DOI 10.

1007/s00702-003-0072-0 J Neural Transm (2003) 110: 14451453

Allelic variation in 5-HT1A receptor expression is associated with anxiety- and depression-related personality traits Rapid Communication
A. Strobel1; , L. Gutknecht2; , C. Rothe3 , A. Reif2 , R. Mssner2, Y. Zeng2 , B. Brocke1; , and K.-P. Lesch2; o
Differential and Personality Psychology, Institute of Psychology II, Technical University of Dresden, Dresden, 2 Molecular and Clinical Psychobiology, Department of Psychiatry and Psychotherapy, University of Wrzburg, Wrzburg, and u u 3 Department of Psychiatry, University of Munster, Munster, Germany Received September 10, 2003; accepted September 21, 2003
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Summary. The 5-HT1A receptor plays a critical role in the pathophysiology of anxiety and depression as well as in the mode of action of anxiolytic and antidepressant drugs. Human 5-HT1A gene transcription is modulated by a common C-1016G single nucleotide polymorphism (SNP) in its upstream regulatory region. In the present study, we evaluated the role of the HTR1A-1019 polymorphism in the modulation of individual differences in personality traits by an association study of a sample of healthy volunteers. Personality traits were assessed with two different methods, NEO personality inventory (NEOPI-R) and Tridimensional Personality Questionnaire (TPQ). There was a signicant effect of the HTR1A-1019 polymorphism on NEO Neuroticism with carriers of the G allele showing higher scores than individuals homozygous for the C variant. The effect was primarily due to associations with the Neuroticism facets Anxiety and Depression. Carriers of the G allele also exhibited higher TPQ Harm Avoidance scores. Our ndings indicate a role of allelic variation in 5-HT1A receptor expression in the development and modulation of anxiety- and depression-related personality traits. Keywords: 5-HT1A gene promoter, polymorphism, neuroticism, anxiety- and depression-related traits, association.

These authors contributed equally to the work.

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Introduction Brain serotonin (5-HT) has been implicated in a number of physiologic processes and pathologic conditions. These effects are mediated by at least 14 different 5-HT receptors. A role of the 5-HT1A receptor subtype in the pathophysiology of anxiety and depression as well as in the mode of action of anxiolytic and antidepressant drugs has long been suspected (Griebel, 1995; Lesch and Mssner, 1999; Lesch et al., 2003). o The 5-HT1A receptor is encoded by an intronless gene (HTR1A) located on human chromosome 5q12.3. Several rare missense polymorphisms have been found within the protein coding region of HTR1A. While a Gly22Ser variant shows differences in agonist-elicited downregulation compared with the most prevalent 5-HT1A receptor allele, a functional C-1019G single nucleotide polymorphism (SNP) in the transcriptional control region of the HTR1A gene (HTR1A-1019) is associated with severe depression (Lemonde et al., 2003). In vitro experiments demonstrated that the G variant displays differential binding efciency of transcriptional regulators (repressors=enhancers) (Albert, 2002; Lemonde et al., 2003). In the present study, we evaluated the role of the HTR1A-1019 polymorphism in the modulation of individual differences in personality traits by a population genetic study of a sample of healthy volunteers recruited according to a protocol previously described (Strobel et al., 2002, 2003). We predicted that the HTR1A-1019 genotype would be associated with personality traits related to anxiety and depression, particularly with Neuroticism and Harm Avoidance as assessed by the NEO personality inventory (NEO-PI-R; (Costa and McCrae, 1992)), and the Tridimensional Personality Questionnaire (TPQ; (Cloninger et al., 1993)), respectively. Our hypothesis was based on several lines of evidence: selective 5-HT uptake inhibitors (SSRIs) are an effective treatment for anxiety and depressive spectrum disorders; changes in 5-HT function are associated with these disorders; and manipulation of 5-HT1A receptor agonists=antagonists alter anxiety-related behaviors in experimental animals (Griebel, 1995; Lesch et al., 2003). In addition, an anxiety-related personality trait of the TPQ, Harm Avoidance, was originally hypothesized to be mediated by serotonergic function (Cloninger et al., 1993). Materials and methods Participants and procedure
The sample consisted of 284 healthy students and staff at the University of Technology, Dresden (213 females and 71 males; mean age: 22.2 5.0 years, age range: 1859 years), which had been recruited in order to investigate associations between subsequently identied genomic variations and personality=behavioral traits (Strobel et al., 2002, 2003). All of the participants were of German ethnicity and 92% of the participants were born in the former GDR which renders ethnic admixture unlikely in this sample. The study was carried out in accordance with the Declaration of Helsinki. After an explanation of the details and the goals of the study, participants gave written informed consent, and a nurse who was authorized by a physician obtained 200 ml of blood from earlobes. All participants completed the German versions of the NEO-PI-R and the TPQ (Weyers et al., 1995; Ostendorf and Angleitner, 2003). The NEO-PI-R is based on the ve factor model of personality (Costa and McCrae, 1992). It consists of 241 Likert-type items and

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assesses individual differences in 30 personality facets, which can be aggregated to the ve personality domains Neuroticism, Extraversion, Openness to Experience, Agreeableness, and Conscientiousness. The TPQ is based on Cloningers model of personality (Cloninger et al., 1993). Its 100 items assess individual differences along the temperament dimensions Novelty Seeking, Harm Avoidance, and Reward Dependence. Each of the three temperament scales comprises four subscales, the Reward Dependence subscale Persistence mostly being considered as a separate fourth temperament factor. The German versions of the NEO-PI-R, and the TPQ, respectively, exhibit acceptable psychometric properties (Weyers et al., 1995; Ostendorf and Angleitner, 2003).

Genotyping
DNA was extracted from EDTA blood using the QIAamp Blood Kit (Qiagen, Hilden, Germany) A 163-bp fragment (position 1158 to 996 from the translation start site ATG) containing the SNP at nucelotide position 1019 was amplied by polymerase chain reaction (PCR) using the following reaction mix: 20 ng of genomic DNA in 75 mM Tris-HCl (pH 9.0), 20 mM ammonium sulfate, 0.01% Tween 20, 1.5 mM magnesium chloride, 0.4 mM of each of the primers, SNPR1Anor (50 -GGC TGG ACT GTT AGA TGA TAA CG) and SNPR1A-mod (50 -GGA AGA AGA CCG AGT GTG TCA T), 0.4 mM dNTP, and 1 U Taq polymerase. Because the HTR1A-1019 SNP fails to create or delete a recognition site for restriction endonucleases, the reverse primer (SNPR1Amod) was modied (A-1016T) to introduce a variable restriction site dependent on a C or a G in position 1019. After an initial denaturation step for 5 min. at 95 C, 35 cycles of denaturating at 95 C for 30 s, annealing at 59.5 C for 40 s and extension of 72 C for 50 s were perfomed, followed by a nal extension step of 72 C for 5 min. PCR products were digested with BseGI. The undigested PCR product (163 bp) carries the C variant while the digested product with two fragments of 17 bp and 146 bp contains the G allele. PCR amplication was carried out blind to the participants identity.

Statistical analysis
All analyses were carried out using SPSS 9.0.1 (SPSS Inc., Chicago, USA). HTR1A-1019 SNP allele frequencies were 54.2% for the G allele and 45.8% for the C variant. Genotype frequencies were distributed according the Hardy-Weinberg equilibrium (12 0.014, p 0.904): 29.2% G=G (N 83), 50.0% G=C (N 142), and 20.8% C=C (N 59). Because anxiety-like behavior was apparent not only in homozygous 5HT1A-=- knockout mice but also in heterozygous = mice, indicating that a partial receptor decit is sufcient to cause the behavioral phenotype (Toth, 2003), the sample was dichotomized according to absence (G) vs. presence (G) of the G allele. Association tests were performed by means of analysis of variance (ANOVA) with the HTR1A-1019 SNP (Gvs. G) as independent variable. To avoid possible confounding effects of age and gender, multiple regression analyses with age and gender as predictors and with the personality scales and subscales, respectively, as criteria were performed, the z-standardized residuals were calculated and were entered as dependent variables into the ANOVA.

Results Means and standard deviations of NEO-PI-R Neuroticism domain and facet scale scores (raw scores, and age- and gender-residualized scores, respectively) grouped by absence vs. presence of the HTR1A-1019 G allele are given in Table 1. To test the hypothesis whether individuals with the G allele exhibit higher Neuroticism scores, a univariate ANOVA with HTR1A-1019 SNP (G vs. G) as independent variable and Neuroticism as dependent variable was performed (note that here and in the following, the dependent variables were age- and gender-residualized and z-standardized scores; see Materials and Methods).

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Table 1. Means and standard deviations of NEO-PI-R Neuroticism domain and facet scale scores grouped by absence vs. presence of the HTR1A-1019 G allele HTR1A-1019 Raw scores Mean N: Neuroticism N1: Anxiety N2: Angry hostility N3: Depression N4: Self-consciousness N5: Impulsiveness N6: Vulnerability G2 G1 G G G G G G G G G G G G 89.24 97.23 15.56 17.73 13.22 14.23 13.46 15.88 17.15 17.92 17.80 18.06 12.05 13.40 SD 23.18 25.58 6.13 6.59 4.73 4.94 5.20 6.27 5.27 5.01 4.80 4.44 4.68 5.44 Age- and gender-residualized z-scores Mean 20.26 0.07 0.27 0.07 0.17 0.05 0.31 0.08 0.11 0.03 0.05 0.01 0.21 0.06 SD 0.94 1.00 0.95 1.00 0.99 1.00 0.85 1.02 1.04 0.98 1.06 0.98 0.91 1.01

There was a signicant effect of HTR1A-1019 SNP on Neuroticism (F1,282 5.07, p 0.025, 2 0.018, d 0.271). Carriers of the G allele exhibited higher Neuroticism scores than non-carriers (Fig. 1). Subsequent analyses revealed that the effect of the HTR1A-1019 SNP on Neuroticism was primarily due to associations of this polymorphism with N1: Anxiety (F1,282 5.60, p 0.019, 2 0.019, d 0.278) and with N3: Depression (F1,282 7.37, p 0.007, 2 0.025, d 0.320), whereas no signicant

Fig. 1. Role of the HTR1A-1019 G allele in the modulation of NEO-PI-R Neuroticism; carriers of the G allele (N 225) exhibit signicantly higher age- and gender-residualized Neuroticism z-scores than individuals homozygous for the C variant (N 59)

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associations with the other Neuroticism facets were detected (all p>0.05; see Table 1). Because we had no a priori hypothesis, which of the six Neuroticism facets would be associated with the HTR1A-1019 SNP, the level of signicance of was Bonferroni-adjusted resulting in a 0.008. At this level, only the association of the polymorphism with N3: Depression reached signicance. It has to be noted, however, that the Neuroticism facets are substantially intercorrelated. Pearson-correlations between the facets ranged from 0.23 (N3N5) to 0.76 (N1N3) in our sample. Thus, Bonferroni-correction may be regarded as too conservative in this case. Subsequent analyses focused on the discriminant and the convergent validity of the nding of higher Neuroticism scores in carriers of the HTR1A-1019 G allele. ANOVA with the NEO-PI-R domain scales Extraversion, Openness, Agreeableness, and Conscientiousness as dependent variables were performed to assess discriminant validity (i.e. no associations between the HTR1A-1019 SNP and these four personality domains). No associations emerged for these variables (all p>0.35; all Z2 <0.003). Regarding convergent validity, an ANOVA with TPQ Harm Avoidance as dependent variable was performed in order to examine whether the effect of the HTR1A-1019 SNP on personality features related to anxiety and depression remained stable across methods of measurement. There was a signicant effect of the HTR1A-1019 SNP (F1,282 4.57, p 0.033, Z2 0.016, d 0.255) with carriers of the G allele exhibiting higher Harm Avoidance scores. Finally, in order to determine whether pooling of the G=G and G=C genotypes led to biased results, all three genotypes were compared with respect to their Neuroticism domain and facet scale scores, and their Harm Avoidance scores, respectively (G=G vs. G=C vs. C=C). In these analyses, only the association between the HTR1A-1019 SNP and N3: Depression remained signicant at the conventional level (F2,281 3.72, p 0.025), whereas the results were marginally signicant for the Neuroticism domain scale (F2,281 2.56, p 0.079), the Neuroticism facet N1: Anxiety (F2,281 2.85, p 0.060), and the Harm Avoidance scale (F2,281 2.41, p 0.092). Discussion The result of the present study suggest that allelic variation in 5-HT1A receptor expression modulates individual differences in anxiety- and depression-related personality traits. Carriers of the HTR1A-1019 G allele exhibited signicantly higher scores in NEO Neuroticism. The effect was primarily due to associations with the Neuroticism facets Anxiety and Depression. Carriers of the G allele also exhibited higher TPQ Harm Avoidance scores. Our ndings further support the evidence that implicates the 5-HT1A receptor in the pathophysiology of anxiety and depression as well as in the mode of action of anxiolytic and antidepressant drugs (Griebel, 1995; Olivier et al., 1999). Patients with panic disorder and depression exhibit an attenuation of 5-HT1A receptor-mediated hypothermic and neuroendocrine responses, reecting dysfunction of both pre- and postsynaptic 5-HT1A receptors (Lesch et al., 1990b, 1992). Likewise, a decrease in ligand binding to 5-HT1A receptors as

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assessed by positron emission tomography has been shown in forebrain areas and in the raphe of depressed patients (Drevets et al., 1999; Sargent et al., 2000). Downregulation and hyporesponsivity of 5-HT1A receptors in patients with major depression are not reversed by the antidepressant drug treatment (Lesch et al., 1990a, 1991; Lerer et al., 1999; Sargent et al., 2000), raising the possibility that low receptor function is a trait feature and therefore a pathogenetic mechanism of the disease. 5-HT1A receptors operate both as somatodendritic autoreceptors and as postsynaptic receptors. Somatodendritic 5-HT1A autoreceptors are predominantly located on 5-HT neurons and dendrites in the brainstem raphe complex. Their activation by 5-HT or 5-HT1A agonists decreases the ring rate of serotonergic neurons and subsequently reduces the synthesis, turnover, and release of 5-HT from nerve terminals in projection areas (Hamon et al., 1990). Postsynaptic 5-HT1A receptors are widely distributed in forebrain regions that receive serotonergic input, notably in the cortex, hippocampus, septum, amygdala, and hypothalamus. Their activation results in membrane hyperpolarization and decreased neuronal excitability. In hippocampal heteroreceptors, neuronal inhibition is mediated by coupling to the GIRK2 potassium channel. Physiological responses depend upon the function of the target cells (e.g. hypothermia, activation of the hypothalamic pituitary adrenocortical system). Moreover, 5HT1A receptor expression is modulated by steroid hormones and 5-HT1A mediated signaling is an important regulator of gene expression through its coupling to G-proteins that inhibit adenylyl cyclase and modulation of GIRK2 channels. The effects of 5-HT1A receptor selective agents, such as the agonist 8hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and the partial agonists ipsapirone and gepirone, have been extensively studied in rodents (De Vry, 1995). Both agonists and partial agonists induce a dose-dependent anxiolytic effect which correlates with the inhibition of serotonergic neuron ring, decrease of 5-HT release as well as the reduction of 5-HT signaling at postsynaptic target receptors. Blockade of the negative feedback by selective 5-HT1A receptor antagonists, such as WAY 100635 increases ring of the serotonergic neurons but exerts no effect on 5-HT neurotransmission or behavior (Olivier and Miczek, 1999), while the combination with SSRIs augments increases in 5-HT levels in terminal regions. The converging lines of evidence that 5-HT1A receptor deciency or dysfunction is involved in mood and anxiety disorders encouraged investigators to genetically manipulate the 5-HT1A receptor in mice. As anticipated, mice with a targeted inactivation of the 5-HT1A receptor gene display a spontaneous phenotype that is associated with a gender-modulated and gene=dose-dependent increase of anxiety-related behavior and stress reactivity in several conict paradigms (Lesch et al., 2003; Toth, 2003). Activation of presynaptic 5-HT1A receptors provide the brain with an autoinhibitory feedback system controlling 5-HT neurotransmission. Thus, enhanced anxiety-related behavior most likely represents a consequence of increased terminal 5-HT availability resulting from the lack or reduction in presynaptic somatodendritic 5-HT1A autoreceptor negative feedback function (Lesch and Mssner, 1999). o

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This mechanism is also consistent with recent theoretical models of fear and anxiety that are primarily based upon pharmacologically-derived data. The cumulative reduction in serotonergic impulse ow to septohippocampal and other limbic and cortical areas involved in the control of anxiety is believed to explain the anxiolytic effects of ligands with selective afnity for the 5-HT1A receptor in some animal models of anxiety-related behavior. This notion is based, in part, on evidence that 5-HT1A agonists (e.g. 8-OH-DPAT) and antagonists (e.g. WAY 100635) have anxiolytic or anxiogenic effects, respectively. However, to complicate matters further, 8-OH-DPAT has anxiolytic effects when injected in the raphe nucleus, whereas it is anxiogenic when applied to the hippocampus. Thus, stimulation of postsynaptic 5-HT1A receptors has been proposed to elicit anxiogenic effects, while activation of 5-HT1A autoreceptors is thought to induce anxiolytic effects via suppression of serotonergic neuronal ring resulting in attenuated 5-HT release in limbic terminal elds. Since the 5-HT1A receptor is expressed in different brain subsystems, it is of interest to clarify whether pre- or post-synaptic receptors are required to maintain normal expression of anxiety-related behavior in both humans and the animal model. With an elegant conditional rescue approach, Gross and coworkers (Gross et al., 2002) showed that expression of the 5-HT1A receptor in the hippocampus and cortex but not in the raphe nuclei is required to rescue the behavioral phenotype of 5-HT1A knockout mice. The ndings indicate that deletion of the 5-HT1A receptor in mice, specically in forebrain structures, results in a robust anxiety-related phenotype and that this phenotype in 5-HT1A knockout mice is caused by the absence of the receptor during a critical period of postnatal development, whereas inactivation of 5-HT1A in adulthood does not affect anxiety. Even more importantly, the ndings further support the notion of a central role for 5-HT in the early development of neurocircuits mediating emotion (Di Pino et al., 2003; Lesch, 2003). Although there is converging evidence that the 5-HT1A receptor mediates anxiety-related behavior, the neurodevelopmental mechanism that renders 5-HT1A receptor-decient mice more anxious are highly complex and remain to be elucidated in its details. While increased 5-HT availability and activation of other serotonergic receptor subtypes that have been shown to mediate anxiety may contribute to anxiety-related behavior, multiple downstream neurotransmitter pathways or neurocircuits, including noradrenergic, GABAergic, glutamatergic, and peptidergic transmission, as suggested by overexpression or targeted inactivation of critical genes within these systems (Lesch et al., 2003), have been implicated to participate in the processing of this complex behavioral trait. Since avoidance induced by conict and fear is only one dimension of anxiety-related responses, other components including autonomic systems activation, responsiveness to stress, 5-HT dynamics, and neuronal excitability in limbic circuitries appear to be involved in fear and anxiety. In conclusion, allelic variation in 5-HT1A receptor expression is likely to play a critical role in the development and modulation of individual differences in anxiety- and depression-related personality traits. Whether this 5-HT1A receptor gene variation contributes to the general tendency for individuals who score higher on neuroticism or anxiety factors in different personality tests

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to be at higher risk for anxiety or personality disorders as well as depression is currently the objective of further study (Rothe et al., 2003). It likewise remains to be investigated whether therapeutic responses to serotonergic agents are inuenced by this polymorphism. Acknowledgements
The authors would like to thank J. Mller for helpful comments during the preparation of the u article. The study was supported by a grant from the Deutsche Forschungsgemeinschaft (SFB 581).

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