Catechol-O-methyltransferase (COMT) genotype moderates the effects of childhood trauma on cognition and symptoms in schizophrenia
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 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 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) – the Catechol-O-methyltransferase (COMT) single nucleotide polymorphism (SNP; rs4680) – 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 and Bentall, 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 (5-HTTLPR) 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) (Meyer-Lindenberg 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 (low-activity) 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).
Section snippets
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).
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
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
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
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2019, Schizophrenia Research: CognitionCitation Excerpt :The potential predisposition of genetic risk factors to both CT and cognitive deficits in psychosis has received growing attention in recent years, in particular with the onset of candidate gene studies. Functional polymorphisms of the Catechol-O-Methyltransferase (COMT) genotype (Green et al., 2014), the FK506 binding protein 5 gene (Green et al., 2015) and brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (Theleritis et al., 2014; Aas et al., 2013) have been associated to cognitive deficits after the experience of CT. A relationship between CT exposure and cognitive deficits in psychosis has previously been hypothesized (Gilbertson et al., 2002; Cancel et al., 2015; Belanoff et al., 2001; Millan et al., 2012).