Exploring the moderating effects of dopaminergic polymorphisms and childhood adversity on brain morphology in schizophrenia-spectrum disorders
Introduction
Schizophrenia is a psychiatric illness that typically emerges during late adolescence, and often results in a lifetime of disability (Lewis and Lieberman, 2000). Although the disorder appears to lack a discretely causal aetiology, dopaminergic abnormalities remain a central hypothesis of the pathophysiology of schizophrenia and are the primary target of current pharmacological treatments (Howes and Kapur, 2009). The dopamine hypothesis of schizophrenia suggests that characteristic symptoms such as hallucinations, delusions and abnormal cognitive functioning are caused by a synergistic imbalance of dopamine neurotransmission in cortical and subcortical brain regions (Howes and Kapur, 2009). Thus, genetic variants and brain regions implicated in the function of the dopaminergic system may contribute to the disorder's aetiology.
A number of variants within genes in the dopaminergic system have been studied, and among them, the dopamine receptor D2 (DRD2) and catechol-o-methytransferase (COMT) genes have arguably been interrogated the most. DRD2 was recently identified as one of 108 loci associated with schizophrenia in the largest schizophrenia genome-wide association study to date (Psychiatric Genomics Consortium, 2014). One highly researched DRD2 variant that occurs at rs1076560 (G > T) determines whether mRNA splices into long or short isoforms (Zheng et al., 2012). Past literature has identified this substitution as a risk-conferring variant for schizophrenia, most likely due to the resultant decrease of dopamine transmission in the frontal cortex (Tallerico et al., 2001, Zheng et al., 2012). Another relevant DRD2 mutation is located at rs12364283 (T > C). This polymorphism results in enhanced total D2 mRNA expression, which may exacerbate already elevated striatal dopamine transmission in patients with schizophrenia (Bertolino et al., 2009a). A third DRD2 variant relevant to schizophrenia occurs at rs1801028 (C > G), where cysteine production replaces serine production. A meta-analysis has suggested that there is a link between this polymorphism and an increased susceptibility to schizophrenia through alteration of D2 receptor physiology and functioning (Glatt et al., 2003). Some of these DRD2 variants have also been shown to effect schizophrenia-associated intermediate phenotypes such as disrupted prefrontal-striatal activity (Bertolino et al., 2008) and morphological changes including smaller caudate volumes (Bertolino et al., 2009b). Lastly, a mutation in the COMT gene at rs4680 (A > G) enhances coding of valine instead of methionine, resulting in a higher enzymatic catabolism of dopamine in the prefrontal cortex (Egan et al., 2001). Whilst some studies have identified COMT as a possible candidate gene for schizophrenia (Kunugi et al., 1997, Li et al., 2000, Wonodi et al., 2003), others have revealed no association between the val/met polymorphism and the disorder (de Chaldée et al., 2001, Okochi et al., 2009). As opposed to the manifested clinical outcome, the COMT polymorphism is much more strongly associated with schizophrenia-related intermediate phenotypes such as brain morphology; for example, volumetric changes in the hippocampus and dorsolateral prefrontal cortex (DLPFC) (Cerasa et al., 2008, Honea et al., 2009, Kates et al., 2006). It has been widely accepted that these observed gene-brain associations are likely due to the interactive and cumulative effect of molecular mechanisms downstream from genotype (Harrison and Weinberger, 2005), which are heavily affected by environmental influences (van Os et al., 2008a).
One potent and established environmental risk factor for schizophrenia and other psychiatric disorders is childhood adversity (Matheson et al., 2013). Childhood adversity has been defined as any form of emotional or physical ill-treatment, sexual abuse, exploitation or neglect during childhood or teen years (Rosenman and Rodgers, 2004). Perhaps the most frequently reported types of early trauma associated with psychosis are sexual and physical abuse, which are often examined together (Davies-Netzley et al., 1996, Read et al., 2003, Read and Argyle, 1999). Since attributing salience to threatening or adverse environmental stimuli (Kapur, 2003) and stress-mediated responses (Laruelle, 2000) both implicate the dopamine system, childhood adversity may contribute to pathological dopamine neurotransmission and, in turn, alter neurobiology (Read et al., 2005, Van Winkel et al., 2008, Walker et al., 2008). In those who have experienced early maltreatment, atrophy has been especially noted in the hippocampus (Bremner et al., 1997, Hoy et al., 2012, Rao et al., 2010, Woon and Hedges, 2008) and may occur in other dopamine-related regions such as the prefrontal cortex and striatal structures (Cohen et al., 2006, Frodl et al., 2010, Tomoda et al., 2009). It has been proposed that early physical and emotional adversities each have specific neurobiological targets, as different neural mechanisms and pathways are employed to cope with different types of traumatic experience (Edmiston et al., 2011, Teicher and Samson, 2016). As such, exposure to physical abuse, emotional abuse or emotional neglect may have regionally-specific effects on the brain.
Notably, not all individuals who carry ‘risk’ polymorphisms or experience childhood adversity develop schizophrenia, suggesting genetic and environmental factors likely interact rather than act alone. As such, the current study used a gene × environment (G × E) framework to investigate the interaction between genetic variation in dopaminergic genes (DRD2 and COMT) and childhood adversity in determining schizophrenia-associated brain morphology. Although there is a wealth of G × E literature examining schizophrenia (Tienari et al., 2004, van Os et al., 2008a, Wahlberg et al., 1997), few studies have utilized this framework to investigate intermediate phenotypes associated with the disorder. The present study focused on brain structures which have shown to be both atrophied in schizophrenia patients and influenced by genetic and environmental factors, thus fulfilling the two defining targets of an intermediate phenotype (Meyer-Lindenberg and Weinberger, 2006). These structures were the hippocampus, DLPFC, nucleus accumbens, caudate nucleus and putamen. It was hypothesised that individuals with a high proportion of dopaminergic ‘risk’ polymorphisms, elevated levels of childhood adversity and a diagnosis of schizophrenia-spectrum disorders would have the lowest volumes in these brain regions.
Section snippets
Participants
Participant data was obtained from the Australian Schizophrenia Research Bank (ASRB); an ongoing register that commenced data collection in 2010 and is funded by the National Health and Medical Research Council (Loughland et al., 2010). Participants were screened by clinical assessment officers over the telephone. Exclusion criteria for ASRB participation included severe brain injury, organic brain syndrome, movement disorders, mental retardation categorized by an intellectual quotient below
Results
As indicated in Supplementary Table S1, CAQ scores of the schizophrenia-spectrum cohort ranged from 0 to 19 and had a mean (SD) of 5.53 (4.52) out of 21. These scores were significantly higher (p < 0.001) than those of the healthy controls, who had scores ranging from 0 to 14 and a mean (SD) of 2.83 (3.49). CAQ scores did not differ between males and females (t = −0.3, p = 0.602). The schizophrenia-spectrum cohort were more likely to report physical abuse (p = 0.009), emotional abuse (p
Discussion
The current study used the dopamine hypothesis of schizophrenia to identify genetic and environmental factors which may play a role in disorder-associated brain morphology. With the exception of the left putamen, there were no brain regions whose size was predicted by a main effect of dopaminergic RAL. This is in contrast with past literature which has found an association between the COMT polymorphism and volumetric alterations in the hippocampus and DLPFC (Cerasa et al., 2008, Honea et al.,
Acknowledgments
We thank the Chief Investigators and ASRB Manager: Carr V, Schall U, Scott R, Jablensky A, Mowry B, Michie P, Catts S, Henskens F, Pantelis C, Loughland C. We acknowledge the help of Jason Bridge for ASRB database queries.
Financial support
Data for this study were provided by the Australian Schizophrenia Research Bank (ASRB), which is supported by the Australian National Health and Medical Research Council (NHMRC) (Enabling Grant No. 386500), the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation and the Schizophrenia Research Institute. TVR was supported by an NHMRC Peter Doherty Fellowship (1088785). SS was supported by One-in-Five Association Incorporated. CSW is funded by the NSW Ministry of Health,
Conflict of interest
None.
Ethical standards
The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008.
References (78)
- et al.
Confirmation of reduced temporal limbic structure volume on magnetic resonance imaging in male patients with schizophrenia
Psychiatry Res.
(1996) - et al.
Magnetic resonance imaging-based measurement of hippocampal volume in posttraumatic stress disorder related to childhood physical and sexual abuse—a preliminary report
Biol. Psychiatry
(1997) - et al.
Striatal enlargement in rats chronically treated with neuroleptic
Biol. Psychiatry
(1998) - et al.
No evidence for linkage between COMT and schizophrenia in a French population
Psychiatry Res.
(2001) - et al.
Early life stress and morphometry of the adult anterior cingulate cortex and caudate nuclei
Biol. Psychiatry
(2006) - et al.
Neurobiological findings in early phase schizophrenia
Brain Res. Rev.
(2000) - et al.
An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest
Neuroimage
(2006) - et al.
Childhood adversity is associated with left basal ganglia dysfunction during reward anticipation in adulthood
Biol. Psychiatry
(2009) - et al.
Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain
Neuron
(2002) - et al.
Interaction of childhood stress with hippocampus and prefrontal cortex volume reduction in major depression
J. Psychiatr. Res.
(2010)
Network-level neuroplasticity in cortico-basal ganglia pathways
Parkinsonism Relat. Disord.
Caudate, putamen, and globus pallidus volume in schizophrenia: a quantitative MRI study
Psychiatry Res.
Impact of interacting functional variants in COMT on regional gray matter volume in human brain
Neuroimage
Gray matter volume reduction in rostral middle frontal gyrus in patients with chronic schizophrenia
Schizophr. Res.
The role of endogenous sensitization in the pathophysiology of schizophrenia: implications from recent brain imaging studies
Brain Res. Rev.
Childhood adversity predicts earlier onset of major depression but not reduced hippocampal volume
Psychiatry Res.
Catching up on schizophrenia: natural history and neurobiology
Neuron
Meta-analysis of association between genetic variants in COMT and schizophrenia: an update
Schizophr. Res.
Hippocampal changes associated with early-life adversity and vulnerability to depression
Biol. Psychiatry
Schizophrenia: elevated mRNA for dopamine D2(Longer) receptors in frontal cortex
Brain Res. Mol. Brain Res.
Reduced prefrontal cortical gray matter volume in young adults exposed to harsh corporal punishment
Neuroimage
Rs1076560, a functional variant of the dopamine D2 receptor gene, confers risk of schizophrenia in Han Chinese
Neurosci. Lett.
Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database
Nat. Genet.
Amygdala enlargement in bipolar disorder and hippocampal reduction in schizophrenia: an MRI study demonstrating neuroanatomic specificity
Arch. Gen. Psychiatry
Functional variants of the dopamine receptor D2 gene modulate prefronto-striatal phenotypes in schizophrenia
Brain
Functional variants of the dopamine receptor D2 gene modulate prefronto-striatal phenotypes in schizophrenia
Brain
Genetically determined interaction between the dopamine transporter and the D2 receptor on prefronto-striatal activity and volume in humans
J. Neurosci.
The adolescent brain
Ann. N. Y. Acad. Sci.
The diagnostic interview for psychoses (DIP): development, reliability and applications
Psychol. Med.
Impact of catechol-O-methyltransferase Val108/158 Met genotype on hippocampal and prefrontal gray matter volume
Neuroreport
Increase in caudate nuclei volumes of first-episode schizophrenic patients taking antipsychotic drugs
Am. J. Psychiatry
COMT Val158Met-stress interaction in psychosis: role of background psychosis risk
CNS Neurosci. Ther.
Biological insights from 108 schizophrenia-associated genetic loci
Nature
Childhood abuse as a precursor to homelessness for homeless women with severe mental illness
Violence Vict.
Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor
Hum. Mol. Genet.
Corticostriatal-limbic gray matter morphology in adolescents with self-reported exposure to childhood maltreatment
Arch. Pediatr. Adolesc. Med.
Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia
Proc. Natl. Acad. Sci.
Automatically parcellating the human cerebral cortex
Cereb. Cortex
Meta-analysis identifies an association between the dopamine D2 receptor gene and schizophrenia
Mol. Psychiatry
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2021, Neuroscience and Biobehavioral ReviewsCitation Excerpt :However, the responsiveness of the PFC to stress appears to make the region highly sensitive to stress-induced remodelling. Several sMRI studies have associated psychological stress with reductions in cortical volume across the medial PFC (mPFC) (Ansell et al., 2012; Hanson et al., 2010), orbitofrontal cortex (OFC) (Holz et al., 2015; Monninger et al., 2020), ventromedial PFC (VMPFC) (Moreno et al., 2017; Gold et al., 2016), dorsolateral PFC (DLPFC) (Underwood et al., 2019; Hoffmann et al., 2018), cingulate cortex (Heim et al., 2013; Gianaros et al., 2007) and the underlying white matter (Gianaros et al., 2013) (Table 1). An extensive review by Savitz and Drevets (2009) also notes that the PFC, including the OFC, VMPFC, DLPFC, and cingulate cortex, generally exhibit decreased volume, and reduced functional activation in cases of depression and bipolar disorder.