Journal of Psychiatric Research 49 (2014) 43e50

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Catechol-O-methyltransferase (COMT) genotype moderates the effects of childhood trauma on cognition and symptoms in schizophrenia Melissa J. Green a, b, *, T.-Yunn Chia a, b, Murray J. Cairns b, c, d, Jingqin Wu c, d, Paul A. Tooney b, c, d, Rodney J. Scott b, c, d, e, Vaughan J. Carr a, b, on behalf of the Australian Schizophrenia Research Bank a

School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia Schizophrenia Research Institute, Darlinghurst, NSW, Australia School of Biomedical Sciences and Pharmacy, Faculty of Health, The University of Newcastle, Callaghan, NSW 2308, Australia d Centre for Brain and Mental Health and Centre for Information-Based Medicine, University of Newcastle and Hunter Medical Research Institute, Newcastle, NSW, Australia e Hunter Area Pathology Service, Newcastle, NSW, Australia b c

a r t i c l e i n f o

a b s t r a c t

Article history: Received 29 November 2012 Received in revised form 28 October 2013 Accepted 29 October 2013

The interaction of genetic and environmental factors may affect the course and development of psychotic disorders. We examined whether the effects of childhood trauma on cognition and symptoms in schizophrenia were moderated by the Catechol-O-methyltransferase (COMT) Val158Met polymorphism, a common genetic variant known to affect cognition and prefrontal dopamine levels. Participants were 429 schizophrenia/schizoaffective cases from the Australian Schizophrenia Research Bank (ASRB). Cognitive performance was assessed using the Repeatable Battery for Assessment of Neuropsychological Status (RBANS), Controlled Oral Word Association Test (COWAT), Letter Number Sequencing (LNS) test, and the Wechsler Test of Adult Reading (WTAR). Hierarchical regression was used to test the main effects and additive interaction effects of genotype and childhood trauma in the domains of physical abuse, emotional abuse, and emotional neglect, on cognition and symptom profiles of clinical cases. Consistent with previous findings, COMT Val homozygotes performed worse on cognitive measures in the absence of childhood adversity. In addition, a significant interaction between COMT genotype and physical abuse was associated with better executive function in Val homozygotes, relative to those of the same genotype with no history of abuse. Finally, the severity of positive symptoms was greater in Met carriers who had experienced physical abuse, and the severity of negative symptoms in Met carriers was greater in the presence of emotional neglect. These results suggest that the possible epigenetic modulation of the expression of the COMT Val158Met polymorphism and consequent effects on cognition and symptoms in schizophrenia, with worse outcomes associated with adverse childhood experiences in Met carriers. Ó 2013 Elsevier Ltd. All rights reserved.

Keywords: Catechol-O-methyltransferase (COMT) Childhood adversity Trauma Cognition Symptoms Psychosis Epigenetics Genetics

1. Introduction The development of psychotic disorders is believed to involve the interaction of multiple biological and environmental factors, and it is increasingly recognized that epigenetic processes set in motion by early social experiences, play a crucial role in modulating neurocognitive development (Champagne and Curley, 2009; Read et al., 2009). In particular, adverse events in childhood, including * Corresponding author. c/- UNSW Research Unit for Schizophrenia Epidemiology, St. Vincent’s Hospital, Darlinghurst, NSW 2031, Australia. Tel.: þ61 (0)2 9382 8382; fax: þ61 (0)2 8382 1584. E-mail address: [email protected] (M.J. Green). 0022-3956/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jpsychires.2013.10.018

maltreatment, may be important causal influences during the growth and maturation of the brain throughout development (Husted et al., 2010). Maltreated children show smaller cerebral and intra-cranial volumes compared to healthy controls (De Bellis et al., 1999), such that the substantial variance in brain volume reduction in schizophrenia may be partially explained by childhood abuse (Sheffield et al., 2013). While childhood trauma and other types of adversity are now well established as a significant risk factor for the development of several mental disorders, including psychosis (Janssen et al., 2004; Kessler et al., 2010; Read and Bentall, 2010), the non-specific impact of early childhood trauma on adult mental health outcomes implies a modulatory role of common genetic variants, and/or the influence of epigenetic processes set off by

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M.J. Green et al. / Journal of Psychiatric Research 49 (2014) 43e50

early maltreatment, producing long-lasting effects on the brain (Weaver, 2007). It is plausible also that clinical manifestations differ according to individual variation in common genetic polymorphisms. This study examined whether variation in a common polymorphism associated with prefrontal dopamine availability (and cognitive function) e the Catechol-O-methyltransferase (COMT) single nucleotide polymorphism (SNP; rs4680) e moderates the influence of childhood adversity on cognition and symptoms in schizophrenia and schizoaffective disorder. Childhood adversity refers to a number of experiences in the early stages of life including maltreatment (encompassing physical, sexual or emotional abuse and various forms of neglect), parental loss or divorce, parental substance abuse, and poverty (Rosenberg et al., 2007). Considerable evidence implicates physical, emotional and sexual abuse, as well as emotional neglect, in the development of mental disorders (Kessler et al., 2010; Spataro et al., 2004), including the psychoses (Hammersley et al., 2003; Janssen et al., 2004; Matheson et al., 2013; Read et al., 2010; Varese et al., 2012). While sexual abuse has been reported as a significant risk factor alone (Cutajar et al., 2010), a recent meta-analysis shows no evidence that any particular type of trauma is a stronger predictor of psychosis than the others (Varese et al., 2012). However, one recent study reported higher rates of emotional neglect in psychotic patients, with higher rates of physical abuse and neglect differentiating individuals with schizophrenia spectrum from those with bipolar (affective) psychosis (Larsson et al., 2013). These types of childhood adversities have also been associated with lower intelligence and reading ability in healthy people (Koenen et al., 2003; Pears et al., 2008; Perez and Widom, 1994), and to contribute to neurocognitive deficits in borderline personality disorder (Afifi et al., 2011; Minzenberg et al., 2008), schizophrenia (Lysaker et al., 2001; Shannon et al., 2009) and first episode psychosis (Aas et al., 2011); although there is other evidence demonstrating no association between childhood adversity and executive function or verbal ability in schizophrenia (Schenkel et al., 2005). Several studies have recently investigated the effects of trauma in the context of common genetic variation, showing a significant interaction between variants of the serotonin transporter (5HTTLPR) gene and physical childhood trauma (neglect and abuse) contributing to worse cognitive functioning in first-episode patients (Aas et al., 2012). Three studies of the interaction of the COMT Val158Met genotype and stress reactivity have shown increased symptoms in response to stress in psychotic individuals homozygous for the Met allele (Collip et al., 2011; Peerbooms et al., 2012; van Winkel et al., 2008). In addition, one recent study shows differential effects of childhood adversity according to the COMT Val158Met genotype in the context of cannabis use; notably, Met/ Met homozygotes demonstrated the more severe psychotic symptom expression in those who did not use cannabis, while the main finding of this study was that Val/Val homozygotes showed the highest levels of psychotic symptoms in the context of cannabis use (Vinkers et al., 2013). The COMT Val158Met SNP has been long implicated in cognitive function owing to its effects on the enzyme that regulates dopamine concentration in the prefrontal cortex (PFC) (MeyerLindenberg et al., 2006; Savitz et al., 2006). In particular, the (high-activity) Val allele on the COMT Val158Met SNP is associated with faster dopamine catabolism compared to the (lowactivity) Met allele, resulting in a greater breakdown of dopamine within the PFC (Savitz et al., 2006). The low-activity Met allele of the COMT Val158Met SNP is associated with better PFC function (and associated cognitive processes) in healthy people, as well as in schizophrenia patients and their unaffected siblings, such that Met carriers perform better than Val/Val homozygotes on tasks assessing executive (PFC) function (Egan

et al., 2001; Joober et al., 2002; Wirgenes et al., 2010). There is also evidence that the Val allele of the COMT Val158Met SNP is associated with changes in brain morphology in schizophrenia, such as decreased brain volume in the left anterior cingulate cortices and amygdala, relative to healthy individuals (Ohnishi et al., 2006), though this is not unequivocally supported (Ho, Wassink, O’Leary, Sheffield, & Andreasen, 2005). Finally, the COMT Val158Met SNP (Val allele) has also been associated with greater positive symptoms in schizophrenia (Goghari and Sponheim, 2008). With consideration of the evidence from parallel streams of literature which support associations of the COMT Val158Met SNP with cognition and symptom expression in schizophrenia, as well as associations between childhood adversity and cognitive impairment, and childhood adversity and psychosis, we reasoned that a combination of both these risk factors may interact to contribute to the variation in the cognitive profile and clinical presentation of schizophrenia and schizoaffective disorder (Bilder et al., 2002; Golimbet et al., 2006; Lysaker et al., 2001). The effect of interaction of the COMT Val158Met SNP and the presence of childhood adversity on cognition and symptom profiles was examined in schizophrenia participants to determine if a combination of specific genetic variation and childhood adversity has a greater influence on clinical phenomenology and cognitive functioning compared to the effects of each of these risk factors alone. We expected that individuals homozygous for the Val allele on the COMT Val158Met SNP would demonstrate greater cognitive deficits, and more severe expression of positive and negative symptoms, in the presence of childhood adversity (physical abuse, emotional abuse and emotional neglect). 2. Materials and methods The study procedures were approved by the Human Research Ethics Committee of the University of New South Wales (UNSW Protocol No. 07167). 2.1. Participants Participants were recruited from the Australian Schizophrenia Research Bank (ASRB), an established register of participants and research data collected by scientific collaborators across five Australian states/territories (i.e., New South Wales, Australian Capital Territory, Queensland, Victoria, Western Australia) (Loughland et al., 2011). The ASRB represents a bio-bank funded by the Australian National Health and Medical Research Council that is open for access by any team of scientists wanting to test particular hypotheses afforded by these data; formal access protocols ensure appropriate use of the data for relevant scientific purposes. The profile of childhood adversity scores for the full ASRB sample have been published elsewhere (McCabe et al., 2012); the ASRB participants included in this study were those with genotyped DNA available, including 429 participants with an ICD-10 diagnosis of schizophrenia (360 cases) or schizoaffective disorder (69 cases) confirmed on the basis of structured diagnostic interview (Castle et al., 2006). Together, the cases analysed comprised 282 males [65.7%] and 147 females [34.3%], with a mean age of 39.31 (SD ¼ 0.53; range 20e65 years). Exclusion criteria included an inability to converse fluently in English, organic brain disorder, brain injury with greater than 24 h post-traumatic amnesia, mental retardation (IQ < 70), movement disorders, current diagnosis of substance dependence, and/or electroconvulsive therapy received in the last 6 months. The majority of the cases were medicated, with 398 participants taking anti-psychotic medication, 69 taking a mood stabiliser, and 145 taking anti-depressants. A comparison

M.J. Green et al. / Journal of Psychiatric Research 49 (2014) 43e50

group of 652 healthy controls comprising 118 males (50.2%) and 117 females (49.8%) with a mean age of 37.49 (SD ¼ 0.83; range 18e62 years) provided a comparison group for descriptive characteristics and the frequency of childhood adversity. The control participants had no personal history of DSM-IV Axis 1 disorder, and no history of psychotic disorder in their first-degree biological relatives. 2.2. Clinical assessments Clinical and diagnostic information was obtained using the Diagnostic Interview for Psychosis (DIP), conducted by trained research staff (Castle et al., 2006). We used specific DIP items to determine the severity of positive and negative symptoms. A positive symptom count was obtained by computing the total score of lifetime hallucination and delusion scores from the DIP (DIP items 49 to 53 and 58 to 64, respectively), while a negative symptom count was obtained via summation of DIP items assessing restricted affect, blunted affect, and negative formal thought disorder (DIP items 90, 91 and 97) as well as indices of social functioning (two items assessing social withdrawal and lack of interest) obtained from the Socio-demographic and Clinical History Schedule of the ASRB interview. Cases of schizophrenia and schizo-affective disorder were combined to form a single group for statistical analyses, hereafter referred to as schizophrenia spectrum disorders. 2.3. Neuropsychological assessments Neuropsychological indices of attention and memory function were derived from the Repeatable Battery for Neuropsychological Status - memory and attention subtests (Randolph, 1998), and executive function was assessed using the Controlled Oral Word Association Test (COWAT) (Spreen and Benton, 1969) and the Letter number sequencing (LNS) subtest of the WAIS-III (Wechsler, 1997). The Wechsler Test of Adult Reading (WTAR) (Wechsler, 2001) was used to estimate intelligence quotient (IQ). 2.4. Measures of childhood adversity The Childhood Adversity Questionnaire (CAQ) (Rosenman and Rodgers, 2004) was administered to all participants to provide a measure of childhood maltreatment within the immediate family. The CAQ comprises 21 items, with three items each for seven subscales, referring to physical abuse, emotional abuse, emotional neglect, sexual abuse, loss, family dysfunction and financial difficulties (Moore et al., 2011). A total childhood adversity score was derived by summing values from 21 items, as well as two items obtained from the ASRB assessment of the developmental history of participants referring to experiences of parental loss (e.g., parental death) and sibling loss that were not assessed by the CAQ. In addition, we undertook specific investigation of the CAQ responses on three particular subscales (namely, physical abuse, emotional abuse, and emotional neglect) on the basis of previous evidence implicating these types of adversity in psychosis and cognition. 2.5. Genotyping COMT Val158Met genotyping for SNP rs4680 was performed using Infinium Human 610 K BeadChips according to the manufacturer’s instructions (Illumina). Briefly, 200 ng of gDNA was amplified, fragmented and denatured before hybridization. After washing, extension, and staining steps, the BeadChips were dried and scanned on the Illumina BeadArray Reader. A gene call threshold of 0.15 and standard cluster file, provided by Illumina using a multi-ethnic HapMap population, were used to calculate

45

SNP and sample statistics. The potential for population stratification artefact was considered via Principal Components Analysis of these data on a genome-wide scale, following methods reported by Price et al. (Price et al., 2006) revealed that less than 2% of cases analysed in the current study (i.e., 5 of 429 schizophrenia spectrum participants) were likely to be of non-caucasian descent. 2.6. Statistical analysis All analyses were performed using SPSS version 21 with a significance threshold set at p < 0.01 to partially control for Type 1 error. The interacting effects of genotype and childhood adversity on cognition and symptomatology in schizophrenia were examined via two series of hierarchical regression analyses: the first series investigated the effects of genotype and total childhood adversity score on cognition and symptoms in schizophrenia spectrum cases; the second series of analyses examined the effects of genotype on the same cognitive and symptom variables in the context of specific types of childhood adversity (i.e., physical abuse, emotional abuse and emotional neglect respectively). For both sets of analyses, interaction terms between the COMT Val158Met SNP and components of childhood adversity were created for multivariate analyses to test the effects of (1) childhood adversity, (2) COMT genotype, and (3) their interaction (G  E) on cognition and symptom profiles in schizophrenia spectrum cases. The equations for analyses involving total childhood adversity scores, and subtypes of childhood adversity, respectively, are as follows: 1. Dependent variable ¼ b0 þ b1(COMT) þ b2(total childhood adversity scores) þ b3 (COMT  total childhood adversity scores). 2. Dependent Variable ¼ b0 þ b1(COMT) þ b2(Physical abuse) þ b3(Emotional abuse) þ b4(Emotional neglect) þ b5 (COMT  physical abuse) þ b6 (COMT x emotional abuse) þ b7 (COMT  emotional neglect). The COMT genotypes were coded as 2 ¼ Val/Val, 1 ¼ Val/Met, 0 ¼ Met/Met, and each childhood adversity item was coded dichotomously (1 ¼ childhood adversity present, 0 ¼ no childhood adversity). Main-effect terms were entered into the first step of the model and interaction terms were entered in the second step. Posthoc analyses were carried out for significant interactions, using linear regressions conducted on binary data, in order to determine the effect of each COMT genotype on cognition and symptomatology in the presence of various subtypes of childhood adversity. For post-hoc regressions contrasting effects of Met and Val homozygotes, genotype data was recoded to exclude the heterozygotes, with 0 ¼ Met/Met and 1 ¼ Val/Val. 3. Results 3.1. Sample characteristics Sample demographics, neurocognitive performance, observed genotype frequencies and total childhood adversity scores within each group are shown in Table 1. Clinical cases were more likely to be younger males, less educated and unemployed, and were significantly impaired in performance across all cognitive domains compared to healthy controls (Table 1). The schizophrenia spectrum cases reported higher rates of childhood adversity compared to healthy controls across all subtypes of interest on the CAQ (Table 1). Given the low rates of childhood adversity in the control sample, focal analyses were restricted to schizophrenia spectrum disorders, to determine G  E effects on cognition and psychotic symptoms (Table 2).

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M.J. Green et al. / Journal of Psychiatric Research 49 (2014) 43e50

Table 1 Sample characteristics of schizophrenia participants (Sz) and healthy controls (HC).

Gender (% male) Age (mean, SD) Years of education (mean, SD) % Employed (past year) WTAR scores (IQ estimate, mean, SD) Total COWAT score (executive functioning) (mean, SD) LNS score (working memory) (mean, SD) RBANS attention score (mean, SD) RBANS immediate memory score (mean, SD) RBANS delayed memory score (mean, SD) Total childhood adversity score (mean, SD) Sexual abuse Physical abuse Emotional abuse Emotional neglect Loss (parental death or divorce; sibling loss) Financial disadvantage Family dysfunction Genotype (%) a) Val/Val b) Val/Met c) Met/Met

Sz (n ¼ 617)

HC (n ¼ 659)

Comparison/OR (95% CI)

415(67.3%) 39.65(10.82) 12.92 (2.87) 318 (53.6%) 97.49 (15.04) 34.23 (12.43) 9.05 (2.98) 81.94 (17.28) 79.26 (17.89) 81.57 (17.26) 6.25 (4.87) 33 (5.35%) 125 (20.26%) 203 (32.90%) 251 (40.68%) 251 (40.68%) 115 (18.6%) 409 (66.29%)

291(44.2%) 42.48 (13.58) 14.97 (3.09) 621 (95.5%) 105.47 (10.67) 43.58 (11.60) 11.90 (2.79) 104.12 (15.29) 101.12 (14.87) 98.31 (11.02) 2.85 (3.19) 6 (0.91%) 68 (10.32%) 102 (15.48%) 129 (20.91%) 205 (31.11%) 86 (13.05%) 356 (54.02%)

c21 ¼ 68.82; p ¼ 0.000, OR ¼ 0.385 (95% CI 0.306e0.483) t ¼ 4.111; p ¼ 0.000 t ¼ 12.25; p ¼ 0.000 c21 ¼ 294.85; p ¼ 0.000, OR ¼ 0.05 (95% CI 0.04e0.08) t ¼ 10.95; p ¼ 0.000 t ¼ 7.13.89; p ¼ 0.000 t ¼ 17.52; p ¼ 0.000 t ¼ 24.26; p ¼ 0.000 t ¼ 23.75. p ¼ 0.000 t ¼ 20.74; p ¼ 0.000 t ¼ 12.25; p ¼ 0.000 c21 ¼ 22.41; p ¼ 0.000, OR ¼ 6.47 (95% CI 2.68e15.58) c21 ¼ 28.79; p ¼ 0.000, OR ¼ 2.42 (95% CI 1.74e3.36) c21 ¼ 64.99; p ¼ 0.000, OR ¼ 3.16 (95% CI 2.38e4.21) c21 ¼ 85.08; p ¼ 0.000, OR ¼ 3.53 (95% CI 2.69e4.63) c21 ¼ 12.10; p ¼ 0.001, OR ¼ 1.51 (95% CI 1.20e1.90) c21 ¼ 9.56; p ¼ 0.002, OR ¼ 1.64 (95% CI 1.20e2.24) c21 ¼ 55.13; p ¼ 0.000, OR ¼ 3.85 (95% CI 2.65e5.59)

109 (25.4%) 224 (52.2%) 96 (22.4%)

c22 ¼ 6.82; p ¼ 0.03

56 (23.8%) 105 (44.7%) 74 (31.5%)

adversity scores and/or COMT genotype on positive (F ¼ 0.94; p ¼ 0.42) or negative symptom severity (F ¼ 0.60; p ¼ 0.62).

3.2. Genotype frequencies and differences among genotypes The frequencies of the three COMT genotypes in all participants are shown in Table 1. The distribution of the COMT genotypes were in HardyeWeinberg equilibrium for both clinical cases (c2 ¼ 0.88, df ¼ 1, p ¼ 0.65) and controls (c2 ¼ 2.4, df ¼ 1, p ¼ 0.88), and there was a statistically non-significant trend towards difference in allelic distribution between clinical cases and healthy controls, suggesting a greater proportion of control participants with Met homozygosity (c2 ¼ 6.82; df ¼ 2, p ¼ 0.03). There were no differences in the severity of positive or negative symptoms among genotype groups. However, there was a significant difference between genotypes in the use of mood stabilisers, with Met/Met homozygotes more likely to be taking mood stabilisers than Val carriers or homozygotes (c2 ¼ 13.14, df ¼ 2, p ¼ 0.01). 3.3. Effects of COMT genotype and total childhood adversity on cognition and symptoms The first set of hierarchical regressions involving total childhood adversity scores in schizophrenia spectrum cases revealed no significant main effects or interactions of COMT genotype or total adversity on any cognitive measure, including the WTAR (F ¼ 0.66; p ¼ 0.58), COWAT (F ¼ 0.13, p ¼ 0.94), LNS (F ¼ 0.12; p ¼ 0.95), RBANS attention (F ¼ 0.14; p ¼ 0.94), RBANS immediate memory (F ¼ 0.59; p ¼ 0.62) and RBANS delayed memory (F ¼ 0.42; p ¼ 0.74). Likewise, there were no significant main effects of total

3.4. Effects of COMT genotype and subtypes of childhood adversity Separate hierarchical regressions in schizophrenia spectrum cases for physical abuse, emotional abuse and emotional neglect were conducted for all cognitive measures, and both positive and negative symptom count. There was a significant main effect of COMT genotype on the RBANS subscales of attention, and immediate memory (P < 0.01) with significantly worse performance on these cognitive measures among Val/Val homozygotes, relative to other genotypes. In addition, there was a statistically non-significant trend towards an interaction between genotype and physical abuse for COWAT scores (Table 3); post-hoc regressions showed that this effect was explained by Val/Val homozygotes showing increased performance in the presence of physical abuse, relative to Val/Val homozygotes without a history of abuse. (Table 4; and see Fig. 1). 3.5. Symptoms Multivariate regression results for symptom severity measures are summarised in Table 3. For positive symptoms, there was a significant main effect of physical abuse (P < 0.01) and a significant interaction between genotype and physical neglect (P < 0.01). For negative symptoms, there were significant main effects for genotype (Val carriers) and emotional neglect (both P < 0.01), and a

Table 2 Results of significant regression analysis testing on geneeenvironment interaction effects on cognitive measures in cases. Predictor

WTAR scores B value SE

Genetic and environmental main effects COMT rs4680 4.679 Physical abuse 5.497 Emotional abuse 7.790 Emotional neglect 2.742 Gene  environment Interactions COMT rs4680  physical abuse 5.787 COMT rs4680  emotional 8.122 abuse COMT rs4680 x emotional 2.215 neglect

2.361 5.186 5.578 5.662

COWAT scores p

B value SE

RBANS attention scores RBANS immediate memory scores RBANS delayed memory scores p

B value

0.048 0.650 1.973 0.742 8.247 0.290 6.699 4.334 0.123 3.224 0.164 2.051 4.662 0.660 6.203 0.629 5.203 4.732 0.272 12.208

SE

p

B value

2.708 5.949 6.398 6.495

0.003 8.697 0.588 0.341 0.333 6.894 0.061 7.088

SE

p

B value

SE

p

2.791 6.132 6.595 6.695

0.002 0.956 0.297 0.291

6.314 5.327 4.284 8.531

2.724 5.984 6.437 6.534

0.021 0.374 0.506 0.193

9.071 4.536 0.046 1.080 4.366 0.805

6.051 6.226 0.332 7.532 5.992 0.210

2.348 6.626

6.418 6.176

0.715 0.284

1.543 4.195

6.263 6.028

0.806 0.487

5.082 0.663 5.783 4.272 0.174

11.293 5.829 0.054

7.045

6.009

0.242

6.829

5.865

0.245

5.428 0.287 5.224 0.121

M.J. Green et al. / Journal of Psychiatric Research 49 (2014) 43e50

abuse in our sample precluded analyses for this type of abuse (Lysaker et al., 2001), our findings suggest that the effects of child maltreatment may be moderated by genetic factors that exist as a biological foundation upon which these experiences tread. The apparent ‘plasticity’ of the (high-activity enzyme) Val allele in the context of childhood adversity is particularly intriguing given it’s usual detrimental effects on prefrontal dopamine function and cognition. In line with other studies of childhood trauma and psychosis, we found a significant main effect of physical (but not emotional) abuse, on positive symptomatology, despite previous evidence of a strong relationship between emotional abuse and positive symptoms (Lysaker et al., 2001; Malinosky-Rummell and Hansen, 1993; Read et al., 2003; Read, van Os, Morrison, & Ross, 2005). However, both physical abuse and emotional neglect alone were associated with greater severity of positive and negative symptoms, respectively (both as main effects), and abuse  genotype interactions pointed towards greater positive and negative symptoms in Met homozygotes in the presence of physical abuse and emotional neglect (respectively). The more severe expression of symptoms shown here for Met homozygotes in the context of childhood trauma may reflect an epigenetically mediated exacerbation of the normally higher dopamine (DA) levels associated with the lowactivity Met allele, consistent with recent studies demonstrating greater symptoms in Met-homozygotes in response to stressful life events (Collip et al., 2011; Peerbooms et al., 2012; van Winkel et al., 2008). Moreover, the main effects of the (Val/Val; high activity) genotype in relation to poor attention and immediate memory performance is consistent with effects of low DA activity in the prefrontal cortex affecting the efficiency of function; similarly the association of Val/Val with increased negative symptoms in the absence of childhood adversity may also be seen as consistent with the effects of low DA in the prefrontal cortex. Conversely, in the presence of physical abuse, the effect of better cognition for Val/Val genotypes suggests an indirect effect of trauma to increase prefrontal DA activity in the context of trauma; likewise, in the presence of emotional neglect, the finding of fewer negative symptoms in Val/ Val genotypes also suggests (unusually, for this genotype) increased prefrontal cortical DA activity arising in the context of emotional neglect. Together, these findings suggest that childhood adversities may instigate an epigenetically mediated down-regulation of the Val/Val genotype expression (and consequent reduction in enzyme activity) with a resulting increase in DA activity. In this respect, it might be that ‘abusive’ trauma epigenetically instigates dysfunction in fear/stress pathways in the brain, affecting the expression of genetic loci relevant to DA levels such as the COMT Val158Met polymorphism. Recent understanding of epigenetic mechanisms has also been pioneered by animal work showing that early maternal deprivation leads to aberrant development of brain regions specifically associated with memory and regulation of the hypothalamic-pituitary

Table 3 Results of Significant Regression Analysis testing on GeneeEnvironment interaction Effects on Symptomatology in Cases. Predictor

Positive symptom count Negative symptom count B value

SE

Genetic and environmental main effects COMT rs4680 0.740 0.656 Physical abuse 3.673 1.440 Emotional abuse 0.599 1.549 Emotional neglect 2.950 1.572 Gene  environment interactions COMT rs4680  physical 3.685 1.507 abuse COMT rs4680  emotional 1.281 1.450 abuse COMT rs4680  emotional 2.748 1.411 neglect

p

B value

SE

p

0.260 0.011 0.699 0.062

1.106 0.137 0.430 2.656

0.286 0.629 0.676 0.686

0.000 0.828 0.525 0.000

0.015

0.027

0.658

0.967

0.378

0.518

0.633

0.414

0.053

2.176

0.616

0.000

47

significant interaction between genotype and emotional neglect (P < 0.01). Post-hoc regressions showed that Met homozygotes showed more severe negative symptoms in the presence of emotional neglect, and more severe positive symptoms in the presence of physical abuse, relative to Met/Met homozygotes without a history of these types of trauma. (Table 4; and see Fig. 1). 4. Discussion This study examined potential the moderating effect of the COMT Val158Met genotype on the effects of childhood adversity in cognitive deficits and symptom severity in patients with schizophrenia or schizoaffective disorder, following many significant associations between childhood trauma and psychosis (Kessler et al., 2010; Matheson et al., 2013; Read and Bentall, 2010), including a previous report in a larger cohort of this ASRB sample (McCabe et al., 2012). First, it is notable that there were no main effects of total childhood adversity on cognitive functioning in schizophrenia spectrum cases, consistent with one previous finding (Schenkel et al, 2005), though at odds with another study of first-episode psychosis (Aas et al., 2011). Our main findings with respect to cognitive functioning were that COMT Val homozygotes performed worse on measures of attention and immediate memory e regardless of experiences of childhood adversity and consistent with the usual effects of this allele (Egan et al., 2001; Joober et al., 2002; Wirgenes et al., 2010); in addition, an interaction between genotype and physical abuse impacted executive functioning in a positive direction, such that Val/Val homozygotes showed better executive function in the presence of physical abuse. With respect to symptomatology, there was a significant interaction between genotype and emotional neglect, in increasing the severity of negative symptoms for Met homozygotes. In addition, a significant interaction between physical abuse and genotype reflected greater positive symptoms in Met carriers with a history of this type of abuse. While the low prevalence of sexual

Table 4 Post Hoc regressions analysing the modulating effect of each COMT genotype for positive and negative symptom count. Genotype

Comparing Val/Val and Val/Met

Comparing Val/Met and Met/Met

Comparing Val/Val and Met/Met

B value Positive symptom count COMT rs4680 0.242 Physical abuse 2.256 Interaction between COMT rs4680 and physical abuse 1.144 Negative symptom count COMT rs4680 0.061 Emotional neglect 0.085 Interaction between COMT rs4680 and emotional neglect 0.159

SE

p

B value

SE

p

B value

SE

p

0.707 1.941 1.341

0.733 0.246 0.394

1.122 1.482 0.366

0.770 1.279 1.623

0.147 0.248 0.882

1.707 2.273 4.253

0.823 1.233 2.593

0.040 0.068 0.103

0.370 0.717 0.507

0.869 0.905 0.754

1.077 1.612 1.609

0.440 0.461 0.580

0.015 0.001 0.006

1.793 2.131 3.602

0.634 0.631 1.180

0.005 0.001 0.003

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M.J. Green et al. / Journal of Psychiatric Research 49 (2014) 43e50

Fig. 1. a: COWAT score is moderated by variations in the COMT rs4680 SNP in the presence of physical abuse as shown in Sz cases. b: Positive symptom count is moderated by variations in the COMT rs4680 SNP in the presence of physical abuse in Sz cases. c: Negative symptom count is moderated by variations in the COMT rs4680 SNP in the presence of emotional neglect as shown in Sz cases.

adrenal (HPA) axis (Weaver, 2007; Weaver et al., 2004). Adverse childhood experiences may affect dopamine systems via interactions with dysregulated HPA function that leads to hypercortisolaemia (Corcoran et al., 2003). Glucocorticoids are known to augment the action of dopamine in brain regions such as the mesolimbic system and the striatum (Czyrak et al., 2003; Dallman et al., 2004; Marinelli et al., 2006). Further neurobiological investigations of potential epigenetic mechanisms affecting DA and HPA function are therefore warranted. Limitations of this study include the possible effects of medication for which we have not controlled in this study owing to limited detail of medication dosage collected at the time of testing. These medications could have interacted with genotype to affect the cognition and symptomatology of clinical cases (Bilder et al.,

2002; Wang et al., 2010). In addition, despite the high relevance of sexual abuse for the development of psychosis (Cutajar et al., 2010), we were unable to assess the effects of this specific type of abuse owing to its low prevalence in this sample. We also acknowledge the limitations of the instrument used to assess sexual trauma from the parent only, which may therefore have been under reported if perpetrated by a second-degree relative. This limitation of the CAQ in focusing on adversities experienced at the hands of the parent/s meant that we were not able to consider other adverse effects arising in relationships with other individuals, which may not capture all possible experiences of abuse from other non-immediate family members and other life stresses which could have affected the severity of cognitive deficits and psychotic symptoms (Majer et al., 2010).

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With respect to the precise biological mechanisms of the current findings, these remain unclear since the COMT Val158Met polymorphism not only acts on dopamine catabolism, but also plays a role in the methylation of other catecholamine neurotransmitters including noradrenaline and adrenaline (Weinberger et al., 2001). We were unable to determine whether the effects of COMT on cognition and symptoms in this study reflect changes in dopamine activity or other biogenic amine neurotransmission (Bilder et al., 2002), nor can we determine the precise biological effects that early adversity is predicted to have on brain function (e.g. HPA axis dysregulation), including the proposed cascading effects on catecholamine neurotransmitters. Furthermore, we cannot discount the possibility that other genetic and biological factors not assessed here may also modulate the effects of childhood adversity in schizophrenia. In summary, this study provides evidence for a moderating role of the COMT Val158Met polymorphism in relation to the clinical and cognitive features of schizophrenia in the context of childhood experiences, suggesting that the functional alteration in the activity of COMT due to the amino acid change imparted by the different alleles, may act in combination with other genetic or environmental risk factors in the development of schizophrenia. Our findings suggest a potential protective role of the Val allele of the COMT Val158Met polymorphism with regard to the effects of childhood adversity on cognition, and a possible synergistic effect of adversity on Met carriers to increase the severity of symptoms. Future studies to replicate this finding, and address the limitations of the current study, are warranted. At the same time, clinical practice may be improved by asking about history of trauma and the development of psychotic symptoms, pointing to the role of anxiety and post-traumatic stress processes that may impact the clinical manifestations of psychosis. Role of the funding source The funding bodies acknowledged as providing financial support for this project had no role in the design of the study, collection and analysis of data, or the decision to publish. Contributors Author MJG conceptualised the study and oversaw the data analyses, and wrote the first draft of the manuscript; T-YC undertook the statistical analyses and contributed to the initial drafts of the manuscript; Authors MJC, JW, PAT, and RJS undertook the genotyping and assisted with the preparation of the manuscript; VJC oversaw the ASRB data collection and genetic analyses, and contributed to the interpretation of the analyses and preparation of the manuscript. Conflict of interest The authors declare no conflicts of interest. Acknowledgements This study used samples and data from the Australian Schizophrenia Research Bank (ASRB), funded by NHMRC Enabling Grant (No. 386500) held by V. Carr, U. Schall, R. Scott, A. Jablensky, B. Mowry, P. Michie, S. Catts, F. Henskens and C. Pantelis (Chief Investigators), and the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation, as well the Schizophrenia Research Institute, using an infrastructure grant from the NSW Ministry of Health. The work was also supported by NHMRC Project Grant (No. 630471) held by Green, and the Neurobehavioral Genetics Unit at

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the University of Newcastle using funding from NSW Health. MJG was supported by an Australian Research Council Future Fellowship (FT0991511) and the Netherlands Institute for Advanced Study in the Humanities and Social Sciences (NIAS: September 2013). We would like to acknowledge Carmel Loughland, Kathryn McCabe, and Jason Bridge for management and quality control of data obtained from the Australian Schizophrenia Research Bank. We also gratefully acknowledge the assistance of Bing Liu in relation to the assessment of population stratification. References Aas M, Dazzan P, Fisher HL, Morgan C, Morgan K, Reichenberg A, et al. Childhood trauma and cognitive function in first-episode affective and non-affective psychosis. Schizophr Res 2011;129:12e9. Aas M, Djurovic S, Athanasiu L, Steen NE, Agartz I, Lorentzen S, et al. Serotonin transporter gene polymorphism, childhood trauma, and cognition in patients with psychotic disorders. Schizophr Bull 2012;38:15e22. 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