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Published in final edited form as: Am J Med Genet B Neuropsychiatr Genet. 2013 Mar 8;162B(3):245–252. doi: 10.1002/ajmg.b.32141

Catechol-O-Methyltransferase gene val158met polymorphism and depressive symptoms during early childhood

Haroon I Sheikh 1, Katie R Kryski 2, Heather J Smith 3, Lea R Dougherty 4, Daniel N Klein 5, Sara J Bufferd 6, Shiva M Singh 7, Elizabeth P Hayden 8
PMCID: PMC5288403  NIHMSID: NIHMS842993  PMID: 23475824

Abstract

Catechol-O-Methyltransferase (COMT) is a critical regulator of catecholamine levels in the brain. A functional polymorphism of the COMT gene, val158met, has been linked to internalizing symptoms (i.e., depression and anxiety) in adolescents and adults. We extended this research by investigating whether the val158met polymorphism was associated with childhood symptoms of depression and anxiety in two independent samples of young children (Ns = 476 and 409). In both samples, preschool-aged children were genotyped for the COMT val158met polymorphism. Symptoms of psychopathology were assessed via parent interviews and primary caregiver reports. In both samples, children homozygous for the val allele had higher levels of depressive symptoms compared to children with at least one copy of the met allele. Our findings extend previous research in older participants by showing links between the COMT val158met polymorphism and internalizing symptoms in early childhood.

Keywords: Catechol-O-Methyltransferase, val158met, anxiety, depression, internalizing, replication

Introduction

Depression and anxiety (i.e., internalizing disorders) are two of the most common forms of psychiatric disorder and constitute a bulk of the burden related to psychiatric disease [Reiger et al., 1993; Kessler et al., 1994; Olfson et al., 2002]. The etiology of these disorders is unclear but heritability estimates from twin cohorts suggest a substantial genetic component [Kendler and Prescott, 1999; Bierut et al., 1999; Eley and Stevenson, 1999; Kendler et al., 2006]. With respect to specific genes, the extant psychiatric genetics research implicates gene polymorphisms that regulate neurotransmitter release, transport and degradation [Krishnan and Nestler, 2010] in internalizing disorders. One such class of neurotransmitters is catecholamines, which include dopamine and epinephrine; optimal levels of catecholamines are critical in modulating sensory and motor responses and executive functions [Willner, 1995; Goldman-Rakic, 1998; Arnsten and Li, 2005; Brocki et al., 2009]. Animal models and studies of adult humans have consistently pointed to alterations in mesocorticolimbic catecholamine levels, and dopamine levels in particular, in depressive and anxious phenotypes [Pegorolev et al., 2005; Nestler and Carlezon, 2006; Ruhe et al., 2007; Dremencov et al., 2009]. For example, functional imaging research from human adults indicates that diminished cortical dopamine levels may play a role in behaviors related to some internalizing disorders, such as memory deficits, sleep and behavioral disturbances, and psychomotor retardation [Martinot et al., 2001; Fox et al., 2005; Golimbet et al., 2007; Demetrovics et al., 2010; Meyers et al., 2011; Meyers, 2012].

Catechol-O-methyltransferase (COMT), a catabolic enzyme that degrades cortical catecholamines, including dopamine and epinephrine, plays a vital role in regulating mesocorticolimbic catecholamine levels [Meyer-Lindenberg and Weinberger, 2006]. The gene encoding COMT (Gene ID: 1312) is mapped to chromosome 22p11, and contains four exons [Brahe et al., 1986]. Further, a non-synonymous G→A single nucleotide polymorphism (rs4680) in exon four leads to a valine (val) to methionine (met) peptide change in the mature protein, and is called the val158met polymorphism (GenBank accession no. Z26491). This substitution impacts the thermostability of the COMT protein and reduces the enzyme catabolic function, therefore reducing dopamine degradation in carriers with at least one copy of the met allele by more than one-third compared to carriers homozygous for the val allele [Lotta et al. 1995; Lachman et al., 2006; Chen et al. 2004].

Due to the functional nature of the COMT val158met polymorphism on cortical dopamine levels, links between COMT and internalizing disorders have been extensively explored in adult psychiatric populations. For example, Hamilton et al., (2002) reported a strong association between the COMT val158met polymorphism and panic disorder in a family-based sample of 70 panic disorder pedigrees and 83 parent-offspring triads. Hettema et al. (2008) extended these findings by showing that the COMT val158met polymorphism may form part of a genetic risk haplotype shared across a range of internalizing disorders, including major depression, trait-anxiety and panic disorder. Although the literature is consistent on the association between the COMT val158met locus and internalizing phenotypes, there is considerable disagreement in the adult literature on which COMT gene allele confers psychopathological risk. According to data by Massat et al. (2005), the val allele has been associated with early-onset major depression, and others have shown that this variant may increase risk for panic disorders and anxiety [Rothe et al., 2006; Hosak, 2007; Domschke et al., 2007]. However, some studies have either failed to replicate these results [Middeldrop et al., 2010; Opmeer, Kortekaas and Aleman, 2010] or have identified the met allele as the risk allele for internalizing disorders [Baekken et al., 2008; Wray et al., 2008; Aberg et al., 2011].

Researchers have posited that the inconsistencies in this literature stem from a number of factors, including lack of statistical power to detect genetic associations, as most studies have used small samples (i.e., fewer than 200 subjects; Chen et al., 2011]. There is strong agreement in the literature on the need for larger samples, and, more importantly, replication of gene/phenotype associations in independent samples [Ioannidis et al., 2001; Zintzaras and Lau, 2008; Bosker et al., 2011]. Furthermore, to better understand the etiology of internalizing disorders, theorists emphasize the need for study designs that investigate the early developmental origins of these conditions [Zahn–Waxler, Klimes–Dougan and Slattery, 2000]. Early childhood is a period of critical brain development when cortical and limbic regions, and the dopaminergic neurotransmitter system in particular, are undergoing maturation through processes such as neuronal synaptogenesis, myelination and synaptic pruning [Sowell et al., 2008]. This period of increased brain plasticity is thought to influence sensory and perceptual functions that may have long-term consequences for shaping adaptive and maladaptive behavior [Nestler et al., 2002; Sowell et al., 2008; Krishnan and Nestler, 2010]. It is important to note that longitudinal studies have shown continuities between internalizing symptoms from childhood to adolescence and recurrence of depression in adult life [Bardone et al., 1996; Lavigne et al., 1998; Mesman and Koot, 2001; Mesman, Bongers and Koot, 2001; Woodward and Fergusson, 2001; Fergusson and Woodward, 2002; Hofstra et al., 2002], suggesting that research identifying early-emerging risk markers for depressive symptoms may have important preventative implications. However, little work has been done on appropriate candidate genes, such as the COMT val158met, and emerging internalizing symptoms in early-life.

The aim of this study is to examine links between the COMT val158met polymorphism and early-emerging internalizing symptoms. Due to the important role of the COMT enzyme in the brain’s catecholamine metabolism, we hypothesized that functional polymorphisms of this gene would be associated with symptoms of anxiety and depression in preschoolers. Furthermore, based on findings from adult samples, we tentatively hypothesized that the val allele of the COMT functional polymorphism would be associated with higher levels of internalizing symptoms. To increase confidence in our findings, we tested these hypotheses in two independent samples of preschoolers.

Methods

Participants

Table 1 lists the demographic information for the study samples. The primary sample (hereafter referred to as Study 1) consisted of 559 children and their parents residing in Long Island, NY, USA. Of these, 476 children (254 males) contributed DNA and were therefore available for genetic analysis. Children’s mean age was 42.2 months (SD = 3.1). Most participants came from middle-class families (M = 44.8; SD = 10.9), as measured by Hollingshead’s Four Factor Index of Social Status [Hollingshead, 1975]. Children were of average cognitive ability (M = 103.1, SD = 13.7), indexed by the Peabody Picture Vocabulary Test [PPVT-4, Dunn & Dunn, 1997].

Table 1.

Demographic characteristics of study samples

Study 1
(Stony Brook, N=476)		 Study 2
(Western University, N=409)
Child Age [mean months (SD)] 42.24 (3.14) 43.20 (3.60)
Child Sex, Male [% (N)] 252 (55.0) 201 (49.1)
Child Race, Caucasian [%(N)] 487 (87.1) 371 (90.5)
Maternal Age [mean years (SD)] 36.04 (4.44) 35.30 (4.97)
Paternal Age [mean years (SD)] 38.30 (5.39) 37.22 (4.15)
Parent marital status [married, % (N)] 93.7 (524) 80.5 (330)
Maternal Employment [%(N)] 51.2 (286) 52.4 (215)
Family income [%(N)]
 < $50,000 9.2 (50) 55.6 (228)
 $50,000–$100,000 51.3 (287) 26.6 (109)
 > $101,000 39.7 (222) 17.8 (73)
Report/interview Completion [%(N)] 85.1 (476) 99.2 (406)
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Note: Stony Brook = Stony Brook University, Long Island, NY, USA; UWO = Western University, London, ON, Canada.

Replication Sample

In this sample (hereafter referred to as Study 2), participants were an unselected community sample of 409 (201 males) children and their primary caregivers (93% were the child’s mother) from southwestern Ontario, recruited for a larger study of genetic and other biological and contextual influences on child temperament and psychopathology risk. Children’s mean age was 36.2 months (SD = 0.16). Over half of participants (50.4%) in this sample also came from middle-income families with family income ranging from $40,000 to $100,000 CAD (see Table 1 for further details). The family demographic data for this sample closely resembles the most recent London, Ontario census data available [Statistics Canada, 2006]. Children were administered the PPVT-4 to screen for gross cognitive impairment and English proficiency (M = 112.4, SD = 14.8).

Informed consent was obtained from the parent prior to participation. Both studies were approved by the respective university’s human subjects ethics review committees.

Genotyping

Genomic DNA was purified from buccal swab cellular extracts and stored according to manufacturer instructions (Qiagen, Valencia, CA, USA). Following Ruiz-Sanz et al. (2007), an allele-specific PCR detection method was used to determine the COMT val158met genotype. Briefly, allele specific primers containing specificity enhancing mismatches, 5′-CGGATGGTGGATTTCGCTGaCG-3′ (G-allele specific) and TCAGGCATGCACACCTTGTCCTTtAT (A-allele specific), were used in the presence of control primers to amplify allele specific amplicons. The PCR conditions used were: 5 minutes of initial denaturation at 94 °C followed by 30 cycles of 30 s of denaturation at 94 °C, 30s annealing at 62°C and 20 s of extension at 72 °C, followed by a final extension of 5 minutes at 72 °C. To improve reaction fidelity, we used the Invitrogen PCRx Enhancer (Invitrogen, Carlsbad, CA, USA) as an adjuvant in our PCR amplifications. Amplicons were separated on 6% polyacrylamide gels, visualized using ethidium bromide and documented using the Bio-Rad 2000 gel documentation system (Bio-Rad Laboratories, Mississauga, ON, Canada). All genotyping was performed by technicians unaware of other study data.

In Study 1, 141 children (34.1%) were valine homozygous, 199 (48.2%) were heterozygous, and 73 (17.7%) children were homozygous for the methionine substitution. These genotypic frequencies are in Hardy-Weinberg equilibrium (χ2 = 0.04; p = 0.85). In Study 2, 118 children (29.4%) were valine homozygous, 190 (46.3%) were heterozygous, and 93 (23.2%) children were homozygous for the methionine substitution, also in Hardy-Weinberg equilibrium [χ2 = 0.95; p = 0.33].

In Study 1, the Preschool Age Psychiatric Assessment [PAPA; Egger et al., 2006] Version 1.4 was used to assess symptoms of psychopathology as defined by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria [American Psychiatric Association, 1994] relevant to children in this age group. The PAPA is the first published diagnostic interview to assess parent-reported psychopathology in children between the ages of two and five years. It uses a structured format and an interviewer-based approach. Symptoms occurring three months prior to the interview are rated to enhance accurate recall. Adequate test–retest reliability has been reported [range of intra-class correlations (ICC) for dimensional symptom scores = 0.56–0.80, median = 0.66, Egger et al., 2006]. For this study, we used PAPA indices of depressive and anxious symptoms. We also used symptoms of oppositional defiant disorder (ODD) and attention deficit/hyperactivity disorder (ADHD) to determine whether the COMT genotypes were related specifically to depressive and anxious symptoms or general manifestations of psychopathology. Dimensional scores were created by summing the ratings of all items included in the algorithms created by Egger et al. [2006] to derive child’s depressive and anxiety symptoms and symptoms of ODD and ADHD. Interviews were conducted by advanced graduate students in clinical psychology who received training on the administration of the PAPA from a member of the PAPA group. To examine inter-rater reliability, a second rater independently rated audiotapes of 21 PAPA interviews. ICCs for the symptom scales used in this study were as follows: depression (0.85), anxiety (1.00), ODD (0.99) and ADHD (0.99). Internal consistency (α) was calculated for each symptom scale and indicated good reliability for depression (α = 0.75), anxiety (α = 0.83), ODD (α = 0.84) and ADHD (α = 0.89).

In Study 2, symptom data were obtained by having the child’s primary caregiver complete the Early Childhood Inventory-4 [ECI-4; Gadow and Sprafkin, 1997]. The ECI-4 is a 108-item behavior rating scale that assesses symptoms of 15 DSM-IV childhood emotional and behavioral disorders. The ECI-4 has shown satisfactory test-retest reliability, as well as concurrent and predictive validity [Sprafkin et al., 2002]. For the present study, symptom count scores for depression, generalized anxiety disorder, ODD and ADHD were created using the sums of those symptoms rated as occurring “often” or “very often” [Gadow and Sprafkin, 2000].

Data Analyses

First, associations were examined between COMT genotypes and child psychopathology symptoms on the PAPA (Study 1) and ECI-4 (Study 2). These associations were tested under dominant, recessive and co-dominant models for the ancestral allele (val allele). To address potential population stratification, we conducted our analyses on the Caucasian participants based on parent-reported ethnicity in both samples. After excluding non-whites, for final analysis, we had 413 and 371 children from Study 1 and Study 2, respectively. As some children had no parent-reported symptoms, we used non-parametric tests (Mann-Whitney U test) for some analyses as needed. All tests were conducted using PSAW 18.

Results

Symptoms were unassociated with demographic variables such as child gender and socioeconomic status in either sample (all ps > 0.56). We also did not find any associations between child gender and the COMT genotypes (all ps > 0.10). In Study 1, we found significant associations between COMT genotypes and PAPA symptoms under a valine recessive model (Table 2). The COMT val158met polymorphism was associated with child internalizing symptoms assessed by the PAPA, such that children with at least one copy of the val allele had significantly higher symptoms of anxiety and depression (all ps < 0.05). In contrast, the two COMT val158met allelic groups did not differ significantly on ODD and ADHD symptoms (all ps > 0.42).

Table 2.

Study variables by child COMT genotype.

Variable Child COMT val158met Genotype
Study 1 (Stony Brook University)a Study 2 (Western University)b
val/val (N = 73) val/met + met/met (N =340) val/val (N = 102) val/met + met/met (N =260)
M (SD) M (SD) M (SD) M (SD)
Anxiety 11.09 (7.23)* 9.19 (8.39)* 9.66 (2.18)† 9.02 (1.92)†
Depression 5.12 (4.19)** 3.89 (4.37)** 13.21 (0.70)* 12.65 (1.52)*
ODD 5.36 (7.83) 4.81 (6.74) 13.44 (3.24) 12.99 (3.12)
ADHD 2.60 (6.19) 2.75 (6.50) 36.70 (9.22) 35.79 (8.01)
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†

p < 0.10,

*

p < .05,

**

p < .01.

1

Mean ranks were tested using Wilcoxon rank sum test, as symptom scores were not normally distributed due to absence of internalizing symptoms in some children. These children received a score of ‘0’ on the relevant symptom sub-scale on the PAPA.

a

Symptom data based on maternal interview reports from the PAPA.

b

Primary caregiver reports from the ECI-4.

Note: N, sample size; SD, standard deviation; PPVT, Peabody Picture Vocabulary Test; SES, socioeconomic status as indexed by Hollingshead’s Four Factor Index of Social Status [Hollingshead, 1975]; PAPA, Preschool Age Psychiatric Assessment; ECI-4, Early Childhood Inventory-4 [Gadow and Sprafkin, 1997]; COMT, Catechol-O-methyltransferase; val, valine; met, methionine.

Table 2 also shows associations between COMT val158met genotype and primary caregiver reported emotional and behavioral symptoms on the ECI-4. Consistent with the results from Study 1, we observed positive associations between child depressive symptoms and the COMT val158met genotype under a val recessive model. According to primary caregiver reports, val homozygotes exhibited higher symptoms of depression than children with at least one copy of the met allele. The relationship between val158met genotypes and symptom reports on the ECI-4 generalized anxiety disorder (GAD) reached only a trend level. No associations were found between COMT genotype and externalizing symptoms such as ODD and ADHD (all ps > 0.22).

Discussion

We examined whether the COMT val158met gene polymorphism was associated with psychopathological symptoms in preschoolers in two separate samples. Findings from both samples indicate that the COMT val158met functional polymorphism is associated with symptoms of depression (and anxiety in one of the samples) in young children but not with child externalizing symptoms. More specifically, our analysis shows that children homozygous for the val allele have more depressive symptoms than children with at least one copy of the met allele. These findings are consistent with recent association studies in samples of adolescents [Wahlstrom et al., 2007; Nobile et al., 2010] and adults [Enoch et al., 2003; McGrath et al., 2004; Massat, 2005], in which the val allele was associated with significantly higher anxious and depressive symptoms.

The associations we found may be mediated by the influence of the COMT genotype on dopamine function in the brain, which has been implicated in neurobiological models of depression. Dopamine plays a critical role in synaptic plasticity through multiple mechanisms. For example, it controls the activity of AMPA and NMDA receptors through phosphorylation, and it also regulates voltage-gated ion channels such as sodium and calcium channels by affecting their phosphorylation state as well (Girault and Greengard, 2004). The increased clearing of dopamine in val homozygotes may affect synaptic plasticity through secondary mechanisms involving AMPA and NMDA receptor activity, which may lead to cognitive and other deficits, and thus increased depressive and anxious symptoms. While speculative, some observations support this hypothesis; for example, in a recent study of a community sample of pre-adolescent children, met carriers performed better on prefrontal-dependent tests of cognition such as working memory tasks (Barnett et al., 2007). Data from functional neuroimaging studies also show decreased prefrontal activation in the val homozygotes compared with the met carriers while completing tests of executive function [Mier, Kirsch and Meyer-Lindenberg, 2010]. In light of the fact that both decreased prefrontal activation and early cognitive deficits, such as poor performance on working memory tasks, have been consistently associated with increased risk for both anxiety and depression later in life [see Drevets, Price and Furey, 2008; Gotlib and Joormann, 2010; Marazziti et al., 2010, for reviews], genetic influences on cognition may shape one early-emerging pathway to internalizing disorder.

Our findings are contrary to some reports in the adult literature indicating that the met allele increases risk for internalizing disorders [Baekken et al., 2008; Wray et al., 2008; Aberg et al., 2011], and studies that show no effect for this gene polymorphism at all [Middledrop et al., 2010]. Some have posited that the failures of replication and inconsistent nature of findings regarding the COMT val158met polymorphism in adults could be due to confounding influences such as sex, ethnicity, and current or previous history of mental disorders. First, with regard to sex, COMT enzyme activity differs greatly in adult males and females, with females having significantly lower prefrontal cortex COMT activity [Chen et al., 2004]; furthermore, some data indicate that estradiol acts as a regulator of COMT expression in adult females [Karayiorgou et al., 1999; Worda et al., 2003]. Therefore, the influence of estradiol may be an important confound in studies exploring links between the COMT polymorphism and internalizing symptoms in adults that has not been consistently or effectively addressed in study designs. Second, in a recent meta-analysis, Domscke et al. (2007) found ethnicity-specific associations between COMT gene and internalizing disorders, with Caucasian adults homozygous for the val allele exhibiting greater internalizing problems; in contrast, the met allele carriers of Asian descent reported higher internalizing problems. Taken together, the use of an ethnically homogenous sample of preschoolers may have helped us minimize these possible confounds.

A major strength of our study is the use of two independent samples to investigate links between the COMT val158met polymorphism and depressive symptoms, but our study also had a few limitations. Although we conducted our associations in an ethnically homogenous sample, population stratification could still be a factor, although experts differ in opinion regarding the impact of population stratification [Hutchison et al., 2004]. It is also plausible that other functional polymorphisms flanking the COMT SNP could be in linkage-disequilibrium with these loci and may lead to type I errors, but the functional nature of this polymorphism, and the replication of our results, makes this an unlikely possibility. Furthermore, complex phenotypes of high heritability such as depression and anxiety are influenced by the interplay of many different genes [Reif and Lesch, 2003]. Therefore, the role of the dopamine system in the development of internalizing disorders is likely regulated by the interaction between multiple genes [see Opmeer, Kortekaas and Aleman, 2010 for an overview]; future research designs should investigate the effect of such interactions on early neurodevelopment. In spite of these limitations, we believe that the current study makes an important addition to the literature on molecular genetics of internalizing phenotypes. To our knowledge, this is the first study of its kind to report and replicate associations between COMT val158met polymorphism and early-emerging depressive symptoms.

Acknowledgments

This research was supported by research grants from Canadian Institutes of Health Research Institutes (CIHR), Children’s Health Research Institute and Ontario Ministry of Research and Innovation to Dr. Elizabeth P. Hayden. This work is also supported by research grants from CIHR and Ontario Mental Health Foundation to Dr. Shiva M. Singh.

This study was supported by a Young Investigator award from NARSAD and a CIHR operating grant to Elizabeth P. Hayden. This research was also funded by GCRC grant no. M01-RR10710 to Stony Brook University from the National Center for Research Resources and a National Institute of Mental Health grant R01 MH069942 to Daniel N. Klein.

Footnotes

Financial Disclosure

Authors have no financial disclosures or conflicts of interests to declare.

Contributor Information

Haroon I. Sheikh, Western University

Katie R. Kryski, Western University

Heather J. Smith, Western University

Lea R. Dougherty, University of Maryland

Daniel N. Klein, Stony Brook University

Sara J. Bufferd, Stony Brook University

Shiva M. Singh, Western University

Elizabeth P. Hayden, Western University

References

  1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th. Washington, DC: Author; 2000. [Google Scholar]
  2. Aberg E, Fandiño-Losada A, Sjöholm LK, Forsell Y, Lavebratt C. The functional Val(158)Met polymorphism in catechol-O-methyltransferase (COMT) is associated with depression and motivation in men from a Swedish population-based study. J Affect Disord. 2011;129:158–66. doi: 10.1016/j.jad.2010.08.009. [DOI] [PubMed] [Google Scholar]
  3. Arnsten AF, Li BM. Neurobiology of executive functions: catecholamine influences on prefrontal cortical functions. Biol Psychiatry. 2005;57:1377–84. doi: 10.1016/j.biopsych.2004.08.019. [DOI] [PubMed] [Google Scholar]
  4. Baekken PM, Skorpen F, Stordal E, Zwart JA, Hagen K. Depression and anxiety in relation to catechol-O-methyltransferase Val158Met genotype in the general population: the Nord-Trøndelag Health Study (HUNT) BMC Psychiatry. 2008;25:48. doi: 10.1186/1471-244X-8-48. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bardone AM, Moffitt TE, Caspi A, Dickson N, Silva PA. Adult mental health and social outcomes of adolescent girls with depression and conduct disorder. Dev Psychopathol. 1996;8:811–829. [Google Scholar]
  6. Bierut LJ, Heath AC, Bucholz KK, Dinwiddie SH, Madden PA, Statham DJ, et al. Major depressive disorder in a community-based twin sample: are there different genetic and environmental contributions for men and women? Arch Gen Psychiatry. 1999;56:557–63. doi: 10.1001/archpsyc.56.6.557. [DOI] [PubMed] [Google Scholar]
  7. Brahe C, Bannetta P, Meera-Khan P, Arwert F, Serra A. Assignment of the catechol-O-methyltransferase gene to human chromosome 22 in somatic cell hybrids. Hum Genet. 1986;74:230–234. doi: 10.1007/BF00282539. [DOI] [PubMed] [Google Scholar]
  8. Brocki K, Clerkin SM, Guise KG, Fan J, Fossella JA. Assessing the molecular genetics of the development of executive attention in children: focus on genetic pathways related to the anterior cingulate cortex and dopamine. Neuroscience. 2009;164:241–246. doi: 10.1016/j.neuroscience.2009.01.029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Bosker FJ, Hartman CA, Nolte IM, Prins BP, Terpstra P, Posthuma D, et al. Poor replication of candidate genes for major depressive disorder using genome-wide association data. Mol Psychiatry. 2011;16:516–32. doi: 10.1038/mp.2010.38. [DOI] [PubMed] [Google Scholar]
  10. Chen J, Lipska BK, Halim N, Ma QD, Matsumoto M, Melhem S, et al. Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet. 2004;75:807–821. doi: 10.1086/425589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Chen C, Chen C, Moyzis R, Dong Q, He Q, Zhu B, et al. Sex modulates the associations between the COMT gene and personality traits. Neuropsychopharmacology. 2011;36:1593–1598. doi: 10.1038/npp.2011.39. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Demetrovics Z, Varga G, Szekely A, Vereczkei A, Csorba J, Balazs H, et al. Association between Novelty Seeking of opiate-dependent patients and the catechol-O-methyltransferase Val(158)Met polymorphism. Compr Psychiatry. 2010;51:510–515. doi: 10.1016/j.comppsych.2009.11.008. [DOI] [PubMed] [Google Scholar]
  13. Domschke K, Deckert J, O’donovan MC, Glatt SJ. Meta-analysis of COMT val158met in panic disorder: ethnic heterogeneity and gender specificity. Am J Med Genet B Neuropsychiatr Genet. 2007;144B:667–73. doi: 10.1002/ajmg.b.30494. [DOI] [PubMed] [Google Scholar]
  14. Dremencov E, El Mansari M, Blier P. Effects of sustained serotonin reuptake inhibition on the firing of dopamine neurons in the rat ventral tegmental area. J Psychiatry Neurosci. 2009;4:223–229. [PMC free article] [PubMed] [Google Scholar]
  15. Drevets WC, Price JL, Furey ML. Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Struct Funct. 2008;213:93–118. doi: 10.1007/s00429-008-0189-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Dunn LM, Dunn LM. Peabody picture vocabulary test. 3rd. Circle Pines, Minnesota: American Guidance Service; 1997. [Google Scholar]
  17. Egger HL, Erkanli A, Keeler G, Potts E, Walter BK, Angold A. Test-retest reliability of the preschool age psychiatric assessment (PAPA) J Am Acad Child Adolesc Psychiatry. 2006;45:538–549. doi: 10.1097/01.chi.0000205705.71194.b8. [DOI] [PubMed] [Google Scholar]
  18. Eley TC, Stevenson J. Exploring the covariation between anxiety and depression symptoms: A genetic analysis of the effects of age and sex. J Child Psychol Psych. 1999;40:1273–1282. [PubMed] [Google Scholar]
  19. Enoch MA, Xu K, Ferro E, Harris CR, Goldman D. Genetic origins of anxiety in women: a role for a functional catechol-O-methyltransferase polymorphism. Psychiatr Genet. 2003;13(1):33–41. doi: 10.1097/00041444-200303000-00006. [DOI] [PubMed] [Google Scholar]
  20. Fergusson DM, Woodward LJ. Mental health, educational and social role outcomes of adolescents with depression. Arch Gen Psych. 2002;59:225–231. doi: 10.1001/archpsyc.59.3.225. [DOI] [PubMed] [Google Scholar]
  21. Fox NA, Henderson HA, Marshall PJ, Nichols KE, Ghera MM. Behavioral inhibition: Linking biology and behavior within a developmental framework. Annu Rev Psychol. 2005;56:235–262. doi: 10.1146/annurev.psych.55.090902.141532. [DOI] [PubMed] [Google Scholar]
  22. Gadow KD, Sprafkin J. Early Childhood Inventory-4 Norms Manual. New York: Checkmate Plus; 1997. [Google Scholar]
  23. Gogos JA, Morgan M, Luine V, Santha M, Ogawa S, Pfaff D, Karayiorgou M. Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proc Natl Acad Sci U S A. 1998;95:9991–6. doi: 10.1073/pnas.95.17.9991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Goldman-Rakic PS. The cortical dopamine system: Role in memory and cognition. Adv Pharmacol. 1998;42:707–711. doi: 10.1016/s1054-3589(08)60846-7. [DOI] [PubMed] [Google Scholar]
  25. Golimbet VE, Alfimova MV, Gritsenko IK, Ebstein RP. Relationship between dopamine system genes and extraversion and novelty seeking. Neurosci Behav Physiol. 2007;37:601–606. doi: 10.1007/s11055-007-0058-8. [DOI] [PubMed] [Google Scholar]
  26. Gotlib IH, Joormann J. Cognition and depression: current status and future directions. Annu Rev Clin Psychol. 2010;6:285–312. doi: 10.1146/annurev.clinpsy.121208.131305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Hamilton SP, Slager SL, Heiman GA, Deng Z, Haghighi F, Klein DF, et al. Evidence for a susceptibility locus for panic disorder near the catechol-O-methyltransferase gene on chromosome 22. Biol Psychiatry. 2002;51:591–601. doi: 10.1016/s0006-3223(01)01322-1. [DOI] [PubMed] [Google Scholar]
  28. Hettema JM, An SS, Bukszar J, van den Oord EJ, Neale MC, Kendler KS, Chen X. Catechol-O-methyltransferase contributes to genetic susceptibility shared among anxiety spectrum phenotypes. Biol Psychiatry. 2008;64:302–10. doi: 10.1016/j.biopsych.2008.03.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Hollingshead AB. Four factor index of social status. 1975 Unpublished manuscript. [Google Scholar]
  30. Hofstra MB, van der Ende J, Verhulst FC. Continuity and change of psychopathology from childhood into adulthood: a 14-year follow-up study. J Am Acad Child Adolesc Psychiatry. 2000;39:850–858. doi: 10.1097/00004583-200007000-00013. [DOI] [PubMed] [Google Scholar]
  31. Hosák L. Role of the COMT gene Val158Met polymorphism in mental disorders: a review. Eur Psychiatry. 2007;22:276–81. doi: 10.1016/j.eurpsy.2007.02.002. [DOI] [PubMed] [Google Scholar]
  32. Hutchison KE, Stallings M, McGeary J, Bryan A. Population stratification in the candidate gene study: fatal threat or red herring? Psychol Bull. 2004;130:66–79. doi: 10.1037/0033-2909.130.1.66. [DOI] [PubMed] [Google Scholar]
  33. Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG. Replication validity of genetic association studies. Nat Genet. 2001;29:306–9. doi: 10.1038/ng749. [DOI] [PubMed] [Google Scholar]
  34. Karayiorgou M, Sobin C, Blundell ML, Galke BL, Malinova L, Goldberg P, et al. Family-based association studies support a sexually dimorphic effect of COMT and MAOA on genetic susceptibility to obsessive-compulsive disorder. Biol Psychiatry. 1999;45:1178–1189. doi: 10.1016/s0006-3223(98)00319-9. [DOI] [PubMed] [Google Scholar]
  35. Kessler RC, McGonagale KA, Zhao S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: results from the National Comorbidity Survey. Arc Gen Psychiatry. 1994;51:8–19. doi: 10.1001/archpsyc.1994.03950010008002. [DOI] [PubMed] [Google Scholar]
  36. Kendler KS, Prescott CA. A population-based twin study of lifetime major depression in men and women. Arch Gen Psychiatry. 1999;56:39–44. doi: 10.1001/archpsyc.56.1.39. [DOI] [PubMed] [Google Scholar]
  37. Kendler KS, Gatz M, Gardner CO, Pedersen NL. A Swedish national twin study of lifetime major depression. Am J Psychiatry. 2006;163:109–14. doi: 10.1176/appi.ajp.163.1.109. [DOI] [PubMed] [Google Scholar]
  38. Krishnan V, Nestler EJ. Linking molecules to mood: new insight into the biology of depression. Am J Psychiatry. 2010;167:1305–20. doi: 10.1176/appi.ajp.2009.10030434. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM. Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics. 1996;6:243–250. doi: 10.1097/00008571-199606000-00007. [DOI] [PubMed] [Google Scholar]
  40. Lavigne JV, Arend R, Rosenbaum D, Binns HJ, Christoffel KK, Gibbons RD. Psychiatric disorders with onset in the preschool years: II: correlates and predictors of stable case status. J Am Acad Child Adolesc Psychiatry. 1998;37:1255–1261. doi: 10.1097/00004583-199812000-00008. [DOI] [PubMed] [Google Scholar]
  41. Lotta T, Vidgren J, Tilgmann C, Ulmanen I, Melén K, Julkunen I, et al. Kinetics of human soluble and membranebound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry. 1995;34:4202–4210. doi: 10.1021/bi00013a008. [DOI] [PubMed] [Google Scholar]
  42. Marazziti D, Consoli G, Picchetti M, Carlini M, Faravelli L. Cognitive impairment in major depression. Eur J Pharmacol. 2010;626:83–6. doi: 10.1016/j.ejphar.2009.08.046. [DOI] [PubMed] [Google Scholar]
  43. Martinot M, Bragulat V, Artiges E, Dollé F, Hinnen F, Jouvent R, Martinot J. Decreased presynaptic dopamine function in the left caudate of depressed patients with affective flattening and psychomotor retardation. Am J Psychiatry. 2001;158:314–6. doi: 10.1176/appi.ajp.158.2.314. [DOI] [PubMed] [Google Scholar]
  44. Massat I, Souery D, Del-Favero J, Nothen M, Blackwood D, Muir W, et al. Association between COMT (Val158Met) functional polymorphism and early onset in patients with major depressive disorder in a European multicenter genetic association study. Mol Psychiatry. 2005;10:598–605. doi: 10.1038/sj.mp.4001615. [DOI] [PubMed] [Google Scholar]
  45. Massat I, Kocabas NA, Crisafulli C, Chiesa A, Calati R, Linotte S, et al. COMT and age at onset in mood disorders: a replication and extension study. Neurosci Lett. 2011;438:218–21. doi: 10.1016/j.neulet.2011.05.012. [DOI] [PubMed] [Google Scholar]
  46. McGrath M, Kawachi I, Ascherio A, Colditz GA, Hunter DJ, De Vivo I. Association between catechol-O-methyltransferase and phobic anxiety. Am J Psychiatry. 2004;161:1703–1705. doi: 10.1176/appi.ajp.161.9.1703. [DOI] [PubMed] [Google Scholar]
  47. Mesman J, Koot H. Early preschool predictors of preadolescent internalizing and externalizing DSM-IV diagnosis. J Am Acad Child Adolesc Psychiatry. 2001;40:1029–1036. doi: 10.1097/00004583-200109000-00011. [DOI] [PubMed] [Google Scholar]
  48. Mesman J, Bongers IL, Koot HM. Preschool Developmental Pathways to Preadolescent Internalizing and Externalizing Problems. J Chil Psychol Psych. 2001;42:679–689. [PubMed] [Google Scholar]
  49. Meyer JH. Neuroimaging markers of cellular function in major depressive disorder: implications for therapeutics, personalized medicine, and prevention. Clin Pharmacol Ther. 2012;91:201–14. doi: 10.1038/clpt.2011.285. [DOI] [PubMed] [Google Scholar]
  50. Meyers N, Fromm S, Luckenbaugh DA, Drevets WC, Hasler G. Neural correlates of sleepiness induced by catecholamine depletion. Psychiatry Res. 2011;194:73–8. doi: 10.1016/j.pscychresns.2011.06.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Meyer-Lindenberg A, Weinberger DR. Intermediate phenotypes and genetic mechanisms of psychiatric disorders. Nat Rev Neurosci. 2006;7:818–827. doi: 10.1038/nrn1993. [DOI] [PubMed] [Google Scholar]
  52. Middeldorp CM, Slof-Op’t Landt MC, Medland SE, van Beijsterveldt CE, Bartels M, et al. Anxiety and depression in children and adults: influence of serotonergic and neurotrophic genes? Genes Brain Behav. 2010;9:808–16. doi: 10.1111/j.1601-183X.2010.00619.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Mier D, Kirsch P, Meyer-Lindenberg A. Neural substrates of pleiotropic action of genetic variation in COMT: a meta-analysis. Mol Psychiatry. 2010;15:918–27. doi: 10.1038/mp.2009.36. [DOI] [PubMed] [Google Scholar]
  54. Nestler EJ, Carlezon WA., Jr The mesolimbic dopamine reward circuit in depression. Biol Psychiatry. 2006;59:1151–1159. doi: 10.1016/j.biopsych.2005.09.018. [DOI] [PubMed] [Google Scholar]
  55. Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron. 2002;34:13–25. doi: 10.1016/s0896-6273(02)00653-0. [DOI] [PubMed] [Google Scholar]
  56. Nobile M, Rusconi M, Bellina M, Marino C, Giorda R, Carlet O, et al. COMT Val158Met polymorphism and socioeconomic status interact to predict attention deficit/hyperactivity problems in children aged 10–14. Eur Child Adolesc Psychiatry. 2010;19:549–57. doi: 10.1007/s00787-009-0080-1. [DOI] [PubMed] [Google Scholar]
  57. Olfson M, Marcus SC, Druss B, Elinson L, Tanielian T, Pincus HA. National trends in the outpatient treatment of depression. JAMA. 2002;287:203–209. doi: 10.1001/jama.287.2.203. [DOI] [PubMed] [Google Scholar]
  58. Opmeer EM, Kortekaas R, Aleman A. Depression and the role of genes involved in dopamine metabolism and signalling. Prog Neurobiol. 2010;92:112–33. doi: 10.1016/j.pneurobio.2010.06.003. [DOI] [PubMed] [Google Scholar]
  59. Papaleo F, Crawley JN, Song J, Lipska BK, Pickel J, Weinberger DR, et al. Genetic dissection of the role of catechol-O-methyltransferase in cognition and stress reactivity in mice. J Neurosci. 2008;28:8709–23. doi: 10.1523/JNEUROSCI.2077-08.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Pogorelov VM, Rodriguiz RM, Insco ML, Caron MG, Wetsel WC. Novelty seeking and stereotypic activation of behavior in mice with disruption of the Dat1 gene. Neuropsychopharmacology. 2005;30:1818–1831. doi: 10.1038/sj.npp.1300724. [DOI] [PubMed] [Google Scholar]
  61. Reif A, Lesch KP. Toward a molecular architecture of personality. Behav Brain Res. 2003;139:1–20. doi: 10.1016/s0166-4328(02)00267-x. [DOI] [PubMed] [Google Scholar]
  62. Reiger DA, Narrow WE, Rae DS, Manderscheid RW, Locke BZ, Goodwin FK. The de facto US mental and addictive disorders service system: Epidemiologic Catchment Area prospective 1-year prevalence rates of disorders and services. Arc Gen Psychiatry. 1993;50:85–94. doi: 10.1001/archpsyc.1993.01820140007001. [DOI] [PubMed] [Google Scholar]
  63. Rothe C, Koszycki D, Bradwejn J, King N, Deluca V, Tharmalingam S, et al. Association of the Val158Met catechol O-methyltransferase genetic polymorphism with panic disorder. Neuropsychopharmacology. 2006;31:2237–2242. doi: 10.1038/sj.npp.1301048. [DOI] [PubMed] [Google Scholar]
  64. Ruiz-Sanz JI, Aurrekoetxea I, del Agua AR, Ruiz-Larrea MB. Detection of catechol-O-methyltransferase Val158Met polymorphism by a simple one-step tetra-primer amplification refractory mutation system-PCR. Mol Cell Prob. 2007;21:202–207. doi: 10.1016/j.mcp.2006.12.001. [DOI] [PubMed] [Google Scholar]
  65. Ruhe HG, Mason NS, Schene AH. Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies. Mol Psychiatry. 2007;12:331–359. doi: 10.1038/sj.mp.4001949. [DOI] [PubMed] [Google Scholar]
  66. Sprafkin J, Volpe RJ, Gadow KD, Nolan EE, Kelly K. A DSM-IV referenced screening instrument for preschool children: The Early Childhood Inventory–4. J Am Acad Chil Adol Psych. 2002;41:604–612. doi: 10.1097/00004583-200205000-00018. [DOI] [PubMed] [Google Scholar]
  67. Sowell ER, Peterson BS, Thompson PM, Welcome SE, Henkenius AL, Toga AW. Mapping cortical change across the human life span. Nat Neurosci. 2003;6:309–315. doi: 10.1038/nn1008. [DOI] [PubMed] [Google Scholar]
  68. Wahlstrom D, White T, Hooper CJ, Vrshek-Schallhorn S, Oetting WS, Brott MJ, et al. Variations in the catechol O-methyltransferase polymorphism and prefrontally guided behaviors in adolescents. Biol Psychiatry. 2007;61:626–632. doi: 10.1016/j.biopsych.2006.05.045. [DOI] [PubMed] [Google Scholar]
  69. Wray NR, James MR, Dumenil T, Handoko HY, Lind PA, Montgomery GW, et al. Association study of candidate variants of COMT with neuroticism, anxiety and depression. Am J Med Genet B Neuropsychiatr Genet. 2008;147:1314–8. doi: 10.1002/ajmg.b.30744. [DOI] [PubMed] [Google Scholar]
  70. Willner P. Animal models of depression: validity and applications. Adv Biochem Psychopharmacol. 1995;49:19–41. [PubMed] [Google Scholar]
  71. Woodward LJ, Fergusson DM. Life course outcomes of young people with anxiety disorders in adolescence. J Am Acad Child Adolesc Psychiatry. 2001;40:1086–93. doi: 10.1097/00004583-200109000-00018. [DOI] [PubMed] [Google Scholar]
  72. Worda C, Sator MO, Schneeberger C, Jantschev T, Ferlitsch K, Huber JC. Influence of the catechol-O-methyltransferase (COMT) codon 158 polymorphism on estrogen levels in women. Hum Reprod. 2003;18:262–266. doi: 10.1093/humrep/deg059. [DOI] [PubMed] [Google Scholar]
  73. Zahn–Waxler, Klimes–Dougan, Slattery MJ. Internalizing problems of childhood and adolescence: Prospects, pitfalls, and progress in understanding the development of anxiety and depression. Dev & Psychopathol. 2000;12:443–466. [PubMed] [Google Scholar]
  74. Zintzaras E, Lau J. Synthesis of genetic association studies for pertinent gene-disease associations requires appropriate methodological and statistical approaches. J Clin Epidemiol. 2008;61:634–45. doi: 10.1016/j.jclinepi.2007.12.011. [DOI] [PubMed] [Google Scholar]

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