Oxytocin is a neuropeptide that is involved in the regulation of mood, anxiety and social biology... more Oxytocin is a neuropeptide that is involved in the regulation of mood, anxiety and social biology. Genetic variation in the oxytocin receptor gene (OXTR) has been implicated in anxiety, depression and related stress phenotypes. It is not yet known whether OXTR interacts with other risk factors such as early life trauma to heighten the severity of experienced anxiety and depression. In this study, we examined genotypes in 653 individuals and tested whether SNP variation in OXTR correlates with severity of features of self-reported experience on the Depression Anxiety and Stress Scale (DASS), and whether this correlation is enhanced when early life trauma is taken into account. We also assessed the effects of OXTR SNPs on RNA expression levels in two separate brain tissue cohorts totaling 365 samples. A significant effect of OXTR genotype on DASS anxiety, stress and depression scores was found and ELS events, in combination with several different OXTR SNPs, were significantly associat...
Background / Purpose: Brain connectivity is highly heritable, however the stability of these gene... more Background / Purpose: Brain connectivity is highly heritable, however the stability of these genetic factors across the adult lifespan is unknown.We applied quantitative genetic analyses and used diffusion tensor imaging (DTI) as a measure of brain connectivity to investigate the heritability (h 2) of white matter (WM) spanning 6 decades of the lifespan. Main conclusion: The systematic mapping of major white matter tracts is of pivotal clinical relevance, allowing age stratified characterization of transient neuroimaging biomarkers.The unique genetic topography for WM tracts can lead to better understanding of genetic plasticity underlying brain circuits and ultimately more realistic assessment of psychiatric and neurological disorders
Despite the significant advancements being made in the neurogenetics for mental health, the ident... more Despite the significant advancements being made in the neurogenetics for mental health, the identification and validation of potential endophenotype markers of risk and resilience remain to be confirmed. The TWIN-E study (The Twin study in Wellbeing using Integrative Neuroscience of Emotion) aims to validate endophenotype markers of mental health across cognitive, brain, and autonomic measures by testing the heritability, clinical plausibility, and reliability of each of these measures in a large adult twin cohort. The specific gene and environmental mechanisms that moderate prospective links between endophenotype-phenotype markers and the final outcome of wellbeing will also be identified. TWIN-E is a national prospective study with three phases: I) baseline testing on a battery of online questionnaires and cognitive tasks, and EEG, MRI, and autonomic testing; II) 12-month follow-up testing on the online assessments; and III) randomized controlled trial of brain training. Minimum t...
Biases toward processing negative versus positive information vary as a function of level of awar... more Biases toward processing negative versus positive information vary as a function of level of awareness, and are modulated by monoamines. Excessive biases are associated with individual differences in mood and emotional stability, and emotional disorder. Here, we examined the impact of the catechol-O-methyltransferase (COMT) Val(108/158)Met polymorphism, involved in dopamine and norepinephrine catabolism, on both emotional brain function and self-reported negativity bias. COMT genotyping and self-reported level of negativity bias were completed for 46 healthy participants taking part in the Brain Resource International Database. Functional MRI was undertaken during perception of facial expressions of fear and happiness presented under unmasked (consciously identified) and masked (to prevent conscious detection) conditions. Structural MR images were also acquired. A greater number of COMT Met alleles predicted increased activation in brainstem, amygdala, basal ganglia and medial prefrontal regions for conscious fear, but decreased activation for conscious happiness. This pattern was also apparent for brainstem activation for the masked condition. Effects were most apparent for females. These differences could not be explained by gray matter variations. The Met-related profile of activation, particularly prefrontally, predicted greater negativity bias associated with risk for emotional disorder. The findings suggest that the COMT Met allele modulates neural substrates of negative versus positive emotion processing. This effect may contribute to negativity biases, which confer susceptibility for emotional disorders.
The risk for mental illnesses such as depression is increasingly conceptualized as the product of... more The risk for mental illnesses such as depression is increasingly conceptualized as the product of gene-environment interactions and their impact on brain structure and function. The role of serotonin 3A receptor gene (HTR3A -42C>T polymorphism) and its interaction with early life stress (ELS) was investigated in view of the receptor's localization to brain regions central to emotion processing. Fronto-limbic grey matter (GM) loss was measured using magnetic resonance imaging and assessed using voxel-based morphometry analysis in 397 nonclinical individuals from the Brain Resource International Database. Negative mood symptoms were also assessed. The HTR3A CC genotype group, compared to the T carriers, demonstrated comparative loss to GM in hippocampal structures, which extended to the frontal cortices for those CC genotype individuals also exposed to ELS. Elevations in depressed mood were also evident. These findings suggest that the HTR3A CC genotype may be associated with alterations in brain structures central to emotion processing, particularly when exposed to stress, and further highlight the potential role of the serotonin system in the pathophysiology of affective disorders. In contrast, those individuals with the T allele, in particular the TT genotype, may be more protected from such alterations combined with minimal exposure to ELS events.
In this study, we examined whether the Met allele of the BDNF Val66Met polymorphism is associated... more In this study, we examined whether the Met allele of the BDNF Val66Met polymorphism is associated with selective disruptions to task-relevant information processing. In 475 non-clinical participants for whom BDNF genotype status was determined we used the 'IntegNeuro' computerized battery of neuropsychological tests to assess cognitive performance, an auditory oddball task to elicit the P300 event-related potential (ERP) and, in smaller subsets of these subjects, high resolution structural MRI imaging to quantify fronto-hippocampal grey matter (n=161), and functional magnetic resonance imaging to assess fronto-hippocampal BOLD activation (n=37). Met/Met (MM) homozygotes had higher verbal recall errors, in the absence of differences in attention, executive function, verbal ability or sensori-motor function. Further, MM homozygotes demonstrated a slowed P300 ERP during the oddball task, with corresponding alterations in hippocampal and lateral prefrontal activation, and a localized reduction in hippocampal grey matter. These results are consistent with a subtle impact of the Met allele on fronto-hippocampal systems involved in selective information processing of stimulus context and memory updating within the normal population. The findings also indicate that heritable endophenotypes such as the P300 have value in elucidating genotype-phenotype relationships.
Neuroimaging shows brain-functional differences due to apolipoprotein E (APOE) polymorphisms may ... more Neuroimaging shows brain-functional differences due to apolipoprotein E (APOE) polymorphisms may exist decades before the increased risk period for Alzheimer's disease, but little is known about their effect on cognition and brain function in children and young adults. This study assessed 415 healthy epsilon2 and epsilon4 carriers and matched epsilon3/epsilon3 controls, spanning ages 6-65, on a range of cognitive tests. Subjects were also compared on a new dynamical measure of EEG activity during a visual working memory task using alphabetical stimuli. epsilon4 subjects had better verbal fluency compared to epsilon3, an effect that was strongest in 51-65 year-olds. No epsilon4 deficits in cognition were found. In 6-15 year-olds, there were differences in total spatio-temporal wave activity between epsilon3 and epsilon4 subjects in the theta band, approximately 200ms post-stimulus. Differences in brain function in younger epsilon4 subjects and superior verbal fluency across the entire age range suggest that the APOE epsilon4 allele is an example of antagonistic pleiotropy.
Oxytocin is a neuropeptide that is involved in the regulation of mood, anxiety and social biology... more Oxytocin is a neuropeptide that is involved in the regulation of mood, anxiety and social biology. Genetic variation in the oxytocin receptor gene (OXTR) has been implicated in anxiety, depression and related stress phenotypes. It is not yet known whether OXTR interacts with other risk factors such as early life trauma to heighten the severity of experienced anxiety and depression. In this study, we examined genotypes in 653 individuals and tested whether SNP variation in OXTR correlates with severity of features of self-reported experience on the Depression Anxiety and Stress Scale (DASS), and whether this correlation is enhanced when early life trauma is taken into account. We also assessed the effects of OXTR SNPs on RNA expression levels in two separate brain tissue cohorts totaling 365 samples. A significant effect of OXTR genotype on DASS anxiety, stress and depression scores was found and ELS events, in combination with several different OXTR SNPs, were significantly associat...
Background / Purpose: Brain connectivity is highly heritable, however the stability of these gene... more Background / Purpose: Brain connectivity is highly heritable, however the stability of these genetic factors across the adult lifespan is unknown.We applied quantitative genetic analyses and used diffusion tensor imaging (DTI) as a measure of brain connectivity to investigate the heritability (h 2) of white matter (WM) spanning 6 decades of the lifespan. Main conclusion: The systematic mapping of major white matter tracts is of pivotal clinical relevance, allowing age stratified characterization of transient neuroimaging biomarkers.The unique genetic topography for WM tracts can lead to better understanding of genetic plasticity underlying brain circuits and ultimately more realistic assessment of psychiatric and neurological disorders
Major efforts have been directed at family-based association and case-control studies to identify... more Major efforts have been directed at family-based association and case-control studies to identify the involvement of candidate genes in the major disorders of mental health. What remains unknown is whether candidate genes are associated with multiple disorders via pleiotropic mechanisms, and/or if other genes are specific to susceptibility for individual disorders. Here we undertook a review of genes that have been identified in prior meta-analyses examining specific genes and specific mental disorders that have core disruptions to emotional and cognitive function and contribute most to burden of illness- major depressive disorder (MDD), anxiety disorders (AD, including panic disorder and obsessive compulsive disorder), schizophrenia (SZ) and bipolar disorder (BD) and attention deficit hyperactivity disorder (ADHD). A literature review was conducted up to end-March 2013 which included a total of 1519 meta-analyses across 157 studies reporting multiple genes implicated in one or more...
Despite the significant advancements being made in the neurogenetics for mental health, the ident... more Despite the significant advancements being made in the neurogenetics for mental health, the identification and validation of potential endophenotype markers of risk and resilience remain to be confirmed. The TWIN-E study (The Twin study in Wellbeing using Integrative Neuroscience of Emotion) aims to validate endophenotype markers of mental health across cognitive, brain, and autonomic measures by testing the heritability, clinical plausibility, and reliability of each of these measures in a large adult twin cohort. The specific gene and environmental mechanisms that moderate prospective links between endophenotype-phenotype markers and the final outcome of wellbeing will also be identified. TWIN-E is a national prospective study with three phases: I) baseline testing on a battery of online questionnaires and cognitive tasks, and EEG, MRI, and autonomic testing; II) 12-month follow-up testing on the online assessments; and III) randomized controlled trial of brain training. Minimum target numbers include 1,500 male/female twins (18-65 years) for the online assessments (Phase I and II), 300 twins for the EEG testing component, and 244 twins for the MRI testing component. For Phase III, each twin out of the pair will be randomized to either the treatment or waitlist control group to test the effects of brain training on mental health over a 30-day period, and to confirm the gene-environment and endophenotype contributions to treatment response. Preliminary heritability results are provided for the first 50% of the MRI subgroup (n = 142) for the grey matter volume, thickness, and surface area measures, and white matter diffuse tensor imaging fractional anisotropy.
Oxytocin is a neuropeptide that is involved in the regulation of mood, anxiety and social biology... more Oxytocin is a neuropeptide that is involved in the regulation of mood, anxiety and social biology. Genetic variation in the oxytocin receptor gene (OXTR) has been implicated in anxiety, depression and related stress phenotypes. It is not yet known whether OXTR interacts with other risk factors such as early life trauma to heighten the severity of experienced anxiety and depression. In this study, we examined genotypes in 653 individuals and tested whether SNP variation in OXTR correlates with severity of features of self-reported experience on the Depression Anxiety and Stress Scale (DASS), and whether this correlation is enhanced when early life trauma is taken into account. We also assessed the effects of OXTR SNPs on RNA expression levels in two separate brain tissue cohorts totaling 365 samples. A significant effect of OXTR genotype on DASS anxiety, stress and depression scores was found and ELS events, in combination with several different OXTR SNPs, were significantly associat...
Background / Purpose: Brain connectivity is highly heritable, however the stability of these gene... more Background / Purpose: Brain connectivity is highly heritable, however the stability of these genetic factors across the adult lifespan is unknown.We applied quantitative genetic analyses and used diffusion tensor imaging (DTI) as a measure of brain connectivity to investigate the heritability (h 2) of white matter (WM) spanning 6 decades of the lifespan. Main conclusion: The systematic mapping of major white matter tracts is of pivotal clinical relevance, allowing age stratified characterization of transient neuroimaging biomarkers.The unique genetic topography for WM tracts can lead to better understanding of genetic plasticity underlying brain circuits and ultimately more realistic assessment of psychiatric and neurological disorders
Despite the significant advancements being made in the neurogenetics for mental health, the ident... more Despite the significant advancements being made in the neurogenetics for mental health, the identification and validation of potential endophenotype markers of risk and resilience remain to be confirmed. The TWIN-E study (The Twin study in Wellbeing using Integrative Neuroscience of Emotion) aims to validate endophenotype markers of mental health across cognitive, brain, and autonomic measures by testing the heritability, clinical plausibility, and reliability of each of these measures in a large adult twin cohort. The specific gene and environmental mechanisms that moderate prospective links between endophenotype-phenotype markers and the final outcome of wellbeing will also be identified. TWIN-E is a national prospective study with three phases: I) baseline testing on a battery of online questionnaires and cognitive tasks, and EEG, MRI, and autonomic testing; II) 12-month follow-up testing on the online assessments; and III) randomized controlled trial of brain training. Minimum t...
Biases toward processing negative versus positive information vary as a function of level of awar... more Biases toward processing negative versus positive information vary as a function of level of awareness, and are modulated by monoamines. Excessive biases are associated with individual differences in mood and emotional stability, and emotional disorder. Here, we examined the impact of the catechol-O-methyltransferase (COMT) Val(108/158)Met polymorphism, involved in dopamine and norepinephrine catabolism, on both emotional brain function and self-reported negativity bias. COMT genotyping and self-reported level of negativity bias were completed for 46 healthy participants taking part in the Brain Resource International Database. Functional MRI was undertaken during perception of facial expressions of fear and happiness presented under unmasked (consciously identified) and masked (to prevent conscious detection) conditions. Structural MR images were also acquired. A greater number of COMT Met alleles predicted increased activation in brainstem, amygdala, basal ganglia and medial prefrontal regions for conscious fear, but decreased activation for conscious happiness. This pattern was also apparent for brainstem activation for the masked condition. Effects were most apparent for females. These differences could not be explained by gray matter variations. The Met-related profile of activation, particularly prefrontally, predicted greater negativity bias associated with risk for emotional disorder. The findings suggest that the COMT Met allele modulates neural substrates of negative versus positive emotion processing. This effect may contribute to negativity biases, which confer susceptibility for emotional disorders.
The risk for mental illnesses such as depression is increasingly conceptualized as the product of... more The risk for mental illnesses such as depression is increasingly conceptualized as the product of gene-environment interactions and their impact on brain structure and function. The role of serotonin 3A receptor gene (HTR3A -42C>T polymorphism) and its interaction with early life stress (ELS) was investigated in view of the receptor's localization to brain regions central to emotion processing. Fronto-limbic grey matter (GM) loss was measured using magnetic resonance imaging and assessed using voxel-based morphometry analysis in 397 nonclinical individuals from the Brain Resource International Database. Negative mood symptoms were also assessed. The HTR3A CC genotype group, compared to the T carriers, demonstrated comparative loss to GM in hippocampal structures, which extended to the frontal cortices for those CC genotype individuals also exposed to ELS. Elevations in depressed mood were also evident. These findings suggest that the HTR3A CC genotype may be associated with alterations in brain structures central to emotion processing, particularly when exposed to stress, and further highlight the potential role of the serotonin system in the pathophysiology of affective disorders. In contrast, those individuals with the T allele, in particular the TT genotype, may be more protected from such alterations combined with minimal exposure to ELS events.
In this study, we examined whether the Met allele of the BDNF Val66Met polymorphism is associated... more In this study, we examined whether the Met allele of the BDNF Val66Met polymorphism is associated with selective disruptions to task-relevant information processing. In 475 non-clinical participants for whom BDNF genotype status was determined we used the 'IntegNeuro' computerized battery of neuropsychological tests to assess cognitive performance, an auditory oddball task to elicit the P300 event-related potential (ERP) and, in smaller subsets of these subjects, high resolution structural MRI imaging to quantify fronto-hippocampal grey matter (n=161), and functional magnetic resonance imaging to assess fronto-hippocampal BOLD activation (n=37). Met/Met (MM) homozygotes had higher verbal recall errors, in the absence of differences in attention, executive function, verbal ability or sensori-motor function. Further, MM homozygotes demonstrated a slowed P300 ERP during the oddball task, with corresponding alterations in hippocampal and lateral prefrontal activation, and a localized reduction in hippocampal grey matter. These results are consistent with a subtle impact of the Met allele on fronto-hippocampal systems involved in selective information processing of stimulus context and memory updating within the normal population. The findings also indicate that heritable endophenotypes such as the P300 have value in elucidating genotype-phenotype relationships.
Neuroimaging shows brain-functional differences due to apolipoprotein E (APOE) polymorphisms may ... more Neuroimaging shows brain-functional differences due to apolipoprotein E (APOE) polymorphisms may exist decades before the increased risk period for Alzheimer's disease, but little is known about their effect on cognition and brain function in children and young adults. This study assessed 415 healthy epsilon2 and epsilon4 carriers and matched epsilon3/epsilon3 controls, spanning ages 6-65, on a range of cognitive tests. Subjects were also compared on a new dynamical measure of EEG activity during a visual working memory task using alphabetical stimuli. epsilon4 subjects had better verbal fluency compared to epsilon3, an effect that was strongest in 51-65 year-olds. No epsilon4 deficits in cognition were found. In 6-15 year-olds, there were differences in total spatio-temporal wave activity between epsilon3 and epsilon4 subjects in the theta band, approximately 200ms post-stimulus. Differences in brain function in younger epsilon4 subjects and superior verbal fluency across the entire age range suggest that the APOE epsilon4 allele is an example of antagonistic pleiotropy.
Oxytocin is a neuropeptide that is involved in the regulation of mood, anxiety and social biology... more Oxytocin is a neuropeptide that is involved in the regulation of mood, anxiety and social biology. Genetic variation in the oxytocin receptor gene (OXTR) has been implicated in anxiety, depression and related stress phenotypes. It is not yet known whether OXTR interacts with other risk factors such as early life trauma to heighten the severity of experienced anxiety and depression. In this study, we examined genotypes in 653 individuals and tested whether SNP variation in OXTR correlates with severity of features of self-reported experience on the Depression Anxiety and Stress Scale (DASS), and whether this correlation is enhanced when early life trauma is taken into account. We also assessed the effects of OXTR SNPs on RNA expression levels in two separate brain tissue cohorts totaling 365 samples. A significant effect of OXTR genotype on DASS anxiety, stress and depression scores was found and ELS events, in combination with several different OXTR SNPs, were significantly associat...
Background / Purpose: Brain connectivity is highly heritable, however the stability of these gene... more Background / Purpose: Brain connectivity is highly heritable, however the stability of these genetic factors across the adult lifespan is unknown.We applied quantitative genetic analyses and used diffusion tensor imaging (DTI) as a measure of brain connectivity to investigate the heritability (h 2) of white matter (WM) spanning 6 decades of the lifespan. Main conclusion: The systematic mapping of major white matter tracts is of pivotal clinical relevance, allowing age stratified characterization of transient neuroimaging biomarkers.The unique genetic topography for WM tracts can lead to better understanding of genetic plasticity underlying brain circuits and ultimately more realistic assessment of psychiatric and neurological disorders
Major efforts have been directed at family-based association and case-control studies to identify... more Major efforts have been directed at family-based association and case-control studies to identify the involvement of candidate genes in the major disorders of mental health. What remains unknown is whether candidate genes are associated with multiple disorders via pleiotropic mechanisms, and/or if other genes are specific to susceptibility for individual disorders. Here we undertook a review of genes that have been identified in prior meta-analyses examining specific genes and specific mental disorders that have core disruptions to emotional and cognitive function and contribute most to burden of illness- major depressive disorder (MDD), anxiety disorders (AD, including panic disorder and obsessive compulsive disorder), schizophrenia (SZ) and bipolar disorder (BD) and attention deficit hyperactivity disorder (ADHD). A literature review was conducted up to end-March 2013 which included a total of 1519 meta-analyses across 157 studies reporting multiple genes implicated in one or more...
Despite the significant advancements being made in the neurogenetics for mental health, the ident... more Despite the significant advancements being made in the neurogenetics for mental health, the identification and validation of potential endophenotype markers of risk and resilience remain to be confirmed. The TWIN-E study (The Twin study in Wellbeing using Integrative Neuroscience of Emotion) aims to validate endophenotype markers of mental health across cognitive, brain, and autonomic measures by testing the heritability, clinical plausibility, and reliability of each of these measures in a large adult twin cohort. The specific gene and environmental mechanisms that moderate prospective links between endophenotype-phenotype markers and the final outcome of wellbeing will also be identified. TWIN-E is a national prospective study with three phases: I) baseline testing on a battery of online questionnaires and cognitive tasks, and EEG, MRI, and autonomic testing; II) 12-month follow-up testing on the online assessments; and III) randomized controlled trial of brain training. Minimum target numbers include 1,500 male/female twins (18-65 years) for the online assessments (Phase I and II), 300 twins for the EEG testing component, and 244 twins for the MRI testing component. For Phase III, each twin out of the pair will be randomized to either the treatment or waitlist control group to test the effects of brain training on mental health over a 30-day period, and to confirm the gene-environment and endophenotype contributions to treatment response. Preliminary heritability results are provided for the first 50% of the MRI subgroup (n = 142) for the grey matter volume, thickness, and surface area measures, and white matter diffuse tensor imaging fractional anisotropy.
Uploads
Papers by Justine Gatt