- Email: [email protected]
Effect of tryptophan hydroxylase-2 gene variants on amygdalar and hippocampal volumes
BR A IN RE S E A RCH 1 3 31 ( 20 1 0 ) 5 1 –5 7
available at www.sciencedirect.com
www.elsevier.com/locate/brainres
Research Report
Effect of tryptophan hydroxylase-2 gene variants on amygdalar and hippocampal volumes Hideyuki Inoue a,⁎, Hidenori Yamasue a,b , Mamoru Tochigi a , Kunio Takei c , Motomu Suga a , Osamu Abe d , Haruyasu Yamada d , Mark A. Rogers a,e , Shigeki Aoki d , Tsukasa Sasaki c , Kiyoto Kasai a a
Department of Neuropsychiatry, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan Japan Science and Technology Agency, CREST, 5 Sanbancho, Chiyoda-ku, Tokyo, 102-0075, Japan c Health Service Center, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan d Department of Radiology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan e School of Psychology, Deakin University, Burwood, Victoria 3152, Australia b
A R T I C LE I N FO
AB S T R A C T
Article history:
Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin
Accepted 15 March 2010
(5-HT). Genetic variations in human TPH2, a newly identified isoform of TPH, have been
Available online 21 March 2010
shown to impact on enzymatic activity of TPH and to be associated with emotion-related personality traits and mood/anxiety disorders. Identification of an intermediate phenotype
Keywords:
that bridges the relationship between genes and behavior may be of great importance in the
Tryptophan hydroxylase 2 (TPH2)
further clarification of how hTPH2 contributes to emotional regulation. Previous studies
Amygdala
have shown that a polymorphism in the upstream regulatory region of hTPH2 (SNP G-703T,
Hippocampus
rs4570625) correlates functional MRI response of the amygdala. In this study, we examined
Endophenotype
the effect of this genotype on amygdalar and hippocampal volumes in 208 mentally healthy
Manual tracing
individuals. To measure volumes of amygdala and hippocampus, gray matter regions of
Temperament and Character
interest were outlined manually on three-dimensional MRI data obtained using a 1.5-T
Inventory (TCI)
scanner. Additionally, personality traits were evaluated using the Temperament and Character Inventory (TCI). Those subjects with T allele carriers were associated with significantly smaller volumes in bilateral amygdala and hippocampus and higher reward dependence than those with G allele homozygotes. These results suggest that amygdalar and hippocampal volumes assessed using MRI may be a useful intermediate phenotype that will uncover the biological pathway linking 5-HT synthesis and emotional behaviors and affective disorders. © 2010 Elsevier B.V. All rights reserved.
1.
Introduction
Serotonin (5-hydroxytryptamine or 5-HT) is a widespread neurotransmitter in the central nervous system. 5-HT neurons are mainly found in different raphe nuclei, from which they
project to numerous brain regions regulating mood and affect such as cortical areas, limbic system including amygdala and hippocampus, and basal ganglia (Freedman and Shi, 2001; Parent et al., 1981). 5-HT signaling is an important regulator of early central nervous system development (Lauder, 1993) and
⁎ Corresponding author. Fax: +81 3 5800 6894. E-mail address: [email protected] (H. Inoue). 0006-8993/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2010.03.057
52
BR A IN RE S EA RCH 1 3 31 ( 20 1 0 ) 5 1 –57
of adult neurogenesis (Gould, 1999). 5-HT is involved in many brain functions and neuropsychiatric disorders, and pharmaceuticals targeting the 5-HT system are widely used for the treatment of various psychiatric disorders. The first and rate-limiting enzyme in 5-HT biosynthesis is tryptophan hydroxylase (TPH). It had been thought that TPH was derived from a single gene (now referred to as TPH1) until a second TPH isoform (TPH2) was recently described (Cote et al., 2003; Walther and Bader, 2003; Walther et al., 2003). While TPH1 is primarily expressed in the periphery, TPH2 is predominantly expressed in the brain and exclusively maintains brain 5-HT synthesis across the lifespan (Cote et al., 2003; Gutknecht et al., 2009; Walther et al., 2003; Zhang et al., 2004; Zill et al., 2004a). Furthermore, a relatively rare single nucleotide polymorphism in human TPH2 (hTPH2) has been shown to alter TPH enzymatic efficiency in vitro (Zhang et al., 2005). The association of hTPH2 genetic variation with behavioral phenotypes including neuropsychiatric disorders and personality traits has been investigated. Specific polymorphisms in hTPH2 have been reported to have an association with major depression (Van Den Bogaert et al., 2006; Zhang et al., 2005; Zhou et al., 2005; Zill et al., 2004b), affective disorders (Harvey et al., 2004; Lopez et al., 2007), suicidality (Jollant et al., 2007; Ke et al., 2006; Lopez de Lara et al., 2007; Lopez et al., 2007; Van Den Bogaert et al., 2006; Yoon and Kim, 2009; Zill et al., 2004b), autism (Coon et al., 2005), early onset obsessive-compulsive disorder (Mossner et al., 2006), attention deficit hyperactivity disorder (Sheehan et al., 2005; Walitza et al., 2005), panic disorder (Maron et al., 2007), chronic fatigue syndrome (Goertzel et al., 2006; Smith et al., 2006), and Tourette's syndrome (Mossner et al., 2007). Additionally, previous studies have suggested that TPH2 is associated with personality traits related to emotional instability (Gutknecht et al., 2007; Lopez de Lara et al., 2007) and with risk for cluster B and cluster C personality disorders (Gutknecht et al., 2007). To further clarify the biological pathways underpinning individual differences in emotional behaviors and risk for psychiatric conditions, including anxiety and depression, the identification of an intermediate phenotype for hTPH2 variations is of great importance. In terms of a functional intermediate phenotype, Brown and colleagues reported that T allele carriers of the hTPH2 rs4570625 variant were associated with greater functional magnetic resonance imaging (fMRI) amygdala response while viewing angry or fearful faces than were G/G individuals (Brown et al., 2005). Canli and colleagues replicated the findings by Brown et al. (2005); they reported that T carriers had greater fMRI signal increase in response to faces with both positive or negative valence than G/G individuals (Canli et al., 2005). To our knowledge, however, no studies have investigated an association between hTPH2 variation and brain structural intermediate phenotype. Accordingly, the aim of this study was to investigate the effect of hTPH2 rs4570625 polymorphism on regional brain volume as assessed by structural MRI and personality traits in mentally healthy individuals. Since reduced volume of amygdala and hippocampus has been reported in emotion-related psychiatric disorders including major depression, posttraumatic stress disorder, and suicidality (Geuze et al., 2005; Honea et al., 2005; Kasai et al., 2008; Monkul et al., 2007; Rogers et al., 2009; Strakowski et al., 2002), we predicted that T
allele carriers would be associated with smaller volumes in these regions than G/G homozygotes. We also predicted that this polymorphism would affect personality traits that were evaluated using the Temperament and Character Inventory (TCI) (Cloninger, 1987; Cloninger et al., 1993), especially in harm avoidance (HA) and reward dependence (RD) as HA temperament dimension is frequently and positively associated with mood and anxiety disorders (Ampollini et al., 1999; Bayon et al., 1996; Brown et al., 1992; Cowley et al., 1993; Farmer et al., 2003; Farmer and Seeley, 2009; Hansenne et al., 1998, 1999; Mulder et al., 1994; Naito et al., 2000; Ongur et al., 2005; Richman and Frueh, 1997; Richter et al., 2000; Ruchkin et al., 1998; Saviotti et al., 1991) and with small hippocampal volume (Yamasue et al., 2008a), and RD is also associated with mood and anxiety disorders (Ampollini et al., 1999; Farmer and Seeley, 2009; Ongur et al., 2005; Richman and Frueh, 1997; Ruchkin et al., 1998).
2.
Results
The genotypic distributions of the three genotypes in the TPH2 genes are as follows: G/G 53 (25.5%), G/T 106 (51.0%), T/T 49 (23.6%). The distributions of the three TPH2 genotypes were not significantly different from those expected according to the Hardy–Weinberg equilibrium. The three genotypes in the TPH2 gene were classified into two genotype subgroups according to the previous study (Brown et al., 2005): the genotypes with the T allele (here termed ‘T carriers’) versus the G/G genotype (here termed ‘G/G individuals’). No significant difference was observed in gender, age, handedness, self-socioeconomic status (SES), or parental SES between the two genotype groups (Table 1). Total gray matter, total white matter, cerebrospinal fluid (CSF), and intracranial volume (ICV) volume also did not differ significantly between the two genotype groups (p > 0.29). For the genotype effects on amygdalar and hippocampal volumes, the repeated-measures ANOVA showed that there was a significant main effect of the hTPH2 genotype (F[1,206] = 5.17 p = 0.024). There was no significant interaction between genotype and region (F[1,206] = 0.026, p = 0.87), genotype and hemisphere (F[1,206] = 0.70, p = 0.41), or genotype and region and hemisphere (F[1,206] = 1.67, p = 0.20). The statistical conclusion from the main ANOVA is that subjects with T allele carriers have significantly smaller ROI volumes without either significant laterality or regional specificity among bilateral amygdala and hippocampus than those with homozygous G alleles (Fig. 1). There were no significant interactions between gender and genotype (F[1, 204] = 0.94, p = 0.33), gender and genotype and region (F[1, 204] = 0.27, p = 0.60), gender and genotype and hemisphere (F[1, 204] = 0.46, p = 0.50), or gender and genotype and region and hemisphere (F[1, 204] = 0.18, p = 0.67). Percentage changes and effect sizes of the difference in brain volume between genotypes are described in Table 2. Furthermore, subjects with T allele carriers showed significantly higher scores on reward dependence than those with G/G homozygotes (t[190]= −2.39, p = 0.018) (Table 1). Additionally, genotype effects were re-investigated after excluding outlying data (a single subject with outlying bilateral hippocampal volumes) and the main effect of the hTPH2 genotype did not alter (F[1,205]= 4.91, p = 0.028).
53
BR A IN RE S E A RCH 1 3 31 ( 20 1 0 ) 5 1 –5 7
Table 1 – Clinical and demographic characteristics of the study participants. G/G (n = 53)
T carriers (n = 155)
Mean
SD
Mean
SD
Sex (male/female) Age (range) Socioeconomic status a Parental Socioeconomic status
32 /21 33.5 (21–65) 1.7 2.3
11.1 0.7 0.7
111 /44 33.4 (21–71) 1.6 2.2
11.8 0.6 0.8
Temperament and Character Inventory Harm avoidance Novelty seeking Reward dependence Persistence Self directedness Cooperativeness Self-transcendence
18.1 20.9 14.5 4.6 29.6 28.5 9.4
a b
3.
6.3 5.7 3.8 1.7 5.7 4.7 4.7
16.4 21.4 15.8 4.9 31.0 29.8 9.5
6.7 5.4 3.2 1.7 6.6 5.1 5.3
Group Comparison
Chi-square [1] = 2.32, p = 0.13 t[206] = − 0.23, p = 0.82 t[206] = 1.10, p = 0.27 t[201 b] = 0.49, p = 0.62
t[190 b]=1.57, p = 0.12 t[190 b] = −0.58, p = 0.57 t[190 b] = − 2.39, p = 0.018 t[190 b] = −0.82, p = 0.42 t[190 b] = −1.31, p = 0.19 t[190 b] = −1.58, p = 0.12 t[190 b] = −0.13, p = 0.89
Assessed using the Hollingshead scale (Hollingshead, 1957). Higher scores indicate lower educational and/or occupational status. The degrees of freedom varied due to unavailability of data in some subjects.
Discussion
The T allele carriers were associated with significantly smaller bilateral amygdalar and hippocampal volume and higher reward dependence than G allele homozygotes. These findings suggest that amygdalar and hippocampal volume as assessed by MRI morphometry may be a useful intermediate phenotype for investigating how serotonin synthesis impacts on emotional behavior and affective disorders. Associations have been reported between variations in rs4570625 and a number of behavioral phenotypes including ADHD (Walitza et al., 2005), disorders related to emotional dysregulation (Gutknecht et al., 2007; Reuter et al., 2007), suicidal behavior in major depression (Yoon and Kim, 2009), and personality traits (Gutknecht et al., 2007). Reported intermediate phenotypes include fMRI BOLD signal changes in the amygdala in response to viewing emotional faces (Brown et al., 2005; Canli et al., 2005) and event-related potentials (Lipton et al., 2008) during a passive emotional picture perception task (Herrmann et al., 2007). The current study extends the previous findings by adding evidence of an
association between hTPH2 variations and limbic system structure. We detected a significant association between hTPH2 genotypes and reward dependence, but not harm avoidance, despite our prior prediction. These findings may illustrate a weak association between genes and personality traits and emphasize the importance of utilizing an intermediate phenotype such as neuroimaging index to clarify complex biological pathway linking genes and behavior. It is controversial how rs4570625 influence hTPH2 expression. Chen and colleagues reported that common polymorphisms including rs4570625 had a significant impact on hTPH2 expression in vitro (Chen et al., 2008). Meanwhile, Scheuch and colleagues reported that not rs4570625 itself, but a different SNP (rs11178997) within the haplotype block, might contribute to change in promoter activity of hPTH2 in vitro (Scheuch et al., 2007). We need to comment upon methodological considerations of our study. First, we investigated only one SNP, which can only provide a partial insight into the genetic basis of brain structures at best. Multiple different genes or neurotransmitter systems have been implicated in brain morphology.
Fig. 1 – Manually traced amygdalar and hippocampal volumes and TPH2 genotype. Means and distributions of left and right hemispheres for relative manually traced amygdalar and hippocampal volumes (absolute volume × 100/intracranial content) in which individuals with TPH2 G allele homozygotes exhibited bilateral enlargement compared with individuals with TPH2 T allele carriers (F[1,206] = 5.17, p = 0.024). Means are represented by solid horizontal lines drawn on each group's distribution.
54
BR A IN RE S EA RCH 1 3 31 ( 20 1 0 ) 5 1 –57
Table 2 – Brain volume a and TPH2 polymorphism. G/G (n = 53) Mean Volumetric Measures (ml) Total gray matter Total white matter Cerebrospinal fluid Intracranial volume Amygdala Absolute volume (ml) Relative volume (%) d
Hippocampus Absolute volume (ml) Relative volume (%) d
731.4 446.8 372.3 1550.6
T Carriers (n = 155) SD
80.0 43.6 70.0 159.9
Mean 742.3 452.5 381.9 1576.8
% Difference b
Effect Size c
− 1.47 − 1.26 − 2.51 − 1.66
−0.15 −0.12 −0.14 −0.17
SD 71.1 51.0 65.8 153.3
Left Right Left Right
1.456 1.504 0.094 0.097
0.309 0.331 0.018 0.020
1.376 1.416 0.087 0.090
0.263 0.282 0.016 0.017
5.85 6.20 7.45 7.80
0.19 0.07 0.32 0.19
Left Right Left Right
2.673 2.657 0.173 0.172
0.408 0.399 0.025 0.024
2.596 2.626 0.165 0.167
0.394 0.436 0.024 0.026
2.96 1.17 4.69 2.87
0.29 0.30 0.40 0.39
a
Total gray and white matter, cerebrospinal fluid, and intracranial content were measured using voxel-based morphometry. Hippocampal and amygdala volume were measured using a manual tracing method. b %Difference = (difference score for mean [G/G subjects] relative to mean [T carriers])/mean [T carriers]: the bilateral amygdala and hippocampus volumes were larger in subjects with G/G genotype than in subjects with T allele carriers. c Effect size = (difference score for mean [G/G subjects] relative to mean [T carriers])/pooled SD [all subjects]. d Relative volume = Absolute volume/intracranial content × 100.
Recently, an additive effect between TPH2 and 5-HTT on brain functions has been observed using ERP (Herrmann et al., 2007) and fMRI (Canli et al., 2008). Ideally, association studies should aim to look at possible interactions among multiple genes or multiple polymorphisms. Second, we focused on limbic structures because of the evidence that these regions are a key modulator of mood and affect. However, in future studies, the possibility of genetic impact on other brain regions such as pre- and sub-genual cingulate cortex should be explored. Fourth, the present results should be interpreted cautiously. The currently observed genotype effect on regional brain volumes was weak but significant, since the effect sizes of genotype effects were smaller than those of gender effects (female > male) (data not shown). In conclusion, to our knowledge, this is the first report that genetic variants of the hTPH2 gene affect brain morphology. Further studies are needed to replicate the observed association and to demonstrate that rs4570625 is indeed in the transcriptional control region.
4.
Experimental procedures
4.1.
Subjects
major mental illness. Other exclusion criteria were neurological illness, traumatic brain injury with any known cognitive consequences or loss of consciousness for more than 5 min, a history of substance abuse or addiction, or a family history of an axis I disorder in their first-degree relatives. All were righthanded based on the Edinburgh Inventory (Oldfield, 1971). The socioeconomic status (SES) and parental SES were assessed using the Hollingshead scale (Hollingshead, 1957). After a thorough explanation of the study to the subjects, written informed consent was obtained. The ethical committee of the Faculty of Medicine, University of Tokyo, approved this study (No. 397-1 for MRI project and No. 639-9 for genetic and imaging–genetic association project).
4.2.
A valid Japanese translation (Kijima et al., 2000) of TCI (Cloninger, 1987; Cloninger et al., 1993) was used for measuring the personality trait. Participants completed a 240-item TCI questionnaire within 3 months before or after MR scan. In this study, we focused on the HA and RD subscales of the TCI.
4.3.
The subjects were 208 (143 men and 65 women) Japanese adults (age, mean ± SD: 33.9 ± 11.6 years old), consisting of college students, hospital staff, and their acquaintances. Before MRI scanning, the subjects were screened using the Structured Clinical Interview for DSM-IV Axis I Disorder, Nonpatient Edition (SCID-NP) (First et al., 1997; Japanese version, Kitamura and Okano, 2003) by a trained psychiatrist (H.Y. or M.S.), to confirm that the subjects had no history of
Personality assessment
MRI acquisition
The method of MRI acquisition of 1.5 mm slices was the same as that described in our previous study (Yamasue et al., 2003). The MRI data were obtained using a 1.5-T scanner (General Electric Signa Horizon Lx version 8.2, GE Medical Systems, Milwaukee, WI, USA). We used three-dimensional Fouriertransform spoiled-gradient-recalled acquisition with steady state. The repetition time was 35 ms, the echo time 7 ms with one repetition, the nutation angle 30°, the field of view 24 cm, and the matrix 256 × 256 (192) × 124.
BR A IN RE S E A RCH 1 3 31 ( 20 1 0 ) 5 1 –5 7
4.4. Manual tracing for amygdala and hippocampus volumetry The amygdala and hippocampus gray matter regions of interest (ROIs) were outlined manually by one rater (H.I.) who was blind to the group status or genotype. For the manual tracing, we used a software package for medical image analysis (3D Slicer; software available at http://www.slicer. org), which enables a simultaneous view of orthogonal planes. The landmarks to delineate the ROIs were the same as those of our previous study (Yamasue et al., 2008b). For interrater reliability, two raters (H.I. and M.A.R.) blind to group membership, independently drew ROIs. Ten cases were selected at random, and the raters drew ROIs on every slice. The intraclass correlation coefficient was 0.87/0.85 for the left/ right amygdala and 0.93/0.94 for the left/right hippocampus, respectively. Intrarater reliability, computed by using all of the slices from one randomly selected brain and measured by one rater (H.I.) on two separate occasions (approximately 2 months apart), was >0.95 for all structures. Total gray matter, white matter, and cerebrospinal fluid volumes were calculated using SPM2 (Good et al., 2001). Then ICV was calculated by summing up the total gray matter, white matter, and cerebrospinal fluid volumes. To validate this method, the ICVs of an independent sample of MRI scans for 50 adult subjects were measured by both the current procedure and intensity-based semiautomated segmentation procedure using ANALYZE PC 3.0 (Yamasue et al., 2004). Then we confirmed that the calculated intraclass correlation coefficient for the ICVs was satisfactory (0.96).
4.5.
Genotyping
Genomic DNA was extracted from peripheral leukocytes using a standard phenol-chloroform method. DNA was isolated and amplified from blood samples obtained from all subjects. The hTPH2 G(-844)T promoter single nucleotide polymorphism (GenBank accession number NT_029419, dbSNP accession number rs4570625) was genotyped using fluorescence polarization (Chen et al., 1999). This study was performed in ethnically homogeneous samples (only of Japanese descent).
4.6.
Statistical analyses
The effects of the TPH2 genotype on the manually traced volumes were assessed by repeated-measures analysis of variance (ANOVA) adopting relative volumes [100× absolute ROI volume / (ICV)] as the dependent variable, genotype as the between-subject factor, and region (amygdala/hippocampus) and hemisphere (left/right) as the within-subject factors. To determine whether the findings are due to gender differences or if they really are the results of a gene-specific effect, we further conducted a repeated-measures ANOVA where gender was added as a between-subject factor as well as genotype, region and hemisphere as the within-subject factors. A statistically significant level was set at p < 0.05. For testing regional specificity, the volumes of total gray matter, total white matter, CSF, and ICV were also compared between genotypes using independent t-tests. Supplementarily, effect size and % difference were used to assess the effects of the TPH2 genotype on the
55
absolute and relative volumes of each region. To examine the statistical effects of TPH2 and personality as measured by TCI scores, we used independent t-tests. A statistically significant level was set at p < 0.05.
Acknowledgment This study was supported in part by grants-in-aid for scientific research (No. 18019009 to K.K., No. 17-5234 to M.A.R.) from the Japan Society for the Promotion of Science and the Ministry of Education, Culture, Sports, Science and Technology, Japan, by grants-in-aid (H17-Kokoro-Ippan 009 to K.K.) from the Ministry of Health, Labor and Welfare, Japan, and by Core research for Evolutional Science and Technology (CREST) of Japan Science and Technology Agency (JST).
REFERENCES
Ampollini, P., Marchesi, C., Signifredi, R., Ghinaglia, E., Scardovi, F., Codeluppi, S., Maggini, C., 1999. Temperament and personality features in patients with major depression, panic disorder and mixed conditions. J. Affect. Disord. 52, 203–207. Bayon, C., Hill, K., Svrakic, D.M., Przybeck, T.R., Cloninger, C.R., 1996. Dimensional assessment of personality in an out-patient sample: relations of the systems of Millon and Cloninger. J. Psychiatr. Res. 30, 341–352. Brown, S.L., Svrakic, D.M., Przybeck, T.R., Cloninger, C.R., 1992. The relationship of personality to mood and anxiety states: a dimensional approach. J. Psychiatr. Res. 26, 197–211. Brown, S.M., Peet, E., Manuck, S.B., Williamson, D.E., Dahl, R.E., Ferrell, R.E., Hariri, A.R., 2005. A regulatory variant of the human tryptophan hydroxylase-2 gene biases amygdala reactivity. Mol. Psychiatry 10 (884–8), 805. Canli, T., Congdon, E., Gutknecht, L., Constable, R.T., Lesch, K.P., 2005. Amygdala responsiveness is modulated by tryptophan hydroxylase-2 gene variation. J. Neural Transm. 112, 1479–1485. Canli, T., Congdon, E., Todd Constable, R., Lesch, K.P., 2008. Additive effects of serotonin transporter and tryptophan hydroxylase-2 gene variation on neural correlates of affective processing. Biol. Psychol. 79, 118–125. Chen, X., Levine, L., Kwok, P.Y., 1999. Fluorescence polarization in homogeneous nucleic acid analysis. Genome Res. 9, 492–498. Chen, G.L., Vallender, E.J., Miller, G.M., 2008. Functional characterization of the human TPH2 5′ regulatory region: untranslated region and polymorphisms modulate gene expression in vitro. Hum. Genet. 122, 645–657. Cloninger, C.R., 1987. A systematic method for clinical description and classification of personality variants. A proposal. Arch. Gen. Psychiatry 44, 573–588. Cloninger, C.R., Svrakic, D.M., Przybeck, T.R., 1993. A psychobiological model of temperament and character. Arch. Gen. Psychiatry 50, 975–990. Coon, H., Dunn, D., Lainhart, J., Miller, J., Hamil, C., Battaglia, A., Tancredi, R., Leppert, M.F., Weiss, R., McMahon, W., 2005. Possible association between autism and variants in the brain-expressed tryptophan hydroxylase gene (TPH2). Am. J. Med. Genet. B Neuropsychiatr. Genet. 135B, 42–46. Cote, F., Thevenot, E., Fligny, C., Fromes, Y., Darmon, M., Ripoche, M.A., Bayard, E., Hanoun, N., Saurini, F., Lechat, P., Dandolo, L., Hamon, M., Mallet, J., Vodjdani, G., 2003. Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function. Proc. Natl. Acad. Sci. USA 100, 13525–13530.
56
BR A IN RE S EA RCH 1 3 31 ( 20 1 0 ) 5 1 –57
Cowley, D.S., Roy-Byrne, P.P., Greenblatt, D.J., Hommer, D.W., 1993. Personality and benzodiazepine sensitivity in anxious patients and control subjects. Psychiatry Res. 47, 151–162. Farmer, R.F., Seeley, J.R., 2009. Temperament and character predictors of depressed mood over a 4-year interval. Depress. Anxiety 26, 371–381. Farmer, A., Mahmood, A., Redman, K., Harris, T., Sadler, S., McGuffin, P., 2003. A sib-pair study of the Temperament and Character Inventory scales in major depression. Arch. Gen. Psychiatry 60, 490–496. First, M.B., Spitzer, R.L., Gibbon, M., Williams, J.B.W., 1997. Structured Clinical Interview for DSM-IV Axis I Disorders: Nonpatient Edition. Biometrics Research Department. New York State Psychiatric Institute, New York. Japanese translation: Kitamura, T., Okano, T., 2003. Tokyo: Nihon Hyoron-sha publishers. Freedman, L.J., Shi, C., 2001. Monoaminergic innervation of the macaque extended amygdala. Neuroscience 104, 1067–1084. Geuze, E., Vermetten, E., Bremner, J.D., 2005. MR-based in vivo hippocampal volumetrics: 2. Findings in neuropsychiatric disorders. Mol. Psychiatry 10, 160–184. Goertzel, B.N., Pennachin, C., de Souza Coelho, L., Gurbaxani, B., Maloney, E.M., Jones, J.F., 2006. Combinations of single nucleotide polymorphisms in neuroendocrine effector and receptor genes predict chronic fatigue syndrome. Pharmacogenomics 7, 475–483. Good, C.D., Johnsrude, I., Ashburner, J., Henson, R.N., Friston, K.J., Frackowiak, R.S., 2001. Cerebral asymmetry and the effects of sex and handedness on brain structure: a voxel-based morphometric analysis of 465 normal adult human brains. Neuroimage 14, 685–700. Gould, E., 1999. Serotonin and hippocampal neurogenesis. Neuropsychopharmacology 21, 46S–51S. Gutknecht, L., Jacob, C., Strobel, A., Kriegebaum, C., Muller, J., Zeng, Y., Markert, C., Escher, A., Wendland, J., Reif, A., Mossner, R., Gross, C., Brocke, B., Lesch, K.P., 2007. Tryptophan hydroxylase-2 gene variation influences personality traits and disorders related to emotional dysregulation. Int. J. Neuropsychopharmacol. 10, 309–320. Gutknecht, L., Kriegebaum, C., Waider, J., Schmitt, A., Lesch, K.P., 2009. Spatio-temporal expression of tryptophan hydroxylase isoforms in murine and human brain: convergent data from Tph2 knockout mice. Eur. Neuropsychopharmacol. 19, 266–282. Hansenne, M., Pitchot, W., Gonzalez Moreno, A., Machurot, P.Y., Ansseau, M., 1998. The Tridimensional Personality Questionnaire (TPQ) and depression. Eur. Psychiatry 13, 101–103. Hansenne, M., Reggers, J., Pinto, E., Kjiri, K., Ajamier, A., Ansseau, M., 1999. Temperament and Character Inventory (TCI) and depression. J. Psychiatr. Res. 33, 31–36. Harvey, M., Shink, E., Tremblay, M., Gagne, B., Raymond, C., Labbe, M., Walther, D.J., Bader, M., Barden, N., 2004. Support for the involvement of TPH2 gene in affective disorders. Mol. Psychiatry 9, 980–981. Herrmann, M.J., Huter, T., Muller, F., Muhlberger, A., Pauli, P., Reif, A., Renner, T., Canli, T., Fallgatter, A.J., Lesch, K.P., 2007. Additive effects of serotonin transporter and tryptophan hydroxylase-2 gene variation on emotional processing. Cereb. Cortex 17, 1160–1163. Hollingshead, A.d.B., 1957. Two Factor Index of Social Position. Yale University, Dept. of Sociology, New Haven, Conn. Honea, R., Crow, T.J., Passingham, D., Mackay, C.E., 2005. Regional deficits in brain volume in schizophrenia: a meta-analysis of voxel-based morphometry studies. Am. J. Psychiatry 162, 2233–2245. Jollant, F., Buresi, C., Guillaume, S., Jaussent, I., Bellivier, F., Leboyer, M., Castelnau, D., Malafosse, A., Courtet, P., 2007. The influence of four serotonin-related genes on decision-making in suicide attempters. Am. J. Med. Genet. B Neuropsychiatr. Genet. 144B, 615–624.
Kasai, K., Yamasue, H., Gilbertson, M.W., Shenton, M.E., Rauch, S.L., Pitman, R.K., 2008. Evidence for acquired pregenual anterior cingulate gray matter loss from a twin study of combat-related posttraumatic stress disorder. Biol. Psychiatry 63, 550–556. Ke, L., Qi, Z.Y., Ping, Y., Ren, C.Y., 2006. Effect of SNP at position 40237 in exon 7 of the TPH2 gene on susceptibility to suicide. Brain Res. 1122, 24–26. Kijima, N., Tanaka, E., Suzuki, N., Higuchi, H., Kitamura, T., 2000. Reliability and validity of the Japanese version of the Temperament and Character Inventory. Psychol. Rep. 86, 1050–1058. Lauder, J.M., 1993. Neurotransmitters as growth regulatory signals: role of receptors and second messengers. Trends Neurosci. 16, 233–240. Lipton, J.W., Tolod, E.G., Thompson, V.B., Pei, L., Paumier, K.L., Terpstra, B.T., Lynch, K.A., Collier, T.J., Sortwell, C.E., 2008. 3,4-Methylenedioxy-N-methamphetamine (ecstasy) promotes the survival of fetal dopamine neurons in culture. Neuropharmacology 55, 851–859. Lopez de Lara, C., Brezo, J., Rouleau, G., Lesage, A., Dumont, M., Alda, M., Benkelfat, C., Turecki, G., 2007. Effect of tryptophan hydroxylase-2 gene variants on suicide risk in major depression. Biol. Psychiatry 62, 72–80. Lopez, V.A., Detera-Wadleigh, S., Cardona, I., Kassem, L., McMahon, F.J., 2007. Nested association between genetic variation in tryptophan hydroxylase II, bipolar affective disorder, and suicide attempts. Biol. Psychiatry 61, 181–186. Maron, E., Toru, I., Must, A., Tasa, G., Toover, E., Vasar, V., Lang, A., Shlik, J., 2007. Association study of tryptophan hydroxylase 2 gene polymorphisms in panic disorder. Neurosci. Lett. 411, 180–184. Monkul, E.S., Hatch, J.P., Nicoletti, M.A., Spence, S., Brambilla, P., Lacerda, A.L., Sassi, R.B., Mallinger, A.G., Keshavan, M.S., Soares, J.C., 2007. Fronto-limbic brain structures in suicidal and non-suicidal female patients with major depressive disorder. Mol. Psychiatry 12, 360–366. Mossner, R., Walitza, S., Geller, F., Scherag, A., Gutknecht, L., Jacob, C., Bogusch, L., Remschmidt, H., Simons, M., Herpertz-Dahlmann, B., Fleischhaker, C., Schulz, E., Warnke, A., Hinney, A., Wewetzer, C., Lesch, K.P., 2006. Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in children and adolescents with obsessive-compulsive disorder. Int. J. Neuropsychopharmacol. 9, 437–442. Mossner, R., Muller-Vahl, K.R., Doring, N., Stuhrmann, M., 2007. Role of the novel tryptophan hydroxylase-2 gene in Tourette syndrome. Mol. Psychiatry 12, 617–619. Mulder, R.T., Joyce, P.R., Cloninger, C.R., 1994. Temperament and early environment influence comorbidity and personality disorders in major depression. Compr. Psychiatry 35, 225–233. Naito, M., Kijima, N., Kitamura, T., 2000. Temperament and Character Inventory (TCI) as predictors of depression among Japanese college students. J. Clin. Psychol. 56, 1579–1585. Oldfield, R.C., 1971. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9, 97–113. Ongur, D., Farabaugh, A., Iosifescu, D.V., Perlis, R., Fava, M., 2005. Tridimensional personality questionnaire factors in major depressive disorder: relationship to anxiety disorder comorbidity and age of onset. Psychother. Psychosom. 74, 173–178. Parent, A., Descarries, L., Beaudet, A., 1981. Organization of ascending serotonin systems in the adult rat brain. A radioautographic study after intraventricular administration of [3H]5-hydroxytryptamine. Neuroscience 6, 115–138. Reuter, M., Kuepper, Y., Hennig, J., 2007. Association between a polymorphism in the promoter region of the TPH2 gene and the personality trait of harm avoidance. Int. J. Neuropsychopharmacol. 10, 401–404. Richman, H., Frueh, B.C., 1997. Personality and PTSD II: personality assessment of PTSD-diagnosed Vietnam veterans using the
BR A IN RE S E A RCH 1 3 31 ( 20 1 0 ) 5 1 –5 7
cloninger tridimensional personality questionnaire (TPQ). Depress. Anxiety 6, 70–77. Richter, J., Eisemann, M., Richter, G., 2000. Temperament and character during the course of unipolar depression among inpatients. Eur. Arch. Psychiatry Clin. Neurosci. 250, 40–47. Rogers, M., Yamasue, H., Abe, O., Yamada, H., Ohtani, T., Iwanami, A., Aoki, S., Kato, N., Kasai, K., 2009. Smaller amygdalae volume and reduced anterior cingulate gray matter density associated with history of PTSD. Psychiatry Res. Neuroimaging 174, 210–216. Ruchkin, V.V., Eisemann, M., Hagglof, B., 1998. Juvenile male rape victims: is the level of post-traumatic stress related to personality and parenting? Child Abuse Negl. 22, 889–899. Saviotti, F.M., Grandi, S., Savron, G., Ermentini, R., Bartolucci, G., Conti, S., Fava, G.A., 1991. Characterological traits of recovered patients with panic disorder and agoraphobia. J. Affect. Disord. 23, 113–117. Scheuch, K., Lautenschlager, M., Grohmann, M., Stahlberg, S., Kirchheiner, J., Zill, P., Heinz, A., Walther, D.J., Priller, J., 2007. Characterization of a functional promoter polymorphism of the human tryptophan hydroxylase 2 gene in serotonergic raphe neurons. Biol. Psychiatry 62, 1288–1294. Sheehan, K., Lowe, N., Kirley, A., Mullins, C., Fitzgerald, M., Gill, M., Hawi, Z., 2005. Tryptophan hydroxylase 2 (TPH2) gene variants associated with ADHD. Mol. Psychiatry 10, 944–949. Smith, A.K., White, P.D., Aslakson, E., Vollmer-Conna, U., Rajeevan, M.S., 2006. Polymorphisms in genes regulating the HPA axis associated with empirically delineated classes of unexplained chronic fatigue. Pharmacogenomics 7, 387–394. Strakowski, S.M., Adler, C.M., DelBello, M.P., 2002. Volumetric MRI studies of mood disorders: do they distinguish unipolar and bipolar disorder? Bipolar Disord. 4, 80–88. Van Den Bogaert, A., Sleegers, K., De Zutter, S., Heyrman, L., Norrback, K.F., Adolfsson, R., Van Broeckhoven, C., Del-Favero, J., 2006. Association of brain-specific tryptophan hydroxylase, TPH2, with unipolar and bipolar disorder in a Northern Swedish, isolated population. Arch. Gen. Psychiatry 63, 1103–1110. Walitza, S., Renner, T.J., Dempfle, A., Konrad, K., Wewetzer, C., Halbach, A., Herpertz-Dahlmann, B., Remschmidt, H., Smidt, J., Linder, M., Flierl, L., Knolker, U., Friedel, S., Schafer, H., Gross, C., Hebebrand, J., Warnke, A., Lesch, K.P., 2005. Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder. Mol. Psychiatry 10, 1126–1132. Walther, D.J., Bader, M., 2003. A unique central tryptophan hydroxylase isoform. Biochem. Pharmacol. 66, 1673–1680. Walther, D.J., Peter, J.U., Bashammakh, S., Hortnagl, H., Voits, M.,
57
Fink, H., Bader, M., 2003. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 299, 76. Yamasue, H., Kasai, K., Iwanami, A., Ohtani, T., Yamada, H., Abe, O., Kuroki, N., Fukuda, R., Tochigi, M., Furukawa, S., Sadamatsu, M., Sasaki, T., Aoki, S., Ohtomo, K., Asukai, N., Kato, N., 2003. Voxel-based analysis of MRI reveals anterior cingulate gray-matter volume reduction in posttraumatic stress disorder due to terrorism. Proc. Natl. Acad. Sci. USA 100, 9039–9043. Yamasue, H., Iwanami, A., Hirayasu, Y., Yamada, H., Abe, O., Kuroki, N., Fukuda, R., Tsujii, K., Aoki, S., Ohtomo, K., Kato, N., Kasai, K., 2004. Localized volume reduction in prefrontal, temporolimbic, and paralimbic regions in schizophrenia: an MRI parcellation study. Psychiatry Res. 131, 195–207. Yamasue, H., Abe, O., Suga, M., Yamada, H., Inoue, H., Tochigi, M., Rogers, M., Aoki, S., Kato, N., Kasai, K., 2008a. Gender-common and -specific neuroanatomical basis of human anxiety-related personality traits. Cereb. Cortex 18, 46–52. Yamasue, H., Kakiuchi, C., Tochigi, M., Inoue, H., Suga, M., Abe, O., Yamada, H., Sasaki, T., Rogers, M.A., Aoki, S., Kato, T., Kasai, K., 2008b. Association between mitochondrial DNA 10398A>G polymorphism and the volume of amygdala. Genes Brain Behav. 7, 698–704. Yoon, H.K., Kim, Y.K., 2009. TPH2 -703G/T SNP may have important effect on susceptibility to suicidal behavior in major depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 33, 403–409. Zhang, X., Beaulieu, J.M., Sotnikova, T.D., Gainetdinov, R.R., Caron, M.G., 2004. Tryptophan hydroxylase-2 controls brain serotonin synthesis. Science 305, 217. Zhang, X., Gainetdinov, R.R., Beaulieu, J.M., Sotnikova, T.D., Burch, L.H., Williams, R.B., Schwartz, D.A., Krishnan, K.R., Caron, M.G., 2005. Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 45, 11–16. Zhou, Z., Peters, E.J., Hamilton, S.P., McMahon, F., Thomas, C., McGrath, P.J., Rush, J., Trivedi, M.H., Charney, D.S., Roy, A., Wisniewski, S., Lipsky, R., Goldman, D., 2005. Response to Zhang et al. (2005): loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 45, 11–16 (Neuron. 48, 702-3; author reply 705-6). Zill, P., Buttner, A., Eisenmenger, W., Bondy, B., Ackenheil, M., 2004a. Regional mRNA expression of a second tryptophan hydroxylase isoform in postmortem tissue samples of two human brains. Eur. Neuropsychopharmacol. 14, 282–284. Zill, P., Buttner, A., Eisenmenger, W., Moller, H.J., Bondy, B., Ackenheil, M., 2004b. Single nucleotide polymorphism and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene in suicide victims. Biol. Psychiatry 56, 581–586.
available at www.sciencedirect.com
www.elsevier.com/locate/brainres
Research Report
Effect of tryptophan hydroxylase-2 gene variants on amygdalar and hippocampal volumes Hideyuki Inoue a,⁎, Hidenori Yamasue a,b , Mamoru Tochigi a , Kunio Takei c , Motomu Suga a , Osamu Abe d , Haruyasu Yamada d , Mark A. Rogers a,e , Shigeki Aoki d , Tsukasa Sasaki c , Kiyoto Kasai a a
Department of Neuropsychiatry, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan Japan Science and Technology Agency, CREST, 5 Sanbancho, Chiyoda-ku, Tokyo, 102-0075, Japan c Health Service Center, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan d Department of Radiology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan e School of Psychology, Deakin University, Burwood, Victoria 3152, Australia b
A R T I C LE I N FO
AB S T R A C T
Article history:
Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin
Accepted 15 March 2010
(5-HT). Genetic variations in human TPH2, a newly identified isoform of TPH, have been
Available online 21 March 2010
shown to impact on enzymatic activity of TPH and to be associated with emotion-related personality traits and mood/anxiety disorders. Identification of an intermediate phenotype
Keywords:
that bridges the relationship between genes and behavior may be of great importance in the
Tryptophan hydroxylase 2 (TPH2)
further clarification of how hTPH2 contributes to emotional regulation. Previous studies
Amygdala
have shown that a polymorphism in the upstream regulatory region of hTPH2 (SNP G-703T,
Hippocampus
rs4570625) correlates functional MRI response of the amygdala. In this study, we examined
Endophenotype
the effect of this genotype on amygdalar and hippocampal volumes in 208 mentally healthy
Manual tracing
individuals. To measure volumes of amygdala and hippocampus, gray matter regions of
Temperament and Character
interest were outlined manually on three-dimensional MRI data obtained using a 1.5-T
Inventory (TCI)
scanner. Additionally, personality traits were evaluated using the Temperament and Character Inventory (TCI). Those subjects with T allele carriers were associated with significantly smaller volumes in bilateral amygdala and hippocampus and higher reward dependence than those with G allele homozygotes. These results suggest that amygdalar and hippocampal volumes assessed using MRI may be a useful intermediate phenotype that will uncover the biological pathway linking 5-HT synthesis and emotional behaviors and affective disorders. © 2010 Elsevier B.V. All rights reserved.
1.
Introduction
Serotonin (5-hydroxytryptamine or 5-HT) is a widespread neurotransmitter in the central nervous system. 5-HT neurons are mainly found in different raphe nuclei, from which they
project to numerous brain regions regulating mood and affect such as cortical areas, limbic system including amygdala and hippocampus, and basal ganglia (Freedman and Shi, 2001; Parent et al., 1981). 5-HT signaling is an important regulator of early central nervous system development (Lauder, 1993) and
⁎ Corresponding author. Fax: +81 3 5800 6894. E-mail address: [email protected] (H. Inoue). 0006-8993/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2010.03.057
52
BR A IN RE S EA RCH 1 3 31 ( 20 1 0 ) 5 1 –57
of adult neurogenesis (Gould, 1999). 5-HT is involved in many brain functions and neuropsychiatric disorders, and pharmaceuticals targeting the 5-HT system are widely used for the treatment of various psychiatric disorders. The first and rate-limiting enzyme in 5-HT biosynthesis is tryptophan hydroxylase (TPH). It had been thought that TPH was derived from a single gene (now referred to as TPH1) until a second TPH isoform (TPH2) was recently described (Cote et al., 2003; Walther and Bader, 2003; Walther et al., 2003). While TPH1 is primarily expressed in the periphery, TPH2 is predominantly expressed in the brain and exclusively maintains brain 5-HT synthesis across the lifespan (Cote et al., 2003; Gutknecht et al., 2009; Walther et al., 2003; Zhang et al., 2004; Zill et al., 2004a). Furthermore, a relatively rare single nucleotide polymorphism in human TPH2 (hTPH2) has been shown to alter TPH enzymatic efficiency in vitro (Zhang et al., 2005). The association of hTPH2 genetic variation with behavioral phenotypes including neuropsychiatric disorders and personality traits has been investigated. Specific polymorphisms in hTPH2 have been reported to have an association with major depression (Van Den Bogaert et al., 2006; Zhang et al., 2005; Zhou et al., 2005; Zill et al., 2004b), affective disorders (Harvey et al., 2004; Lopez et al., 2007), suicidality (Jollant et al., 2007; Ke et al., 2006; Lopez de Lara et al., 2007; Lopez et al., 2007; Van Den Bogaert et al., 2006; Yoon and Kim, 2009; Zill et al., 2004b), autism (Coon et al., 2005), early onset obsessive-compulsive disorder (Mossner et al., 2006), attention deficit hyperactivity disorder (Sheehan et al., 2005; Walitza et al., 2005), panic disorder (Maron et al., 2007), chronic fatigue syndrome (Goertzel et al., 2006; Smith et al., 2006), and Tourette's syndrome (Mossner et al., 2007). Additionally, previous studies have suggested that TPH2 is associated with personality traits related to emotional instability (Gutknecht et al., 2007; Lopez de Lara et al., 2007) and with risk for cluster B and cluster C personality disorders (Gutknecht et al., 2007). To further clarify the biological pathways underpinning individual differences in emotional behaviors and risk for psychiatric conditions, including anxiety and depression, the identification of an intermediate phenotype for hTPH2 variations is of great importance. In terms of a functional intermediate phenotype, Brown and colleagues reported that T allele carriers of the hTPH2 rs4570625 variant were associated with greater functional magnetic resonance imaging (fMRI) amygdala response while viewing angry or fearful faces than were G/G individuals (Brown et al., 2005). Canli and colleagues replicated the findings by Brown et al. (2005); they reported that T carriers had greater fMRI signal increase in response to faces with both positive or negative valence than G/G individuals (Canli et al., 2005). To our knowledge, however, no studies have investigated an association between hTPH2 variation and brain structural intermediate phenotype. Accordingly, the aim of this study was to investigate the effect of hTPH2 rs4570625 polymorphism on regional brain volume as assessed by structural MRI and personality traits in mentally healthy individuals. Since reduced volume of amygdala and hippocampus has been reported in emotion-related psychiatric disorders including major depression, posttraumatic stress disorder, and suicidality (Geuze et al., 2005; Honea et al., 2005; Kasai et al., 2008; Monkul et al., 2007; Rogers et al., 2009; Strakowski et al., 2002), we predicted that T
allele carriers would be associated with smaller volumes in these regions than G/G homozygotes. We also predicted that this polymorphism would affect personality traits that were evaluated using the Temperament and Character Inventory (TCI) (Cloninger, 1987; Cloninger et al., 1993), especially in harm avoidance (HA) and reward dependence (RD) as HA temperament dimension is frequently and positively associated with mood and anxiety disorders (Ampollini et al., 1999; Bayon et al., 1996; Brown et al., 1992; Cowley et al., 1993; Farmer et al., 2003; Farmer and Seeley, 2009; Hansenne et al., 1998, 1999; Mulder et al., 1994; Naito et al., 2000; Ongur et al., 2005; Richman and Frueh, 1997; Richter et al., 2000; Ruchkin et al., 1998; Saviotti et al., 1991) and with small hippocampal volume (Yamasue et al., 2008a), and RD is also associated with mood and anxiety disorders (Ampollini et al., 1999; Farmer and Seeley, 2009; Ongur et al., 2005; Richman and Frueh, 1997; Ruchkin et al., 1998).
2.
Results
The genotypic distributions of the three genotypes in the TPH2 genes are as follows: G/G 53 (25.5%), G/T 106 (51.0%), T/T 49 (23.6%). The distributions of the three TPH2 genotypes were not significantly different from those expected according to the Hardy–Weinberg equilibrium. The three genotypes in the TPH2 gene were classified into two genotype subgroups according to the previous study (Brown et al., 2005): the genotypes with the T allele (here termed ‘T carriers’) versus the G/G genotype (here termed ‘G/G individuals’). No significant difference was observed in gender, age, handedness, self-socioeconomic status (SES), or parental SES between the two genotype groups (Table 1). Total gray matter, total white matter, cerebrospinal fluid (CSF), and intracranial volume (ICV) volume also did not differ significantly between the two genotype groups (p > 0.29). For the genotype effects on amygdalar and hippocampal volumes, the repeated-measures ANOVA showed that there was a significant main effect of the hTPH2 genotype (F[1,206] = 5.17 p = 0.024). There was no significant interaction between genotype and region (F[1,206] = 0.026, p = 0.87), genotype and hemisphere (F[1,206] = 0.70, p = 0.41), or genotype and region and hemisphere (F[1,206] = 1.67, p = 0.20). The statistical conclusion from the main ANOVA is that subjects with T allele carriers have significantly smaller ROI volumes without either significant laterality or regional specificity among bilateral amygdala and hippocampus than those with homozygous G alleles (Fig. 1). There were no significant interactions between gender and genotype (F[1, 204] = 0.94, p = 0.33), gender and genotype and region (F[1, 204] = 0.27, p = 0.60), gender and genotype and hemisphere (F[1, 204] = 0.46, p = 0.50), or gender and genotype and region and hemisphere (F[1, 204] = 0.18, p = 0.67). Percentage changes and effect sizes of the difference in brain volume between genotypes are described in Table 2. Furthermore, subjects with T allele carriers showed significantly higher scores on reward dependence than those with G/G homozygotes (t[190]= −2.39, p = 0.018) (Table 1). Additionally, genotype effects were re-investigated after excluding outlying data (a single subject with outlying bilateral hippocampal volumes) and the main effect of the hTPH2 genotype did not alter (F[1,205]= 4.91, p = 0.028).
53
BR A IN RE S E A RCH 1 3 31 ( 20 1 0 ) 5 1 –5 7
Table 1 – Clinical and demographic characteristics of the study participants. G/G (n = 53)
T carriers (n = 155)
Mean
SD
Mean
SD
Sex (male/female) Age (range) Socioeconomic status a Parental Socioeconomic status
32 /21 33.5 (21–65) 1.7 2.3
11.1 0.7 0.7
111 /44 33.4 (21–71) 1.6 2.2
11.8 0.6 0.8
Temperament and Character Inventory Harm avoidance Novelty seeking Reward dependence Persistence Self directedness Cooperativeness Self-transcendence
18.1 20.9 14.5 4.6 29.6 28.5 9.4
a b
3.
6.3 5.7 3.8 1.7 5.7 4.7 4.7
16.4 21.4 15.8 4.9 31.0 29.8 9.5
6.7 5.4 3.2 1.7 6.6 5.1 5.3
Group Comparison
Chi-square [1] = 2.32, p = 0.13 t[206] = − 0.23, p = 0.82 t[206] = 1.10, p = 0.27 t[201 b] = 0.49, p = 0.62
t[190 b]=1.57, p = 0.12 t[190 b] = −0.58, p = 0.57 t[190 b] = − 2.39, p = 0.018 t[190 b] = −0.82, p = 0.42 t[190 b] = −1.31, p = 0.19 t[190 b] = −1.58, p = 0.12 t[190 b] = −0.13, p = 0.89
Assessed using the Hollingshead scale (Hollingshead, 1957). Higher scores indicate lower educational and/or occupational status. The degrees of freedom varied due to unavailability of data in some subjects.
Discussion
The T allele carriers were associated with significantly smaller bilateral amygdalar and hippocampal volume and higher reward dependence than G allele homozygotes. These findings suggest that amygdalar and hippocampal volume as assessed by MRI morphometry may be a useful intermediate phenotype for investigating how serotonin synthesis impacts on emotional behavior and affective disorders. Associations have been reported between variations in rs4570625 and a number of behavioral phenotypes including ADHD (Walitza et al., 2005), disorders related to emotional dysregulation (Gutknecht et al., 2007; Reuter et al., 2007), suicidal behavior in major depression (Yoon and Kim, 2009), and personality traits (Gutknecht et al., 2007). Reported intermediate phenotypes include fMRI BOLD signal changes in the amygdala in response to viewing emotional faces (Brown et al., 2005; Canli et al., 2005) and event-related potentials (Lipton et al., 2008) during a passive emotional picture perception task (Herrmann et al., 2007). The current study extends the previous findings by adding evidence of an
association between hTPH2 variations and limbic system structure. We detected a significant association between hTPH2 genotypes and reward dependence, but not harm avoidance, despite our prior prediction. These findings may illustrate a weak association between genes and personality traits and emphasize the importance of utilizing an intermediate phenotype such as neuroimaging index to clarify complex biological pathway linking genes and behavior. It is controversial how rs4570625 influence hTPH2 expression. Chen and colleagues reported that common polymorphisms including rs4570625 had a significant impact on hTPH2 expression in vitro (Chen et al., 2008). Meanwhile, Scheuch and colleagues reported that not rs4570625 itself, but a different SNP (rs11178997) within the haplotype block, might contribute to change in promoter activity of hPTH2 in vitro (Scheuch et al., 2007). We need to comment upon methodological considerations of our study. First, we investigated only one SNP, which can only provide a partial insight into the genetic basis of brain structures at best. Multiple different genes or neurotransmitter systems have been implicated in brain morphology.
Fig. 1 – Manually traced amygdalar and hippocampal volumes and TPH2 genotype. Means and distributions of left and right hemispheres for relative manually traced amygdalar and hippocampal volumes (absolute volume × 100/intracranial content) in which individuals with TPH2 G allele homozygotes exhibited bilateral enlargement compared with individuals with TPH2 T allele carriers (F[1,206] = 5.17, p = 0.024). Means are represented by solid horizontal lines drawn on each group's distribution.
54
BR A IN RE S EA RCH 1 3 31 ( 20 1 0 ) 5 1 –57
Table 2 – Brain volume a and TPH2 polymorphism. G/G (n = 53) Mean Volumetric Measures (ml) Total gray matter Total white matter Cerebrospinal fluid Intracranial volume Amygdala Absolute volume (ml) Relative volume (%) d
Hippocampus Absolute volume (ml) Relative volume (%) d
731.4 446.8 372.3 1550.6
T Carriers (n = 155) SD
80.0 43.6 70.0 159.9
Mean 742.3 452.5 381.9 1576.8
% Difference b
Effect Size c
− 1.47 − 1.26 − 2.51 − 1.66
−0.15 −0.12 −0.14 −0.17
SD 71.1 51.0 65.8 153.3
Left Right Left Right
1.456 1.504 0.094 0.097
0.309 0.331 0.018 0.020
1.376 1.416 0.087 0.090
0.263 0.282 0.016 0.017
5.85 6.20 7.45 7.80
0.19 0.07 0.32 0.19
Left Right Left Right
2.673 2.657 0.173 0.172
0.408 0.399 0.025 0.024
2.596 2.626 0.165 0.167
0.394 0.436 0.024 0.026
2.96 1.17 4.69 2.87
0.29 0.30 0.40 0.39
a
Total gray and white matter, cerebrospinal fluid, and intracranial content were measured using voxel-based morphometry. Hippocampal and amygdala volume were measured using a manual tracing method. b %Difference = (difference score for mean [G/G subjects] relative to mean [T carriers])/mean [T carriers]: the bilateral amygdala and hippocampus volumes were larger in subjects with G/G genotype than in subjects with T allele carriers. c Effect size = (difference score for mean [G/G subjects] relative to mean [T carriers])/pooled SD [all subjects]. d Relative volume = Absolute volume/intracranial content × 100.
Recently, an additive effect between TPH2 and 5-HTT on brain functions has been observed using ERP (Herrmann et al., 2007) and fMRI (Canli et al., 2008). Ideally, association studies should aim to look at possible interactions among multiple genes or multiple polymorphisms. Second, we focused on limbic structures because of the evidence that these regions are a key modulator of mood and affect. However, in future studies, the possibility of genetic impact on other brain regions such as pre- and sub-genual cingulate cortex should be explored. Fourth, the present results should be interpreted cautiously. The currently observed genotype effect on regional brain volumes was weak but significant, since the effect sizes of genotype effects were smaller than those of gender effects (female > male) (data not shown). In conclusion, to our knowledge, this is the first report that genetic variants of the hTPH2 gene affect brain morphology. Further studies are needed to replicate the observed association and to demonstrate that rs4570625 is indeed in the transcriptional control region.
4.
Experimental procedures
4.1.
Subjects
major mental illness. Other exclusion criteria were neurological illness, traumatic brain injury with any known cognitive consequences or loss of consciousness for more than 5 min, a history of substance abuse or addiction, or a family history of an axis I disorder in their first-degree relatives. All were righthanded based on the Edinburgh Inventory (Oldfield, 1971). The socioeconomic status (SES) and parental SES were assessed using the Hollingshead scale (Hollingshead, 1957). After a thorough explanation of the study to the subjects, written informed consent was obtained. The ethical committee of the Faculty of Medicine, University of Tokyo, approved this study (No. 397-1 for MRI project and No. 639-9 for genetic and imaging–genetic association project).
4.2.
A valid Japanese translation (Kijima et al., 2000) of TCI (Cloninger, 1987; Cloninger et al., 1993) was used for measuring the personality trait. Participants completed a 240-item TCI questionnaire within 3 months before or after MR scan. In this study, we focused on the HA and RD subscales of the TCI.
4.3.
The subjects were 208 (143 men and 65 women) Japanese adults (age, mean ± SD: 33.9 ± 11.6 years old), consisting of college students, hospital staff, and their acquaintances. Before MRI scanning, the subjects were screened using the Structured Clinical Interview for DSM-IV Axis I Disorder, Nonpatient Edition (SCID-NP) (First et al., 1997; Japanese version, Kitamura and Okano, 2003) by a trained psychiatrist (H.Y. or M.S.), to confirm that the subjects had no history of
Personality assessment
MRI acquisition
The method of MRI acquisition of 1.5 mm slices was the same as that described in our previous study (Yamasue et al., 2003). The MRI data were obtained using a 1.5-T scanner (General Electric Signa Horizon Lx version 8.2, GE Medical Systems, Milwaukee, WI, USA). We used three-dimensional Fouriertransform spoiled-gradient-recalled acquisition with steady state. The repetition time was 35 ms, the echo time 7 ms with one repetition, the nutation angle 30°, the field of view 24 cm, and the matrix 256 × 256 (192) × 124.
BR A IN RE S E A RCH 1 3 31 ( 20 1 0 ) 5 1 –5 7
4.4. Manual tracing for amygdala and hippocampus volumetry The amygdala and hippocampus gray matter regions of interest (ROIs) were outlined manually by one rater (H.I.) who was blind to the group status or genotype. For the manual tracing, we used a software package for medical image analysis (3D Slicer; software available at http://www.slicer. org), which enables a simultaneous view of orthogonal planes. The landmarks to delineate the ROIs were the same as those of our previous study (Yamasue et al., 2008b). For interrater reliability, two raters (H.I. and M.A.R.) blind to group membership, independently drew ROIs. Ten cases were selected at random, and the raters drew ROIs on every slice. The intraclass correlation coefficient was 0.87/0.85 for the left/ right amygdala and 0.93/0.94 for the left/right hippocampus, respectively. Intrarater reliability, computed by using all of the slices from one randomly selected brain and measured by one rater (H.I.) on two separate occasions (approximately 2 months apart), was >0.95 for all structures. Total gray matter, white matter, and cerebrospinal fluid volumes were calculated using SPM2 (Good et al., 2001). Then ICV was calculated by summing up the total gray matter, white matter, and cerebrospinal fluid volumes. To validate this method, the ICVs of an independent sample of MRI scans for 50 adult subjects were measured by both the current procedure and intensity-based semiautomated segmentation procedure using ANALYZE PC 3.0 (Yamasue et al., 2004). Then we confirmed that the calculated intraclass correlation coefficient for the ICVs was satisfactory (0.96).
4.5.
Genotyping
Genomic DNA was extracted from peripheral leukocytes using a standard phenol-chloroform method. DNA was isolated and amplified from blood samples obtained from all subjects. The hTPH2 G(-844)T promoter single nucleotide polymorphism (GenBank accession number NT_029419, dbSNP accession number rs4570625) was genotyped using fluorescence polarization (Chen et al., 1999). This study was performed in ethnically homogeneous samples (only of Japanese descent).
4.6.
Statistical analyses
The effects of the TPH2 genotype on the manually traced volumes were assessed by repeated-measures analysis of variance (ANOVA) adopting relative volumes [100× absolute ROI volume / (ICV)] as the dependent variable, genotype as the between-subject factor, and region (amygdala/hippocampus) and hemisphere (left/right) as the within-subject factors. To determine whether the findings are due to gender differences or if they really are the results of a gene-specific effect, we further conducted a repeated-measures ANOVA where gender was added as a between-subject factor as well as genotype, region and hemisphere as the within-subject factors. A statistically significant level was set at p < 0.05. For testing regional specificity, the volumes of total gray matter, total white matter, CSF, and ICV were also compared between genotypes using independent t-tests. Supplementarily, effect size and % difference were used to assess the effects of the TPH2 genotype on the
55
absolute and relative volumes of each region. To examine the statistical effects of TPH2 and personality as measured by TCI scores, we used independent t-tests. A statistically significant level was set at p < 0.05.
Acknowledgment This study was supported in part by grants-in-aid for scientific research (No. 18019009 to K.K., No. 17-5234 to M.A.R.) from the Japan Society for the Promotion of Science and the Ministry of Education, Culture, Sports, Science and Technology, Japan, by grants-in-aid (H17-Kokoro-Ippan 009 to K.K.) from the Ministry of Health, Labor and Welfare, Japan, and by Core research for Evolutional Science and Technology (CREST) of Japan Science and Technology Agency (JST).
REFERENCES
Ampollini, P., Marchesi, C., Signifredi, R., Ghinaglia, E., Scardovi, F., Codeluppi, S., Maggini, C., 1999. Temperament and personality features in patients with major depression, panic disorder and mixed conditions. J. Affect. Disord. 52, 203–207. Bayon, C., Hill, K., Svrakic, D.M., Przybeck, T.R., Cloninger, C.R., 1996. Dimensional assessment of personality in an out-patient sample: relations of the systems of Millon and Cloninger. J. Psychiatr. Res. 30, 341–352. Brown, S.L., Svrakic, D.M., Przybeck, T.R., Cloninger, C.R., 1992. The relationship of personality to mood and anxiety states: a dimensional approach. J. Psychiatr. Res. 26, 197–211. Brown, S.M., Peet, E., Manuck, S.B., Williamson, D.E., Dahl, R.E., Ferrell, R.E., Hariri, A.R., 2005. A regulatory variant of the human tryptophan hydroxylase-2 gene biases amygdala reactivity. Mol. Psychiatry 10 (884–8), 805. Canli, T., Congdon, E., Gutknecht, L., Constable, R.T., Lesch, K.P., 2005. Amygdala responsiveness is modulated by tryptophan hydroxylase-2 gene variation. J. Neural Transm. 112, 1479–1485. Canli, T., Congdon, E., Todd Constable, R., Lesch, K.P., 2008. Additive effects of serotonin transporter and tryptophan hydroxylase-2 gene variation on neural correlates of affective processing. Biol. Psychol. 79, 118–125. Chen, X., Levine, L., Kwok, P.Y., 1999. Fluorescence polarization in homogeneous nucleic acid analysis. Genome Res. 9, 492–498. Chen, G.L., Vallender, E.J., Miller, G.M., 2008. Functional characterization of the human TPH2 5′ regulatory region: untranslated region and polymorphisms modulate gene expression in vitro. Hum. Genet. 122, 645–657. Cloninger, C.R., 1987. A systematic method for clinical description and classification of personality variants. A proposal. Arch. Gen. Psychiatry 44, 573–588. Cloninger, C.R., Svrakic, D.M., Przybeck, T.R., 1993. A psychobiological model of temperament and character. Arch. Gen. Psychiatry 50, 975–990. Coon, H., Dunn, D., Lainhart, J., Miller, J., Hamil, C., Battaglia, A., Tancredi, R., Leppert, M.F., Weiss, R., McMahon, W., 2005. Possible association between autism and variants in the brain-expressed tryptophan hydroxylase gene (TPH2). Am. J. Med. Genet. B Neuropsychiatr. Genet. 135B, 42–46. Cote, F., Thevenot, E., Fligny, C., Fromes, Y., Darmon, M., Ripoche, M.A., Bayard, E., Hanoun, N., Saurini, F., Lechat, P., Dandolo, L., Hamon, M., Mallet, J., Vodjdani, G., 2003. Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function. Proc. Natl. Acad. Sci. USA 100, 13525–13530.
56
BR A IN RE S EA RCH 1 3 31 ( 20 1 0 ) 5 1 –57
Cowley, D.S., Roy-Byrne, P.P., Greenblatt, D.J., Hommer, D.W., 1993. Personality and benzodiazepine sensitivity in anxious patients and control subjects. Psychiatry Res. 47, 151–162. Farmer, R.F., Seeley, J.R., 2009. Temperament and character predictors of depressed mood over a 4-year interval. Depress. Anxiety 26, 371–381. Farmer, A., Mahmood, A., Redman, K., Harris, T., Sadler, S., McGuffin, P., 2003. A sib-pair study of the Temperament and Character Inventory scales in major depression. Arch. Gen. Psychiatry 60, 490–496. First, M.B., Spitzer, R.L., Gibbon, M., Williams, J.B.W., 1997. Structured Clinical Interview for DSM-IV Axis I Disorders: Nonpatient Edition. Biometrics Research Department. New York State Psychiatric Institute, New York. Japanese translation: Kitamura, T., Okano, T., 2003. Tokyo: Nihon Hyoron-sha publishers. Freedman, L.J., Shi, C., 2001. Monoaminergic innervation of the macaque extended amygdala. Neuroscience 104, 1067–1084. Geuze, E., Vermetten, E., Bremner, J.D., 2005. MR-based in vivo hippocampal volumetrics: 2. Findings in neuropsychiatric disorders. Mol. Psychiatry 10, 160–184. Goertzel, B.N., Pennachin, C., de Souza Coelho, L., Gurbaxani, B., Maloney, E.M., Jones, J.F., 2006. Combinations of single nucleotide polymorphisms in neuroendocrine effector and receptor genes predict chronic fatigue syndrome. Pharmacogenomics 7, 475–483. Good, C.D., Johnsrude, I., Ashburner, J., Henson, R.N., Friston, K.J., Frackowiak, R.S., 2001. Cerebral asymmetry and the effects of sex and handedness on brain structure: a voxel-based morphometric analysis of 465 normal adult human brains. Neuroimage 14, 685–700. Gould, E., 1999. Serotonin and hippocampal neurogenesis. Neuropsychopharmacology 21, 46S–51S. Gutknecht, L., Jacob, C., Strobel, A., Kriegebaum, C., Muller, J., Zeng, Y., Markert, C., Escher, A., Wendland, J., Reif, A., Mossner, R., Gross, C., Brocke, B., Lesch, K.P., 2007. Tryptophan hydroxylase-2 gene variation influences personality traits and disorders related to emotional dysregulation. Int. J. Neuropsychopharmacol. 10, 309–320. Gutknecht, L., Kriegebaum, C., Waider, J., Schmitt, A., Lesch, K.P., 2009. Spatio-temporal expression of tryptophan hydroxylase isoforms in murine and human brain: convergent data from Tph2 knockout mice. Eur. Neuropsychopharmacol. 19, 266–282. Hansenne, M., Pitchot, W., Gonzalez Moreno, A., Machurot, P.Y., Ansseau, M., 1998. The Tridimensional Personality Questionnaire (TPQ) and depression. Eur. Psychiatry 13, 101–103. Hansenne, M., Reggers, J., Pinto, E., Kjiri, K., Ajamier, A., Ansseau, M., 1999. Temperament and Character Inventory (TCI) and depression. J. Psychiatr. Res. 33, 31–36. Harvey, M., Shink, E., Tremblay, M., Gagne, B., Raymond, C., Labbe, M., Walther, D.J., Bader, M., Barden, N., 2004. Support for the involvement of TPH2 gene in affective disorders. Mol. Psychiatry 9, 980–981. Herrmann, M.J., Huter, T., Muller, F., Muhlberger, A., Pauli, P., Reif, A., Renner, T., Canli, T., Fallgatter, A.J., Lesch, K.P., 2007. Additive effects of serotonin transporter and tryptophan hydroxylase-2 gene variation on emotional processing. Cereb. Cortex 17, 1160–1163. Hollingshead, A.d.B., 1957. Two Factor Index of Social Position. Yale University, Dept. of Sociology, New Haven, Conn. Honea, R., Crow, T.J., Passingham, D., Mackay, C.E., 2005. Regional deficits in brain volume in schizophrenia: a meta-analysis of voxel-based morphometry studies. Am. J. Psychiatry 162, 2233–2245. Jollant, F., Buresi, C., Guillaume, S., Jaussent, I., Bellivier, F., Leboyer, M., Castelnau, D., Malafosse, A., Courtet, P., 2007. The influence of four serotonin-related genes on decision-making in suicide attempters. Am. J. Med. Genet. B Neuropsychiatr. Genet. 144B, 615–624.
Kasai, K., Yamasue, H., Gilbertson, M.W., Shenton, M.E., Rauch, S.L., Pitman, R.K., 2008. Evidence for acquired pregenual anterior cingulate gray matter loss from a twin study of combat-related posttraumatic stress disorder. Biol. Psychiatry 63, 550–556. Ke, L., Qi, Z.Y., Ping, Y., Ren, C.Y., 2006. Effect of SNP at position 40237 in exon 7 of the TPH2 gene on susceptibility to suicide. Brain Res. 1122, 24–26. Kijima, N., Tanaka, E., Suzuki, N., Higuchi, H., Kitamura, T., 2000. Reliability and validity of the Japanese version of the Temperament and Character Inventory. Psychol. Rep. 86, 1050–1058. Lauder, J.M., 1993. Neurotransmitters as growth regulatory signals: role of receptors and second messengers. Trends Neurosci. 16, 233–240. Lipton, J.W., Tolod, E.G., Thompson, V.B., Pei, L., Paumier, K.L., Terpstra, B.T., Lynch, K.A., Collier, T.J., Sortwell, C.E., 2008. 3,4-Methylenedioxy-N-methamphetamine (ecstasy) promotes the survival of fetal dopamine neurons in culture. Neuropharmacology 55, 851–859. Lopez de Lara, C., Brezo, J., Rouleau, G., Lesage, A., Dumont, M., Alda, M., Benkelfat, C., Turecki, G., 2007. Effect of tryptophan hydroxylase-2 gene variants on suicide risk in major depression. Biol. Psychiatry 62, 72–80. Lopez, V.A., Detera-Wadleigh, S., Cardona, I., Kassem, L., McMahon, F.J., 2007. Nested association between genetic variation in tryptophan hydroxylase II, bipolar affective disorder, and suicide attempts. Biol. Psychiatry 61, 181–186. Maron, E., Toru, I., Must, A., Tasa, G., Toover, E., Vasar, V., Lang, A., Shlik, J., 2007. Association study of tryptophan hydroxylase 2 gene polymorphisms in panic disorder. Neurosci. Lett. 411, 180–184. Monkul, E.S., Hatch, J.P., Nicoletti, M.A., Spence, S., Brambilla, P., Lacerda, A.L., Sassi, R.B., Mallinger, A.G., Keshavan, M.S., Soares, J.C., 2007. Fronto-limbic brain structures in suicidal and non-suicidal female patients with major depressive disorder. Mol. Psychiatry 12, 360–366. Mossner, R., Walitza, S., Geller, F., Scherag, A., Gutknecht, L., Jacob, C., Bogusch, L., Remschmidt, H., Simons, M., Herpertz-Dahlmann, B., Fleischhaker, C., Schulz, E., Warnke, A., Hinney, A., Wewetzer, C., Lesch, K.P., 2006. Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in children and adolescents with obsessive-compulsive disorder. Int. J. Neuropsychopharmacol. 9, 437–442. Mossner, R., Muller-Vahl, K.R., Doring, N., Stuhrmann, M., 2007. Role of the novel tryptophan hydroxylase-2 gene in Tourette syndrome. Mol. Psychiatry 12, 617–619. Mulder, R.T., Joyce, P.R., Cloninger, C.R., 1994. Temperament and early environment influence comorbidity and personality disorders in major depression. Compr. Psychiatry 35, 225–233. Naito, M., Kijima, N., Kitamura, T., 2000. Temperament and Character Inventory (TCI) as predictors of depression among Japanese college students. J. Clin. Psychol. 56, 1579–1585. Oldfield, R.C., 1971. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9, 97–113. Ongur, D., Farabaugh, A., Iosifescu, D.V., Perlis, R., Fava, M., 2005. Tridimensional personality questionnaire factors in major depressive disorder: relationship to anxiety disorder comorbidity and age of onset. Psychother. Psychosom. 74, 173–178. Parent, A., Descarries, L., Beaudet, A., 1981. Organization of ascending serotonin systems in the adult rat brain. A radioautographic study after intraventricular administration of [3H]5-hydroxytryptamine. Neuroscience 6, 115–138. Reuter, M., Kuepper, Y., Hennig, J., 2007. Association between a polymorphism in the promoter region of the TPH2 gene and the personality trait of harm avoidance. Int. J. Neuropsychopharmacol. 10, 401–404. Richman, H., Frueh, B.C., 1997. Personality and PTSD II: personality assessment of PTSD-diagnosed Vietnam veterans using the
BR A IN RE S E A RCH 1 3 31 ( 20 1 0 ) 5 1 –5 7
cloninger tridimensional personality questionnaire (TPQ). Depress. Anxiety 6, 70–77. Richter, J., Eisemann, M., Richter, G., 2000. Temperament and character during the course of unipolar depression among inpatients. Eur. Arch. Psychiatry Clin. Neurosci. 250, 40–47. Rogers, M., Yamasue, H., Abe, O., Yamada, H., Ohtani, T., Iwanami, A., Aoki, S., Kato, N., Kasai, K., 2009. Smaller amygdalae volume and reduced anterior cingulate gray matter density associated with history of PTSD. Psychiatry Res. Neuroimaging 174, 210–216. Ruchkin, V.V., Eisemann, M., Hagglof, B., 1998. Juvenile male rape victims: is the level of post-traumatic stress related to personality and parenting? Child Abuse Negl. 22, 889–899. Saviotti, F.M., Grandi, S., Savron, G., Ermentini, R., Bartolucci, G., Conti, S., Fava, G.A., 1991. Characterological traits of recovered patients with panic disorder and agoraphobia. J. Affect. Disord. 23, 113–117. Scheuch, K., Lautenschlager, M., Grohmann, M., Stahlberg, S., Kirchheiner, J., Zill, P., Heinz, A., Walther, D.J., Priller, J., 2007. Characterization of a functional promoter polymorphism of the human tryptophan hydroxylase 2 gene in serotonergic raphe neurons. Biol. Psychiatry 62, 1288–1294. Sheehan, K., Lowe, N., Kirley, A., Mullins, C., Fitzgerald, M., Gill, M., Hawi, Z., 2005. Tryptophan hydroxylase 2 (TPH2) gene variants associated with ADHD. Mol. Psychiatry 10, 944–949. Smith, A.K., White, P.D., Aslakson, E., Vollmer-Conna, U., Rajeevan, M.S., 2006. Polymorphisms in genes regulating the HPA axis associated with empirically delineated classes of unexplained chronic fatigue. Pharmacogenomics 7, 387–394. Strakowski, S.M., Adler, C.M., DelBello, M.P., 2002. Volumetric MRI studies of mood disorders: do they distinguish unipolar and bipolar disorder? Bipolar Disord. 4, 80–88. Van Den Bogaert, A., Sleegers, K., De Zutter, S., Heyrman, L., Norrback, K.F., Adolfsson, R., Van Broeckhoven, C., Del-Favero, J., 2006. Association of brain-specific tryptophan hydroxylase, TPH2, with unipolar and bipolar disorder in a Northern Swedish, isolated population. Arch. Gen. Psychiatry 63, 1103–1110. Walitza, S., Renner, T.J., Dempfle, A., Konrad, K., Wewetzer, C., Halbach, A., Herpertz-Dahlmann, B., Remschmidt, H., Smidt, J., Linder, M., Flierl, L., Knolker, U., Friedel, S., Schafer, H., Gross, C., Hebebrand, J., Warnke, A., Lesch, K.P., 2005. Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder. Mol. Psychiatry 10, 1126–1132. Walther, D.J., Bader, M., 2003. A unique central tryptophan hydroxylase isoform. Biochem. Pharmacol. 66, 1673–1680. Walther, D.J., Peter, J.U., Bashammakh, S., Hortnagl, H., Voits, M.,
57
Fink, H., Bader, M., 2003. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 299, 76. Yamasue, H., Kasai, K., Iwanami, A., Ohtani, T., Yamada, H., Abe, O., Kuroki, N., Fukuda, R., Tochigi, M., Furukawa, S., Sadamatsu, M., Sasaki, T., Aoki, S., Ohtomo, K., Asukai, N., Kato, N., 2003. Voxel-based analysis of MRI reveals anterior cingulate gray-matter volume reduction in posttraumatic stress disorder due to terrorism. Proc. Natl. Acad. Sci. USA 100, 9039–9043. Yamasue, H., Iwanami, A., Hirayasu, Y., Yamada, H., Abe, O., Kuroki, N., Fukuda, R., Tsujii, K., Aoki, S., Ohtomo, K., Kato, N., Kasai, K., 2004. Localized volume reduction in prefrontal, temporolimbic, and paralimbic regions in schizophrenia: an MRI parcellation study. Psychiatry Res. 131, 195–207. Yamasue, H., Abe, O., Suga, M., Yamada, H., Inoue, H., Tochigi, M., Rogers, M., Aoki, S., Kato, N., Kasai, K., 2008a. Gender-common and -specific neuroanatomical basis of human anxiety-related personality traits. Cereb. Cortex 18, 46–52. Yamasue, H., Kakiuchi, C., Tochigi, M., Inoue, H., Suga, M., Abe, O., Yamada, H., Sasaki, T., Rogers, M.A., Aoki, S., Kato, T., Kasai, K., 2008b. Association between mitochondrial DNA 10398A>G polymorphism and the volume of amygdala. Genes Brain Behav. 7, 698–704. Yoon, H.K., Kim, Y.K., 2009. TPH2 -703G/T SNP may have important effect on susceptibility to suicidal behavior in major depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 33, 403–409. Zhang, X., Beaulieu, J.M., Sotnikova, T.D., Gainetdinov, R.R., Caron, M.G., 2004. Tryptophan hydroxylase-2 controls brain serotonin synthesis. Science 305, 217. Zhang, X., Gainetdinov, R.R., Beaulieu, J.M., Sotnikova, T.D., Burch, L.H., Williams, R.B., Schwartz, D.A., Krishnan, K.R., Caron, M.G., 2005. Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 45, 11–16. Zhou, Z., Peters, E.J., Hamilton, S.P., McMahon, F., Thomas, C., McGrath, P.J., Rush, J., Trivedi, M.H., Charney, D.S., Roy, A., Wisniewski, S., Lipsky, R., Goldman, D., 2005. Response to Zhang et al. (2005): loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 45, 11–16 (Neuron. 48, 702-3; author reply 705-6). Zill, P., Buttner, A., Eisenmenger, W., Bondy, B., Ackenheil, M., 2004a. Regional mRNA expression of a second tryptophan hydroxylase isoform in postmortem tissue samples of two human brains. Eur. Neuropsychopharmacol. 14, 282–284. Zill, P., Buttner, A., Eisenmenger, W., Moller, H.J., Bondy, B., Ackenheil, M., 2004b. Single nucleotide polymorphism and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene in suicide victims. Biol. Psychiatry 56, 581–586.