No interaction between serotonin transporter gene (5-HTTLPR) polymorphism and adversity on depression among Japanese children and adolescents
© Tomoda et al.; licensee BioMed Central Ltd. 2013
Received: 25 January 2013
Accepted: 16 April 2013
Published: 10 May 2013
Identification of gene × environment interactions (G × E) for depression is a crucial step in ascertaining the mechanisms underpinning the disorder. Earlier studies have indicated strong genetic influences and numerous environmental risk factors. In relation to childhood and adolescent depression, evidence is accumulating that the quality of the parental environment is associated with serotonin biology in children. We hypothesized that maternal depression is a crucial environmental risk factor associated with serotonin-regulating genes.
This study was designed to ascertain the G × E interaction for diagnosis of depression in a Japanese pediatric sample. DNA samples from 55 pediatric patients with depression and 58 healthy schoolchildren were genotyped for the 5-HTT (2 short (S) alleles at the 5-HTT locus) promoter serotonin-transporter-linked polymorphic region (5-HTTLPR) polymorphism. We examined whether an adverse parental environment, operationalized as the mother’s history of recurrent major depressive disorder, interacts with 5-HTTLPR polymorphism to predict patients’ depression symptoms.
Binary logistic regression analyses revealed that maternal depression (adversity), gender, and FSIQ significantly affect the diagnosis of depression among children and adolescents. However, no main effect was found for adversity or genotype. Results of multivariable logistic regression analyses using stepwise procedure have elicited some models with a good fit index, which also suggests no interaction between 5-HTTLPR and adversity on depression.
To assess G × E interaction, data obtained from children and adolescents who had been carefully diagnosed categorically and data from age-matched controls were analyzed using logistic regression. Despite an equivocal interaction effect, adversity and gender showed significant main effects.
KeywordsChild depression Gene-by-environment (G × E) interaction Serotonin transporter gene (5-HTTLPR) Polymorphism Early adversity
Depression, an etiologically heterogeneous group of brain disorders characterized by widely various symptoms that reflect altered cognitive, psychomotor, and emotional processes [1, 2], strongly affects 3–5% of children and adolescents . Depression negatively impacts growth and development, school performance, and peer or family relationships; it can lead to suicide [4–6]. Biomedical and psychosocial risk factors include a family history of depression, female sex, childhood abuse or neglect, stressful life events, and chronic illness [3, 7, 8]. Previous results of studies suggest that exposure to childhood adversity is associated with depression symptoms [9–12]. Although people at risk tend to have poor life outcomes, some people do well despite adversity. Protective factors such as good intellectual skills, positive temperament, parental warmth, parental involvement, and strong social connections are believed to play an important role in protecting individuals from poor development, psychological problems, and mental illness from the viewpoint of genetic etiology .
Results of previous studies suggest that homozygous carriers of the short allele (S/S) of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) might be at increased risk for depression if they have also been exposed to early or current adversity or stress .
A growing body of evidence suggests that 5-HTTLPR interacts with adverse environmental influences to produce increased risk for the development of depression, although the underlying mechanisms of this association remain largely unexplored [15–19]. Various reports have described that 5-HTTLPR genotype moderates the relation between stress and depression and interacts to contribute to risk for depression in children [20–22]. However, recent meta-analyses have produced no evidence that the 5-HTTLPR genotype alone or in interaction with stressful life events is associated with an elevated risk of depression , or that the main effect of 5-HTTLPR genotype and the interaction effect between 5-HTTLPR and stressful life events on risk of depression are negligible . Therefore, we should conduct an examination to incorporate consideration of the possibility of other confounding variables such as gender, age, and socioeconomic status along with stressful life events.
Research in this area can recast our thinking about the role of early experience in psychopathology and genetic interaction. Considering previous research, we hypothesized that interaction between 5-HTTLPR and early adversity is involved in the etiology of childhood depression. No study has tested Japanese children and adolescents. Therefore, the aim of this study is to examine whether opposite G (5-HTTLPR genotype) × E (maternal depression) interactions can be confirmed among Japanese children and adolescents. Our additional research findings will contribute to the resolution of inconsistencies in the literature. One principle aim in the current study was to test whether opposite gene-by-environment (G × E) interactions with maternal depression can be found for Japanese children and adolescents with childhood depression. This study examined G × E interactions in a sample of children with Japanese pediatric depression to test the hypothesis that 5-HTTLPR is involved in the etiology of childhood depression.
The Committee of Life Ethics, Graduate School of Medicine, Kumamoto University approved the study protocol, Assurance # KUM0313. During the review of this Project, the committee specifically considered (i) the risks and anticipated benefits, if any, to subjects; (ii) the selection of subjects; (iii) the procedures for securing and documenting informed consent; (iv) the safety of subjects; and (v) the privacy of subjects and confidentiality of the data. All potential participants who declined to participate or otherwise did not participate were eligible for treatment (if applicable) and were not disadvantaged in any other way by not participating in the study. According to the Declaration of Helsinki, parents or guardians of all participants provided written informed consent for children to participate in the study after the study procedures had been explained to them.
Demographics, early adversity, and clinical characteristics in individuals in patients and healthy controls
Healthy controls (n = 58)
Patients (n = 55)
t-test, ANOVA, other t(F)-value
13.8 ± 2.1
14.3 ± 1.9
40 M/18 F
21 M/34 F
4.1 ± 0.6
4.0 ± 0.7
36.47 ± 6.19
56.95 ± 6.42
7.51 ± 4.33
21.92 ± 6.23
Full Scale IQ*
109.56 ± 12.15
94.29 ± 16.49
105.74 ± 9.92
89.24 ± 17.37
108.74 ± 10.69
95.78 ± 15.60
Verbal Comprehension Index*
109.12 ± 13.00
92.38 ± 22.08
104.41 ± 11.98
88.90 ± 21.67
Freedom from Distractibility*
107.35 ± 12.39
91.7 ± 22.36
Processing Speed Index*
109.06 ± 10.50
89.92 ± 25.61
Youth Self Report Score (total)
53.9 ± 25.5
84.5 ± 35.9
Youth Self Report Score (internal)
8.3 ± 7.2
25.1 ± 8.3
Youth Self Report Score (external)
10.2 ± 6.7
14.1 ± 8.6
To obtain data from normal age-matched healthy controls (HC), healthy schoolchildren and adolescents aged 8–16 years were recruited as subjects from the community; school students were targeted. The control group comprised 40 boys and 18 girls (mean age, 13.8 years; SD, 2.1 years). None had below-average IQ, physical problems, or psychiatric psychopathology.
All participants’ race/ethnicity was Japanese. Patients who had undergone treatment with antidepressants or hypotension drugs, or who had diagnoses of neurological illness, migraine, obstructive sleep apnea, below average IQ, or severe psychopathology were excluded from the study. Severe psychopathology was evaluated by referral to at least one pediatric psychiatrist if the patient presented indicative symptoms.
No control subject had any history of DSM-IV-TR Axis I Disorder (based on MINI Kids) including attention deficit hyperactivity disorder (ADHD) or other pervasive developmental disorder, or any history of any form of abuse or drug abuse. Table 1 presents clinical characteristics of the subjects.
As an adult control reference, we also used commercially supplied DNA of Japanese adult subjects (age 44.26 ± 13.58, 50 male and 50 female) supplied by the Health Science Research Resources Bank, Osaka, Japan.
The severity of depressive symptoms was measured using the Zung self-rating depression scale (SDS) and the Birleson Depression Self-Rating Scale for Children (DSRS-C), which are similar to the children’s depression inventory used in pediatric psychiatry. The validity and reliability of Japanese version of these scales were confirmed [25, 26]. Methods used for these analyses were described previously .
Wechsler Intelligence Scale for Children-Third Edition (WISC-III)
An individually administered measure of intelligence intended for children aged 6 years to 16 years and 11 months, WISC-III, was administered by a licensed pediatric-psychological clinician to estimate intellectual capacity . The version is applicable to Japanese children and adolescents.
Child Behavior Checklist Youth Self-Report (CBCL-YSR) and SES
Patients with child depression had mean scores of 25 and 14, respectively, for Internalizing and Externalizing Problems on the CBCL Youth Self-Report .
Low income and poverty might be important developmental risk factors related to psychopathology . The parental socioeconomic status (SES) test was administered as a composite measure of socioeconomic status [31, 32]. Socioeconomic status was classified as follows: annual income below 2 million yen, 1; 2–4 million yen, 2; 4–6 million yen, 3; between 6 and 8 million yen, 4, 8–10 million yen, 5; 10–12 million yen, 6; more than 12 million yen, 7.
The patients’ mothers were also administered a clinical interview by a specialized physician, the Structured Clinical Interview for the DSM-IV (SCID), to assess their Axis-I disorders. They were investigated if they had either (1) no current/past disorder (low early adversity); or (2) at least two major depressive episodes during their children’s lifetime but were currently in remission (high early adversity). Approximately 20% (n = 11) of the mothers had recurrent depression; the remaining 80% (n = 44) had no history of mental health disorders. No control subject’s mother had high early adversity. Selected from the same community sample, control subjects’ mothers with no history of psychiatric problems or exposure to traumatic events served as a no early adversity contrast group.
Genomic DNA was extracted directly from blood samples of patients using standard techniques (MagNa pure LC350; Roche Diagnostics Corp.). In control subjects, we used a mouth swab sampling technique and extracted the DNA from buccal cells using a standard commercial extraction kit QIAamp DNA Micro Kit (Qiagen Inc., Tokyo, Japan). This study was conducted with ethnically homogeneous individuals (all were of Japanese descent) .
The serotonin transporter gene (5-HTTLPR) of the 5-HTT gene regulatory region was amplified by polymerase chain reaction (PCR) with forward primer (5’-GGCGTTGCCGCTCTGAATGC-3’) and reverse primer (5’-GAGGGACTGAGCTGGACAACCAC-3’). For PCR, 10 ng of genomic DNA was used in a 25-μL reaction mixture containing 0.5 U of KOD FX Neo (Toyobo Co. Ltd.) and 10 pmol of each primer in PCR buffer for KOD FX Neo (Toyobo Co. Ltd.). Cycling conditions were the following: denaturation (94°C for 2 min) and 30 cycles of amplification (98°C for 10 s, 63°C for 30 s and 68°C for 30 s). The PCR products were separated using electrophoresis in a 3% agarose gel and visualized by UV after ethidium bromide staining. A 484 bp band was observed for the short (S) allele, and a 528 bp band for the long (L) allele; heterozygous samples showed both the alleles. Two investigators scored allele sizes independently. Any inconsistency was reviewed and procedures were repeated if necessary. Genotyping was conducted blindly without knowledge of the clinical information.
5-HTTLPR genotype distributions and allele frequencies in controls and depressive patients
Genotypes, n (%)
Allele frequencies, n (%)
The clinical variables were compared in both groups using t-tests for quantitative data and Fisher exact tests for qualitative data. Data are expressed as the mean ± SD. To explore the relation between depressive symptoms and the genotypes of the 5-HTTLPR polymorphism, analysis of covariance (ANCOVA) was performed for each of the depression scores (total SDS and DSRS-C scores) using age and gender as covariates because it has been suggested that a variable such as age might affect responses to the depression rating . To confirm the main effect on the diagnosis of depression, we used binary logistic regression and set genetic, environmental factors, and the effect of the interactions between 5-HTTLPR genotype and adversity as independent variables.
Next, multivariable logistic regression analyses were performed. The dependent variable was the status of diagnosis (0 = no diagnosis, 1 = diagnosed as depression). All predictor variables were entered simultaneously into the model. Some possible models were conducted using stepwise procedures. Finally, two-way analysis of variance (ANOVA) was conducted to assess the effect of G × E interaction in each genotype group.
All statistical tests (t-test, ANCOVA and Fisher exact test, logistic regression analyses, and two-way ANOVA for discrete variables) were two-sided; P values less than .05 were inferred as statistically significant. Statistical analyses were conducted using software (SPSS Statistics 20; SPSS Inc., Chicago, IL).
Demographics and IQ
Table 1 shows that the patient and control groups were well matched in terms of age (F =1.21, P = 0.40) and SES (F = 2.62, P = 0.11). Female predominance was found in the patient group (Fisher exact, P = 0.008). Subjects in the patient group were predominantly male (69%), whereas controls were predominantly female (61%; Table 1). Of 55 children and adolescents in the patient group, 11 had early adversity, although none had it in the HC group. As expected, the patient group had high SDS scores with a mean of 57.0 ± 6.4 (F = 235.96, P < 0.001) and high DSRS-C scores with a mean of 21.9 ± 6.2 (F = 189.03, P < 0.001). In addition, those who were diagnosed as having depression had a significantly higher total score of CBCL-YSR (F =23.59, P < 0.001) and internalizing score of that (F = 63.91, P < 0.001) than those of the HC group.
The patient group had significantly lower full-scale IQ (FSIQ) without discrepancies between verbal IQ (VIQ) and performance IQ (PIQ), compared to the HC group (94.3 ± 16.5 vs. 109.6 ± 12.2) (F = 6.43, P = 0.013; Table 1). Similarly, VIQ and PIQ showed significant differences in scores between the two groups (VIQ, F = 9.44, P = 0.003; PIQ, F = 7.67, P = 0.007).
The genotypic and allelic frequencies of the 5-HTTLPR variants are presented in Table 2. The distribution of allelic frequency of the patients and age-matched controls was found to be almost identical to that previously reported in Japanese people, exhibiting a similar tendency to that of our Japanese adult sample (frequency for the L/L, S/L, and S/S genotypes was: 7, 33, and 60% in the patients and 6, 31, and 63% in the age-matched controls, respectively). The overall pattern of results derived by genetic studies of 5-HTTLPR is most suggestive for a dominant mode of action of the S allele . We therefore analyzed S/L heterozygous patients grouped with L/L homozygous patients (i.e., L/L + S/L versus S/S). No significant difference was found in the genotypic or allelic frequencies of 5-HTTLPR between both groups, suggesting that no sampling bias exists in the study.
As shown Table 1, significant differences were found between two groups in FSIQ, depression scores, and scores of CBCL. Because of the significant main effects of FSIQ and gender, we assumed that interaction effects between variables such as SES × age, SES × FSIQ, and gender × age would be large.
Evaluation of binary logistic regression analyses
Binary logistic regression analyses for variables of genotype, adversity, gender, age, SES, FSIQ, and Genotype (G) × Environment (E)
Gene × Environment(E)
Evaluation of multivariable logistic regression analyses
Multivariable logistic regression analyses using stepwise procedure
G × E interaction
Fit index of this model: χ2 = 61.216 (p < 0.001), -2log likelihood = 37.706, discriminate accuracy = 96.9%
Fit index of this model: χ2 = 61.216 (p < 0.001), -2log likelihood = 37.706, discriminate accuracy = 96.9%
Fit index of this model: χ2 = 50.660 (p < 0.001), -2log likelihood = 48.262, discriminate accuracy = 96.9%
Two-way analysis of variance for investigating the main effect and G × E interaction
Type III sum of squares
genotype (G) × adversity (E)
genotype (G) × gender
adversity (G) × gender
Interaction between adverse parental environment and gender showed a significant main effect despite a lack of G × E interaction in a Japanese pediatric sample. Because all participants in this study were ethnically homogenous, this is an important consideration for generalizing the present findings.
Depression is a critical and common condition found in children and adolescents as well as adults [3, 38–40]. Early life stress is a risk factor for major depression, post-traumatic stress disorder (PTSD), and drug abuse, among other conditions [8, 41]. In recent years, a possible association of the 5-HTTLPR with youth depression has been traced in numerous studies [42–54]. Most studies were based on Caucasian populations, except for a few examining the Japanese general population [55, 56]. No significant genotypic association of the 5-HTTLPR polymorphism with depression in a Japanese pediatric population, particularly in patients who have adverse parental environment, was operationalized as the mothers’ history of recurrent major depressive disorder. This report is the first of genotypic association of the 5-HTTLPR polymorphism in a Japanese pediatric population. Particularly, this study examined the interactive effect of 5-HTTLPR and history of maternal depression among children and early adolescents with and without current depression. Moreover, few reports in the literature describe studies of G × E interaction in a sample of young people.
According to logistic regression analyses, our findings suggest that adversity (maternal depression), gender, and FSIQ had a main effect on current depression. Among them, adversity markedly affected the diagnosis of depression. However interpretation of the effect of FSIQ required careful consideration. A low score of FSIQ might be a cause and an effect . More importantly, although G (genotype) × E interaction showed a significant main effect on the diagnosis of depression, it might explain the marked impact of maternal depression mediating the existence of diagnosis. Therefore, no interaction was found between the genotype and environmental factors in this case.
Additionally, no significant effect of G × E interaction was found with influences of adversity, gender, FSIQ, and age using multivariable logistic regression analyses. Our findings suggest that depression at an early age was mediated mainly by direct family adversity and gender. These results resemble findings reported previously in longitudinal studies [41, 58, 59].
Numerous behavioral genetics studies have yielded scientific knowledge related to interaction between genes and the environment . Most importantly, interactive effects of genes and environmental factors are expected to appear cumulatively over a long period, suggesting that onset of depression results from long-term exposure to stressors. Therefore, an effect of G × E interaction might not be confirmed in this study because the sample comprised children and early adolescents. Our findings from models 1–3 and two-way ANOVA were in concordance with results from prior studies [23, 61, 62].
Meta-analyses of the 5-HTTLPR G × E hypothesis have been described in many reports [17, 22–24, 63–65]. Sample age and gender composition emerge as important factors . Furthermore, the S allele of 5-HTTLPR has been implicated in the pathology of several neuropsychiatric phenotypes including mood and anxiety disorders [66, 67] and in psychiatric disorders that involve serotonergic dysfunction [68, 69]. Furthermore, we reported previously that sensitive periods exist, during which brain structures are most susceptible to exposure to early life events such as childhood maltreatment. These sensitive periods tend to correspond to times of rapid developmental change [70, 71]. Therefore, we emphasize that continued monitoring is recommended for children who have early life stress as they pass through puberty. Reasons for the time lag between early life stress and depression are proposed along with potential strategies for early intervention .
Some limitations of this study and its results should be explained. First are the small number of participants and poor statistical power. Second, the covered environmental risk factors in the study were limited. Third, this was not a longitudinal study; no information related to outcomes in late adolescence is available for patients and HC groups. Fourth, the HC group significantly had high IQ than patient group, suggesting difficulty in case control. Fifth, female predominance was found in the patient group (Fisher exact, P = 0.008), which might influence the findings. Given these limitations, it will be important for future studies to ensure an adequate range of environmental variables and populations studied because a restricted range can strongly influence G × E results. Furthermore, to tease apart and thereby discern the respective influences of G × E, G × G, and E × E interactions, employing a molecular framework to extend this research would be beneficial. A follow-up study using both molecular genetics methods and measures of proximal environments is expected to provide a useful extension of the current study.
In a Japanese pediatric sample, we examined whether adverse parental environment, operationalized as a mother’s history of recurrent major depressive disorder, interacts with 5-HTTLPR polymorphism to predict a patient’s symptoms of depression. Data obtained from children and adolescents who had been carefully diagnosed categorically and data from age-matched controls were analyzed using logistic regression to assess G × E interaction. Despite an equivocal interaction effect, adversity and gender showed a significant main effect.
- (G × E):
Serotonin-transporter-linked polymorphic region
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision
Structured Clinical Interview for DSM-IV
Attention deficit hyperactivity disorder
Zung self-rating depression scale
Birleson Depression Self-Rating Scale for Children
Wechsler Intelligence Scale for Children – Third Edition
Child Behavior Checklist Youth Self-Report
Polymerase chain reaction
Analysis of covariance
Analysis of variance
Post-traumatic stress disorder.
We would like to thank Tomoko Yamaguchi, MA, for her excellent technical assistance in recruiting participants.
This work was supported by a Grant-in-Aid for Scientific Research (B) and Challenging Exploratory Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (KAKENHI: grant number 24300149 and 23650223 to A.T.). This work also was partially supported by a Grant-in-Aid for Scientific Research from Japan-U.S. Brain Research Cooperation Program (grant number 210201 to AT), as well as the Research Grants from the University of Fukui to AT.
The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
- American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. 1994, Washington, D.C.: American Psychiatric Press, 4Google Scholar
- Association AP: Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR). 2000, Washington, DC: American Psychiatric AssociationView ArticleGoogle Scholar
- Verhulst FC, van der Ende J, Ferdinand RF, Kasius MC: The prevalence of DSM-III-R diagnoses in a national sample of Dutch adolescents. Arch Gen Psychiatr. 1997, 54 (4): 329-336. 10.1001/archpsyc.1997.01830160049008.View ArticlePubMedGoogle Scholar
- Birmaher B, Ryan ND, Williamson DE, Brent DA, Kaufman J, Dahl RE, Perel J, Nelson B: Childhood and adolescent depression: a review of the past 10 years. Part I. J Am Acad Child Adolesc Psychiatry. 1996, 35 (11): 1427-1439. 10.1097/00004583-199611000-00011.View ArticlePubMedGoogle Scholar
- Shaffer D, Gould MS, Fisher P, Trautman P, Moreau D, Kleinman M, Flory M: Psychiatric diagnosis in child and adolescent suicide. Arch Gen Psychiatr. 1996, 53 (4): 339-348. 10.1001/archpsyc.1996.01830040075012.View ArticlePubMedGoogle Scholar
- Garrison CZ, Waller JL, Cuffe SP, McKeown RE, Addy CL, Jackson KL: Incidence of major depressive disorder and dysthymia in young adolescents. J Am Acad Child Adolesc Psychiatr. 1997, 36 (4): 458-465. 10.1097/00004583-199704000-00007.View ArticleGoogle Scholar
- Reynolds M, Brewin CR, Saxton M: Emotional disclosure in school children. J Child Psychol Psychiatr. 2000, 41 (2): 151-159. 10.1017/S0021963099005223.View ArticleGoogle Scholar
- Bhatia SK, Bhatia SC: Childhood and adolescent depression. Am Fam Physician. 2007, 75 (1): 73-80.PubMedGoogle Scholar
- Lesch KP: Gene-environment interaction and the genetics of depression. J Psychiatr Neurosci. 2004, 29 (3): 174-184.Google Scholar
- Akil H: Stressed and depressed. Nat Med. 2005, 11 (2): 116-118. 10.1038/nm0205-116.View ArticlePubMedGoogle Scholar
- Hamet P, Tremblay J: Genetics and genomics of depression. Metabolism. 2005, 54 (5 Suppl 1): 10-15.View ArticlePubMedGoogle Scholar
- Kendler KS, Kuhn JW, Vittum J, Prescott CA, Riley B: The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: a replication. Arch Gen Psychiatr. 2005, 62 (5): 529-535. 10.1001/archpsyc.62.5.529.View ArticlePubMedGoogle Scholar
- Shalev I, Moffitt TE, Sugden K, Williams B, Houts RM, Danese A, Mill J, Arseneault L, Caspi A: Exposure to violence during childhood is associated with telomere erosion from 5 to 10 years of age: a longitudinal study. Mol Psychiatr. 2013, 18 (5): 576-581. 10.1038/mp.2012.32.View ArticleGoogle Scholar
- Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A: Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003, 301 (5631): 386-389. 10.1126/science.1083968.View ArticlePubMedGoogle Scholar
- Stein MB, Schork NJ, Gelernter J: Gene-by-environment (serotonin transporter and childhood maltreatment) interaction for anxiety sensitivity, an intermediate phenotype for anxiety disorders. Neuropsychopharmacology. 2008, 33 (2): 312-319. 10.1038/sj.npp.1301422.View ArticlePubMedGoogle Scholar
- Alexander N, Kuepper Y, Schmitz A, Osinsky R, Kozyra E, Hennig J: Gene-environment interactions predict cortisol responses after acute stress: implications for the etiology of depression. Psychoneuroendocrinology. 2009, 34 (9): 1294-1303. 10.1016/j.psyneuen.2009.03.017.View ArticlePubMedGoogle Scholar
- Caspi A, Hariri AR, Holmes A, Uher R, Moffitt TE: Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits. Am J Psychiatr. 2010, 167 (5): 509-527. 10.1176/appi.ajp.2010.09101452.View ArticlePubMedPubMed CentralGoogle Scholar
- Mueller A, Armbruster D, Moser DA, Canli T, Lesch KP, Brocke B, Kirschbaum C: Interaction of serotonin transporter gene-linked polymorphic region and stressful life events predicts cortisol stress response. Neuropsychopharmacology. 2011, 36 (7): 1332-1339. 10.1038/npp.2011.11.View ArticlePubMedPubMed CentralGoogle Scholar
- Klucken T, Alexander N, Schweckendiek J, Merz CJ, Kagerer S, Osinsky R, Walter B, Vaitl D, Hennig J, Stark R: Individual differences in neural correlates of fear conditioning as a function of 5-HTTLPR and stressful life events. Soc Cogn Affect Neurosci. 2013, 8 (3): 318-325. 10.1093/scan/nss005.View ArticlePubMedGoogle Scholar
- Kaufman J, Yang BZ, Douglas-Palumberi H, Grasso D, Lipschitz D, Houshyar S, Krystal JH, Gelernter J: Brain-derived neurotrophic factor-5-HTTLPR gene interactions and environmental modifiers of depression in children. Biol Psychiatr. 2006, 59 (8): 673-680. 10.1016/j.biopsych.2005.10.026.View ArticleGoogle Scholar
- Nederhof E, Bouma EM, Oldehinkel AJ, Ormel J: Interaction between childhood adversity, brain-derived neurotrophic factor val/met and serotonin transporter promoter polymorphism on depression: the TRAILS study. Biol Psychiatr. 2010, 68 (2): 209-212. 10.1016/j.biopsych.2010.04.006.View ArticleGoogle Scholar
- Karg K, Burmeister M, Shedden K, Sen S: The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation. Arch Gen Psychiatr. 2011, 68 (5): 444-454. 10.1001/archgenpsychiatry.2010.189.View ArticlePubMedPubMed CentralGoogle Scholar
- Risch N, Herrell R, Lehner T, Liang KY, Eaves L, Hoh J, Griem A, Kovacs M, Ott J, Merikangas KR: Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis. JAMA. 2009, 301 (23): 2462-2471. 10.1001/jama.2009.878.View ArticlePubMedPubMed CentralGoogle Scholar
- Munafo MR, Durrant C, Lewis G, Flint J: Gene X environment interactions at the serotonin transporter locus. Biol Psychiatr. 2009, 65 (3): 211-219. 10.1016/j.biopsych.2008.06.009.View ArticleGoogle Scholar
- Zung WW: A Self-Rating Depression Scale. Arch Gen Psychiatr. 1965, 12: 63-70. 10.1001/archpsyc.1965.01720310065008.View ArticlePubMedGoogle Scholar
- Birleson P: The validity of depressive disorder in childhood and the development of a self-rating scale: a research report. J Child Psychol Psychiatr. 1981, 22 (1): 73-88. 10.1111/j.1469-7610.1981.tb00533.x.View ArticleGoogle Scholar
- Tomoda A, Mizuno K, Murayama N, Joudoi T, Igasaki T, Miyazaki M, Miike T: Event-Related Potentials in Japanese Childhood Chronic Fatigue Syndrome (CCFS). J Pediatr Neurol. 2007, 5: 199-208.Google Scholar
- Wechsler D: Manual for the Wechsler Intelligence Scale for Children–Third edition. 1991, San Antonio, TX: The Psychological CorporationGoogle Scholar
- Achenbach TM: Integrative Guide to the 1991 CBCL/4-18, YSR, and TRF Profiles. 1991, Burlington: University of Vermont, Department of PsychologyGoogle Scholar
- Tomoda A, Kinoshita S, Korenaga Y, Mabe H: Pseudohypacusis in childhood and adolescence is associated with increased gray matter volume in the medial frontal gyrus and superior temporal gyrus. Cortex. 2012, 48 (4): 492-503. 10.1016/j.cortex.2010.10.001.View ArticlePubMedGoogle Scholar
- Hollingshead AB: Hollingshead two factor index of social position, occupational categories. 1965, Rockville, MD: National Institute of Health, Psychopharmacology Research BranchGoogle Scholar
- Hollingshead AB, Redlich FC: Social class and mental illness: a community study. 1958. Am J Publ Health. 2007, 97 (10): 1756-1757.View ArticleGoogle Scholar
- Nishikawa S, Nishitani S, Fujisawa TX, Noborimoto I, Kitahara T, Takamura T, Shinohara K: Perceived parental rejection mediates the influence of serotonin transporter gene (5-HTTLPR) polymorphisms on impulsivity in Japanese adults. PLoS One. 2012, 7 (10): e47608-10.1371/journal.pone.0047608.View ArticlePubMedPubMed CentralGoogle Scholar
- Obayashi K, Olsson M, Anan I, Ueda M, Nakamura M, Okamoto S, Yamashita T, Miida T, Ando Y, Suhr OB: Impact of serotonin transporter and catechol-O-methyl transferase genes polymorphism on gastrointestinal dysfunction in Swedish and Japanese familial amyloidotic polyneuropathy patients. Clin Chim Acta Int J Clin Chem. 2008, 398 (1–2): 10-14.View ArticleGoogle Scholar
- Toyoshima F, Oshima T, Nakajima S, Sakurai J, Tanaka J, Tomita T, Hori K, Matsumoto T, Miwa H: Serotonin transporter gene polymorphism may be associated with functional dyspepsia in a Japanese population. BMC Med Genet. 2011, 12: 88-View ArticlePubMedPubMed CentralGoogle Scholar
- Gelernter J, Kranzler H, Cubells JF: Serotonin transporter protein (SLC6A4) allele and haplotype frequencies and linkage disequilibria in African- and European-American and Japanese populations and in alcohol-dependent subjects. Hum Genet. 1997, 101 (2): 243-246. 10.1007/s004390050624.View ArticlePubMedGoogle Scholar
- Willeit M, Praschak-Rieder N, Neumeister A, Zill P, Leisch F, Stastny J, Hilger E, Thierry N, Konstantinidis A, Winkler D: A polymorphism (5-HTTLPR) in the serotonin transporter promoter gene is associated with DSM-IV depression subtypes in seasonal affective disorder. Mol Psychiatr. 2003, 8 (11): 942-946. 10.1038/sj.mp.4001392.View ArticleGoogle Scholar
- Kazdin AE: Childhood depression. J Child Psychol Psychiatr. 1990, 31 (1): 121-160. 10.1111/j.1469-7610.1990.tb02276.x.View ArticleGoogle Scholar
- Hasin DS, Goodwin RD, Stinson FS, Grant BF: Epidemiology of major depressive disorder: results from the National Epidemiologic Survey on Alcoholism and Related Conditions. Arch Gen Psychiatr. 2005, 62 (10): 1097-1106. 10.1001/archpsyc.62.10.1097.View ArticlePubMedGoogle Scholar
- Teicher MH, Vitaliano GD: Witnessing violence toward siblings: an understudied but potent form of early adversity. PLoS One. 2011, 6 (12): e28852-10.1371/journal.pone.0028852.View ArticlePubMedPubMed CentralGoogle Scholar
- Schilling EA, Aseltine RH, Gore S: Adverse childhood experiences and mental health in young adults: a longitudinal survey. BMC Publ Health. 2007, 7: 30-10.1186/1471-2458-7-30.View ArticleGoogle Scholar
- Aguilera M, Arias B, Wichers M, Barrantes-Vidal N, Moya J, Villa H, van Os J, Ibanez MI, Ruiperez MA, Ortet G: Early adversity and 5-HTT/BDNF genes: new evidence of gene-environment interactions on depressive symptoms in a general population. Psychol Med. 2009, 39 (9): 1425-1432. 10.1017/S0033291709005248.View ArticlePubMedGoogle Scholar
- Araya R, Hu X, Heron J, Enoch MA, Evans J, Lewis G, Nutt D, Goldman D: Effects of stressful life events, maternal depression and 5-HTTLPR genotype on emotional symptoms in pre-adolescent children. Am J Med Genet B Neuropsychiatr Genet. 2009, 150B (5): 670-682. 10.1002/ajmg.b.30888.View ArticlePubMedGoogle Scholar
- Blakely RD, Veenstra-VanderWeele J: Genetic indeterminism, the 5-HTTLPR, and the paths forward in neuropsychiatric genetics. Arch Gen Psychiatr. 2011, 68 (5): 457-458. 10.1001/archgenpsychiatry.2011.34.View ArticlePubMedPubMed CentralGoogle Scholar
- Brown GW, Harris TO: Depression and the serotonin transporter 5-HTTLPR polymorphism: a review and a hypothesis concerning gene-environment interaction. J Affect Disord. 2008, 111 (1): 1-12. 10.1016/j.jad.2008.04.009.View ArticlePubMedGoogle Scholar
- Chen MC, Joormann J, Hallmayer J, Gotlib IH: Serotonin transporter polymorphism predicts waking cortisol in young girls. Psychoneuroendocrinology. 2009, 34 (5): 681-686. 10.1016/j.psyneuen.2008.11.006.View ArticlePubMedPubMed CentralGoogle Scholar
- Cicchetti D, Rogosch FA, Oshri A: Interactive effects of corticotropin releasing hormone receptor 1, serotonin transporter linked polymorphic region, and child maltreatment on diurnal cortisol regulation and internalizing symptomatology. Dev Psychopathol. 2011, 23 (4): 1125-1138. 10.1017/S0954579411000599.View ArticlePubMedPubMed CentralGoogle Scholar
- Cicchetti D, Rogosch FA, Sturge-Apple M, Toth SL: Interaction of child maltreatment and 5-HTT polymorphisms: suicidal ideation among children from low-SES backgrounds. J Pediatr Psychol. 2010, 35 (5): 536-546. 10.1093/jpepsy/jsp078.View ArticlePubMedGoogle Scholar
- Frodl T, Reinhold E, Koutsouleris N, Donohoe G, Bondy B, Reiser M, Moller HJ, Meisenzahl EM: Childhood stress, serotonin transporter gene and brain structures in major depression. Neuropsychopharmacology. 2010, 35 (6): 1383-1390. 10.1038/npp.2010.8.View ArticlePubMedPubMed CentralGoogle Scholar
- Furman DJ, Hamilton JP, Joormann J, Gotlib IH: Altered timing of amygdala activation during sad mood elaboration as a function of 5-HTTLPR. Soc Cogn Affect Neurosci. 2011, 6 (3): 270-276. 10.1093/scan/nsq029.View ArticlePubMedGoogle Scholar
- Gibb BE, Benas JS, Grassia M, McGeary J: Children’s attentional biases and 5-HTTLPR genotype: potential mechanisms linking mother and child depression. J Clin Child Adolesc Psychol. 2009, 38 (3): 415-426. 10.1080/15374410902851705.View ArticlePubMedPubMed CentralGoogle Scholar
- Gibb BE, Grassia M, Stone LB, Uhrlass DJ, McGeary JE: Brooding rumination and risk for depressive disorders in children of depressed mothers. J Abnorm Child Psychol. 2012, 40 (2): 317-326. 10.1007/s10802-011-9554-y.View ArticlePubMedPubMed CentralGoogle Scholar
- Gibb BE, Uhrlass DJ, Grassia M, Benas JS, McGeary J: Children’s inferential styles, 5-HTTLPR genotype, and maternal expressed emotion-criticism: An integrated model for the intergenerational transmission of depression. J Abnorm Psychol. 2009, 118 (4): 734-745.View ArticlePubMedPubMed CentralGoogle Scholar
- Goodyer IM, Bacon A, Ban M, Croudace T, Herbert J: Serotonin transporter genotype, morning cortisol and subsequent depression in adolescents. Br J Psychiatr. 2009, 195 (1): 39-45. 10.1192/bjp.bp.108.054775.View ArticleGoogle Scholar
- Ezaki N, Nakamura K, Sekine Y, Thanseem I, Anitha A, Iwata Y, Kawai M, Takebayashi K, Suzuki K, Takei N: Short allele of 5-HTTLPR as a risk factor for the development of psychosis in Japanese methamphetamine abusers. Ann N Y Acad Sci. 2008, 1139: 49-56. 10.1196/annals.1432.011.View ArticlePubMedGoogle Scholar
- Ohira H, Matsunaga M, Isowa T, Nomura M, Ichikawa N, Kimura K, Kanayama N, Murakami H, Osumi T, Konagaya T: Polymorphism of the serotonin transporter gene modulates brain and physiological responses to acute stress in Japanese men. Stress. 2009, 12 (6): 533-543. 10.3109/10253890902787826.View ArticlePubMedGoogle Scholar
- Staton RD, Wilson H, Brumback RA: Cognitive improvement associated with tricyclic antidepressant treatment of childhood major depressive illness. Percept Mot Skills. 1981, 53 (1): 219-234. 10.2466/pms.19188.8.131.52.View ArticlePubMedGoogle Scholar
- Engert V, Efanov SI, Dedovic K, Duchesne A, Dagher A, Pruessner JC: Perceived early-life maternal care and the cortisol response to repeated psychosocial stress. J Psychiatr Neurosci. 2010, 35 (6): 370-377. 10.1503/jpn.100022.View ArticleGoogle Scholar
- Zwierzynska K, Wolke D, Lereya TS: Peer Victimization in Childhood and Internalizing Problems in. 2012, A Prospective Longitudinal Study. J Abnorm Child Psychol: AdolescenceGoogle Scholar
- Caspi A, Moffitt TE, Morgan J, Rutter M, Taylor A, Arseneault L, Tully L, Jacobs C, Kim-Cohen J, Polo-Tomas M: Maternal expressed emotion predicts children’s antisocial behavior problems: using monozygotic-twin differences to identify environmental effects on behavioral development. Dev Psychol. 2004, 40 (2): 149-161.View ArticlePubMedGoogle Scholar
- Chipman P, Jorm AF, Tan XY, Easteal S: No association between the serotonin-1A receptor gene single nucleotide polymorphism rs6295C/G and symptoms of anxiety or depression, and no interaction between the polymorphism and environmental stressors of childhood anxiety or recent stressful life events on anxiety or depression. Psychiatr Genet. 2010, 20 (1): 8-13. 10.1097/YPG.0b013e3283351140.View ArticlePubMedGoogle Scholar
- Middeldorp CM, de Geus EJ, Willemsen G, Hottenga JJ, Slagboom PE, Boomsma DI: The serotonin transporter gene length polymorphism (5-HTTLPR) and life events: no evidence for an interaction effect on neuroticism and anxious depressive symptoms. Twin Res Hum Genet. 2010, 13 (6): 544-549. 10.1375/twin.13.6.544.View ArticlePubMedGoogle Scholar
- Uher R: The implications of gene-environment interactions in depression: will cause inform cure?. Mol Psychiatr. 2008, 13 (12): 1070-1078. 10.1038/mp.2008.92.View ArticleGoogle Scholar
- Uher R, McGuffin P: The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis. Mol Psychiatr. 2008, 13 (2): 131-146. 10.1038/sj.mp.4002067.View ArticleGoogle Scholar
- Kaufman J, Gelernter J, Kaffman A, Caspi A, Moffitt T: Arguable assumptions, debatable conclusions. Biol Psychiatr. 2010, 67 (4): e19-20. 10.1016/j.biopsych.2009.07.041. author reply e21-13View ArticleGoogle Scholar
- Schinka JA, Busch RM, Robichaux-Keene N: A meta-analysis of the association between the serotonin transporter gene polymorphism (5-HTTLPR) and trait anxiety. Mol Psychiatr. 2004, 9 (2): 197-202. 10.1038/sj.mp.4001405.View ArticleGoogle Scholar
- Sen S, Burmeister M, Ghosh D: Meta-analysis of the association between a serotonin transporter promoter polymorphism (5-HTTLPR) and anxiety-related personality traits. Am J Med Genet B Neuropsychiatr Genet. 2004, 127B (1): 85-89. 10.1002/ajmg.b.20158.View ArticlePubMedGoogle Scholar
- Lotrich FE, Pollock BG: Meta-analysis of serotonin transporter polymorphisms and affective disorders. Psychiatr Genet. 2004, 14 (3): 121-129. 10.1097/00041444-200409000-00001.View ArticlePubMedGoogle Scholar
- Lasky-Su JA, Faraone SV, Glatt SJ, Tsuang MT: Meta-analysis of the association between two polymorphisms in the serotonin transporter gene and affective disorders. Am J Med Genet B Neuropsychiatr Genet. 2005, 133B (1): 110-115. 10.1002/ajmg.b.30104.View ArticlePubMedGoogle Scholar
- Andersen SL, Tomoda A, Vincow ES, Valente E, Polcari A, Teicher MH: Preliminary evidence for sensitive periods in the effect of childhood sexual abuse on regional brain development. J Neuropsychiatry Clin Neurosci. 2008, 20 (3): 292-301. 10.1176/appi.neuropsych.20.3.292.View ArticlePubMedPubMed CentralGoogle Scholar
- Tomoda A, Navalta CP, Polcari A, Sadato N, Teicher MH: Childhood sexual abuse is associated with reduced gray matter volume in visual cortex of young women. Biol Psychiatr. 2009, 66 (7): 642-648. 10.1016/j.biopsych.2009.04.021.View ArticleGoogle Scholar
- Teicher MH, Samson JA, Polcari A, Andersen SL: Length of time between onset of childhood sexual abuse and emergence of depression in a young adult sample: a retrospective clinical report. J Clin Psychiatr. 2009, 70 (5): 684-691. 10.4088/JCP.08m04235.View ArticleGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-244X/13/134/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.