wintererk, Michael Wagnera,l a

Department of Psychiatry and Psychotherapy, University of Bonn, Germany Department of Psychology, University of Bonn, Germany c Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf (UKE), Germany d Department of Psychiatry and Psychotherapy, RWTH Aachen University, Germany e Department of Psychiatry and Psychotherapy, RWTH Aachen University, and JARA -Translational Brain Medicine, Germany f Max-Planck Institute for Molecular Genetics, Berlin, Germany g Department of Psychiatry, Johannes Gutenberg University Mainz, Germany h Department of Psychiatry, Friedrich-Alexander University Erlangen-Nuernberg, Germany i Department of Addictive Behavior and Addictive Medicine, Central Institute of Mental Health, Germany j Cologne Center of Genomics, University of Cologne, Germany k Experimental and Clinical Research Center (ECRC), Charité – University Medicine Berlin, Germany l DZNE, German Center for Neurodegenerative Diseases, Bonn, Germany b

Received 12 August 2015; received in revised form 2 October 2015; accepted 8 November 2015



CHRNA4; Rs1044396; Harm avoidance;

Harm avoidance is a personality trait characterized by excessive worrying and fear of uncertainty, which has repeatedly been related to anxiety disorders. Converging lines of research in rodents and humans point towards an involvement of the nicotinic cholinergic system in the modulation of anxiety. Most notably, the rs1044396 polymorphism in the CHRNA4


Corresponding author. E-mail address: [email protected] (K. Bey). 0924-977X/& 2015 Elsevier B.V. and ECNP. All rights reserved.

Replication of the association between CHRNA4 rs1044396 and harm avoidance TCI; Nicotine



gene, which codes for the α4 subunit of the nicotinic acetylcholine receptor, has been linked to negative emotionality traits including harm avoidance in a recent study. Against this background, we investigated the association between harm avoidance and the rs1044396 polymorphism using data from N= 1673 healthy subjects, which were collected in the context of the German multi-centre study 'Genetics of Nicotine Dependence and Neurobiological Phenotypes'. Homozygous carriers of the C-allele showed significantly higher levels of harm avoidance than homozygous T-allele carriers, with heterozygous subjects exhibiting intermediate scores. The effect was neither modulated by age or gender nor by smoking status. By replicating previous findings in a large population-based sample for the first time, the present study adds to the growing evidence suggesting an involvement of nicotinic cholinergic mechanism in anxiety and negative emotionality, which may pose an effective target for medical treatment. & 2015 Elsevier B.V. and ECNP. All rights reserved.


Harm avoidance is a personality trait characterized by excessive worrying, fear of uncertainty, shyness and fatigability. Conceptualized as a temperament dimension in Cloninger's biosocial model of personality (Cloninger, 1987), it is referred to as an automatic tendency to respond intensely to aversive stimuli. In the present study, we aim to elucidate the neurobiological underpinnings of harm avoidance by investigating its association with the single nucleotide polymorphism (SNP) rs1044396 in the CHRNA4 gene, which is involved in nicotinic cholinergic signalling in the central nervous system. With their widespread and non-uniform distribution throughout the brain, nicotinic acetylcholine receptors (nAChR) are involved in diverse cortical and subcortical processes, rendering them an attractive target for neurobehavioural research. The majority of nAChR is localized presynaptically and/or preterminally where they modulate the release of almost all neurotransmitters, including dopamine, serotonin, gamma-amino-butyric acid (GABA) and glutamate. The nAChR are a family of pentameric cationic channels, whose structure is determined by combinations of different subunits (α1–α10 and β2–β4). Accounting for 90% of the high affinity neuronal nAChR in the mammalian brain, α4β2* receptors, which consist of α4 and β2 subunits (α5 and β3 subunits may also be integrated, hence the asterisk), are the most common type of nAChR (Gotti et al., 2009). The CHRNA4 gene, which determines the structure of the α4 subunit, is located on chromosome 20q13.2–13.3 with rs1044396 localized in exon 5. Although the SNP does not affect the amino acid sequence of the α4 protein, its associations with a wide range of neurocognitive phenotypes (Greenwood et al., 2012; Parasuraman et al., 2005; Tsai et al., 2012; Winterer et al,. 2007; see next paragraph) suggest an involvement in nicotinic cholinergic signalling via other functional mechanisms. On the one hand, the SNP may be in strong linkage disequilibrium with a nonsynonymous SNP. On the other hand, it may cause alterations in RNA stability or regulation (Eggert et al., 2015). Recent evidence for the functional significance of rs1044396 comes from research in Xenopus oocytes. It has been demonstrated that two

exon 5 haplotypes (hap1 and hap2) including the rs1044396 SNP lead to opposite sensitivity changes of α4β2 nAChR in response to increasing doses of acetylcholine (Eggert et al., 2015). For hap1, which includes the rs1044396 C-allele, a switch from low sensitivity at low agonist concentrations to high sensitivity at high agonist concentrations was observed, compared to hap2. These results suggest that hap1 improves the signal-to-noise ratio of nicotinic receptors in response to acetylcholine. Mirroring the extensive distribution of nAChR throughout the brain and its manifold interactions with other neurotransmitter systems, empirical evidence points towards an involvement of nicotinic cholinergic mechanisms in several different functions ranging from attention and working memory to the modulation of depression and anxiety (Greenwood et al., 2012; Parasuraman et al., 2005; Tsai et al., 2012; Winterer et al,. 2007). Notably, nicotine appears to have both anxiolytic and anxiogenic effects: while it is known to reduce anxiety in both chronic smokers and nonsmokers, it has also been shown to increase anxiety levels in non-smokers after intravenous administration (for a review on nAChR function see Graef et al., 2011). These seemingly opposing effects are assumed to be due to dose-dependence, with low doses of nicotine having anxiolytic and high doses having anxiogenic effects. Moreover, the influence of nicotine on anxiety might be modulated by the different nAChR subtypes. For example, the α4β2* agonist ABT-418 has been reported to exhibit anxiolytic effects (Brioni et al., 1994). Further evidence for the involvement of the α4 subunit in anxiety modulation comes from studies showing increased anxiety-like behaviour in knockout mice lacking this subunit (Ross et al., 2000) and knock-in mice with a leucine-to-serine mutation in the α4 receptor resulting in a hypersensitive channel (Labarca et al., 2001). Finally, a study by Markett et al. (2011) reported an association between negative emotionality and the rs1044396 SNP in a sample of N = 574 subjects, primarily comprising psychology students. Compared to carriers of at least one T-allele, carriers of the homozygous CC genotype exhibited higher levels of harm avoidance (p = .006, η2 = .018), neuroticism (p = .019, η2 = .014) and behavioural inhibition. The present study aims to replicate the association


K. Bey et al.

between rs1044396 and harm avoidance in a large, independent, population-based sample.



Data were collected in the context of the population-based German multi-centre study 'Genetics of Nicotine Dependence and Neurobiological Phenotypes', which was conducted between 2007 and 2009 at seven recruitment centres throughout Germany (for details see Lindenberg et al., 2011; Quednow et al., 2012). Harm avoidance scores and rs1044396 genotype data were available for N=1673 subjects (n=718 males, n=955 females). Participants had a mean age of M =34.81 (SD=12.77) and reported a mean of M=11.78 years of education (SD=1.56). The study protocol was approved by the ethics committee of the German Psychological Association.



Harm avoidance was assessed using the German version of the Tridimensional Personality Questionnaire (TPQ; Cloninger, 1987; German translation by Weyers et al., 1995). With respect to the harm avoidance scale, the TPQ is identical to the Temperament and Character Inventory (TCI; Cloninger et al., 1993), which was employed by Markett et al. (2011). For each subject, a sum score was computed based on the 34 binary items of the harm avoidance scale. Given its comparatively large effect size in the study of Markett et al. (2011), harm avoidance was the phenotype of main interest in the present investigation. Still, since data on neuroticism were available for N =1664 subjects, we also tested this trait’s association with rs1044396. As in Markett et al. (2011), neuroticism was assessed using the NEO Five-Factor Inventory (NEO-FFI; Costa and McCrae, 1992), which employs a five-point Likert scale ranging from 0='strongly disagree' to 4='strongly agree'. Based on the 12 items of the neuroticism scale, a mean score was computed for each participant.



All analyses were conducted using the IBM SPSS software package version 22. Discrete variables were examined via Pearson's Χ2-tests and continuous data were analyzed by analyses of variances (ANOVA). The level of significance was set at p=.05 for all analyses.

Experimental procedures




DNA for genotyping was prepared from fresh frozen EDTA blood with Qiagen FlexiGene DNA Kit according to the manufactory protocol. Normalization was based on RNase P copy number measurement using the TaqMan RNase P assay (Applied Biosystems, Foster City, CA, USA). The SNP was genotyped on the 7900HT Sequence Detection System using the C__25765540_10 assay developed by Applied Biosystems. Allelic discrimination analysis was performed on the Prism 7900HT Fast Real-Time PCR system using the software SDSv2.1.1 (Applied Biosystems). Four reference DNA samples and four negative controls without DNA were included in every 384-well plate to ensure the accuracy of the genotyping assay. Analyses of reference DNA samples always yielded the same genotypes.

Table 1



Descriptive characteristics of the study population genotyped for rs1044396 are given in Table 1. As shown, the CHRNA4 variant was not statistically related to age, gender, verbal intelligence, smoking status, and study centre (all p4.10). Overall, 21.4% of the subjects were homozygous carriers of the C-allele, 28.6% were TT-carriers, and 50% carried the heterozygous genotype. This distribution did not deviate from Hardy–Weinberg equilibrium (Χ2(1)= .04, p =.85). Gender was clearly related to harm avoidance with female subjects scoring significantly higher than males (12.875.3 vs. 11.075.4; F(1,1671) = 47.37, po.001). Smokers and non-smokers neither differed with respect to harm avoidance (F(1,1671) = .001, p= .98), nor regarding CHRNA4 genotype (Χ2 = .98, p=.61). Expectedly, harm avoidance and neuroticism were highly correlated, as indicated by Pearson's correlation (N= 1656; r= .63, po.001). The presents study aimed to replicate the significant association between rs1044396 and harm avoidance reported by Markett et al. (2011). As shown in Figure 1, harm avoidance scores declined from homozygous C-allele carriers to homozygous T-allele carriers with subjects of the CT genotype showing intermediate harm avoidance scores. This genotype effect was highly significant as indicated by ANOVA (F(2,1670) = 6.17, p= .002, η2 = .007). Because female gender is clearly related to higher harm avoidance scores, we included gender as a second factor and reran the analysis. In line with Markett et al. (2011), the main effect of CHRNA4 genotype remained highly significant (F(2,1667) = 6.21, p= .002) while no interaction of gender and genotype on harm avoidance was found (F(2,1667) = 1.00, p =.37). Regarding neuroticism, we observed a significant association with rs1044396 when comparing subjects of the TT genotype with participants carrying at least one C-allele (F (1,1662) = 4.22, p= .040, η2 = .003). An ANOVA accounting for all three genotypes yielded a trend towards a significant effect (F(2,1661) = 2.55, p= .086, η2 = .003). Similar results were obtained when gender was included as a second factor in the analyses (F(1,1660) = 3.36, p= .067, and F(2,1658) = 1.89, p= .15, respectively).

Descriptive characteristics (means and SDs) of the study population genotyped for CHRNA4 rs1044396.

Age Gender (% male) Verbal intelligence Smoking status (% smokers) Study centre




Test statistic

p value

34.14 (12.77) 45.5% 110.24 (13.12) 48.6%

34.84 (12.61) 41.0% 110.98 (13.49) 45.9% Seven centres

35.63 (13.12) 43.9% 110.00 (13.63) 47.8%

F(1,1671) =1.40 Χ2(2) =2.66 F(1,1670) =.85 Χ2(2) =.98 Χ2(12) =7.21

.25 .26 .43 .61 .84

Replication of the association between CHRNA4 rs1044396 and harm avoidance

Figure. 1 Association between harm avoidance and CHRNA4 rs1044396 genotype. Error bars indicate standard errors. *po.05; **po.01.



We observed a significant association between the rs1044396 SNP in the CHRNA4 gene and the personality trait harm avoidance. With a positive allelic load effect of the Callele on increased harm avoidance, the results reported by Markett et al. (2011) were replicated in a large populationbased sample for the first time. While the rs1044396 Callele was associated with higher scores in neuroticism, too, the effect of harm avoidance was much more pronounced. This observation is in line with the results of Markett et al. (2011), who also found a smaller effect of NEO-FFI neuroticism than of harm avoidance. The confirmed association fits well with other recent reports on the role of rs1044396 genotype in negative affect. Tsai et al. (2012) report an association of the CC genotype with loneliness and depression in elderly people, and Grazioplene et al. (2013) provide evidence for rs1044396 variation as a putative risk factor for higher neuroticism. Interestingly, this effect was modulated by childhood maltreatment. While the TT genotype was related to higher scores in maltreated children, nonmaltreated carriers of this genotype exhibited significantly lower levels of neuroticism than children carrying at least one C-allele. Assuming that the prevalence of severe childhood maltreatment was low in the present population-based sample, the effect we observed is in line with the results of Grazioplene et al. (2013). At the neurophysiological level, the suggested association between harm avoidance and nicotinic cholinergic signalling is supported by a recent PET-study linking higher harm avoidance scores with greater nAChR availability in various brain regions (Storage et al., 2013). Notably, it has recently been demonstrated (Eggert et al., 2015) with voltage clamp experiments and experimental mRNA expression studies that six non-coding and co-segregating SNPs including rs1044396 of a CHRNA4 exon 5 haplotype together are functionally relevant, and might therefore be causative for the above mentioned association.


The repeatedly observed associations between rs1044396 and negative emotionality are a new lead in CHRNA4 genetic research. CHRNA4 rs1044396 has been predominantly studied in the context of attention, after the first report by Parasuraman et al. (2005) that CHRNA4 relates to reaction time benefits in a visuospatial cueing task. The present replication of the association between rs1044396 and harm avoidance in a population-based sample raises the question whether the conceptualization of a cognitive phenotype for rs1044396 (Greenwood et al., 2012) needs to be revised in favour of a model that also takes the association with affective phenotypes into account. Given the pleiotropic effects of rs1044396 on cognitive phenotypes such as attention and working memory, and affective traits such as harm avoidance, it will be of high interest to study the biological pathways behind this pleiotropy. On the one hand, the widespread distribution of α4β2* across the central nervous system (Gotti et al., 2009) points towards a possible scenario of a general molecular effect which affects nAChR sensitivity in different neural circuits including those underlying attention and those underlying emotion. On the other hand, interactions between affective and cognitive processes may contribute to the phenotypic pleiotropy. It is well known that highly anxious individuals are characterized by an attentional bias towards threat and negative information (Bar-Haim et al., 2007). CHRNA4 rs1044396 has been linked to attentional control (Greenwood et al., 2005) but also to early individual differences in perceptual processing (Kikuno et al., 2013). An alternative scenario might therefore include interactive relations between the prioritizing of threat related information by either top-down or bottom-up signalling and the activity in threat or uncertainty processing circuitry. The confirmed association between CHRNA4 rs1044396 and harm avoidance provides further evidence for a link between anxious personality traits and nicotinic cholinergic signalling. This may have clinical implications and could inform the development of new medication. In line with Cloninger's and Svrakic's (1997) proposal that individual configurations in personality structure influence the risk of psychopathology, high levels of harm avoidance have repeatedly been associated with depression and anxiety disorders (Richter et al., 2000; Fossey et al., 1989). Moreover, there is a striking comorbidity between mood disorders and smoking, supporting the idea that a dysregulation of the cholinergic system might be involved in the aetiology of major depression (Picciotto et al., 2015). Interestingly, nicotine (Cosci et al., 2015) and medication selectively targeting the activity of α4β2* nAChR can improve depressive symptoms (Mineur and Picciotto, 2009), suggesting that nicotinic agents can modulate human mood states. In terms of self-medication, patients may use smoking as a means to regulate genetically codetermined variation in cholinergic signalling. Future research on the relation between nicotine smoking and psychiatric disorders may benefit from taking into account genetic predispositions, such as CHRNA4 rs1044396 genotype. In sum, we observed a significant association between the temperament dimension harm avoidance and the rs1044396 SNP in the CHRNA4 gene, which is implicated in nicotinic cholinergic signalling in the central nervous system. By replicating previous findings in a large population-based

154 sample for the first time, our results add to the growing evidence suggesting an involvement of nicotinic cholinergic mechanism in anxiety and negative emotionality, which may pose an effective target for medical treatment.

Funding The German multi-centre study 'Genetics of Nicotine Dependence and Neurobiological Phenotypes' was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) as part of the Priority Program (Schwerpunktprogramm) SPP1226: 'Nicotine: Molecular and Physiological Effects in the Central Nervous System (CNS)'.

Contributors KB, LL, SM and MW designed the study. KB undertook the statistical analysis and wrote the first draft of the manuscript. MRT was responsible for genotyping. NP, JG, GG, KNS, TFW, AM, ND, NT, JK, FK, PT, MW and GW were involved in data-acquisition for this multicentre study. All authors contributed to and have approved the final manuscript.

Conflict of interest The authors declare that there is no conflict of interests regarding the publication of this paper.

Acknowledgement The authors thank all clinicians, psychiatrists, psychologists, and study nurses involved in the study.

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Replication of the association between CHRNA4 rs1044396 and harm avoidance in a large population-based sample.

Harm avoidance is a personality trait characterized by excessive worrying and fear of uncertainty, which has repeatedly been related to anxiety disord...
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