Anjali Bhat - Academia.edu (original) (raw)
Papers by Anjali Bhat
Maternal immune activation (MIA) during prenatal development is an environmental risk factor for ... more Maternal immune activation (MIA) during prenatal development is an environmental risk factor for psychiatric disorders including schizophrenia (SZ). This link is particularly well established in the case of schizophrenia. Converging lines of evidence from human and animal model studies have suggested that elevated cytokine levels in the maternal and fetal compartments are an important indication of the mechanisms driving this association. However, there is variability in susceptibility to the psychiatric risk conferred by MIA, likely influenced by genetic factors. How MIA interacts with a genetic profile susceptible to SZ is challenging to test in animal models. To address this gap, we examined whether differential gene expression responses occur in forebrain-lineage neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (hiPSC) generated from three individuals with a diagnosis of schizophrenia and three healthy controls. Following acute (24 hour) treatment...
Biology & Philosophy, 2021
There is a steadily growing literature on the role of the immune system in psychiatric disorders.... more There is a steadily growing literature on the role of the immune system in psychiatric disorders. So far, these advances have largely taken the form of correlations between specific aspects of inflammation (e.g. blood plasma levels of inflammatory markers, genetic mutations in immune pathways, viral or bacterial infection) with the development of neuropsychiatric conditions such as autism, bipolar disorder, schizophrenia and depression. A fundamental question remains open:whyare psychiatric disorders and immune responses intertwined? To address this would require a step back from a historical mind–body dualism that has created such a dichotomy. We propose three contributions of active inference when addressing this question:translation,unification, andsimulation.To illustrate these contributions, we consider the following questions. Is there an immunological analogue of sensory attenuation? Is there a common generative model that the brain and immune system jointly optimise? Can the...
Genes, 2021
CYP2D6 and CYP2C19 enzymes are essential in the metabolism of antidepressants and antipsychotics.... more CYP2D6 and CYP2C19 enzymes are essential in the metabolism of antidepressants and antipsychotics. Genetic variation in these genes may increase risk of adverse drug reactions. Antidepressants and antipsychotics have previously been associated with risk of diabetes. We examined whether individual genetic differences in CYP2D6 and CYP2C19 contribute to these effects. We identified 31,579 individuals taking antidepressants and 2699 taking antipsychotics within UK Biobank. Participants were classified as poor, intermediate, or normal metabolizers of CYP2D6, and as poor, intermediate, normal, rapid, or ultra-rapid metabolizers of CYP2C19. Risk of diabetes mellitus represented by HbA1c level was examined in relation to the metabolic phenotypes. CYP2D6 poor metabolizers taking paroxetine had higher Hb1Ac than normal metabolizers (mean difference: 2.29 mmol/mol; p < 0.001). Among participants with diabetes who were taking venlafaxine, CYP2D6 poor metabolizers had higher HbA1c levels comp...
European Neuropsychopharmacology, 2021
European Neuropsychopharmacology, 2019
Journal of Biosciences, 2016
But my eyes and my feelings don't agree, and I must believe my feelings. I know [my left arm and ... more But my eyes and my feelings don't agree, and I must believe my feelings. I know [my left arm and leg] look like mine, but I can feel they are not, and I can't believe my eyes.
Journal of Biosciences, 2015
Neuron
In vitro neurons learn and exhibit sentience when embodied in a simulated game-world Graphical ab... more In vitro neurons learn and exhibit sentience when embodied in a simulated game-world Graphical abstract Highlights d Improvements in performance or ''learning'' over time following closed-loop feedback d Learning observed from both human and primary mouse cortical neurons d Systems with stimulus but no feedback show no learning d Dynamic changes observed in neural electrophysiological activity during embodiment
Frontiers in Psychology
BackgroundAntipsychotic-induced weight gain is a contributing factor in the reduced life expectan... more BackgroundAntipsychotic-induced weight gain is a contributing factor in the reduced life expectancy reported amongst people with psychotic disorders. CYP2D6 is a liver enzyme involved in the metabolism of many commonly used antipsychotic medications. We investigated if CYP2D6 genetic variation influenced weight or BMI among people taking antipsychotic treatment.MethodsWe conducted a systematic review and a random effects meta-analysis of publications in Pubmed, Embase, PsychInfo, and CENTRAAL that had BMI and/or weight measurements of patients on long-term antipsychotics by their CYP2D6-defined metabolic groups (poor, intermediate, normal/extensive, and ultra-rapid metabolizers, UMs).ResultsTwelve studies were included in the systematic review. All cohort studies suggested that the presence of reduced-function or non-functional alleles for CYP2D6 was associated with greater antipsychotic-induced weight gain, whereas most cross-sectional studies did not find any significant associati...
Genes, 2022
Verbal memory impairment is one of the most prominent cognitive deficits in psychosis. However, f... more Verbal memory impairment is one of the most prominent cognitive deficits in psychosis. However, few studies have investigated the genetic basis of verbal memory in a neurodevelopmental context, and most genome-wide association studies (GWASs) have been conducted in European-ancestry populations. We conducted a GWAS on verbal memory in a maximum of 11,017 participants aged 8.9 to 11.1 years in the Adolescent Brain Cognitive Development Study®, recruited from a diverse population in the United States. Verbal memory was assessed by the Rey Auditory Verbal Learning Test, which included three measures of verbal memory: immediate recall, short-delay recall, and long-delay recall. We adopted a mixed-model approach to perform a joint GWAS of all participants, adjusting for ancestral background and familial relatedness. The inclusion of participants from all ancestries increased the power of the GWAS. Two novel genome-wide significant associations were found for short-delay and long-delay re...
Scientific Reports, 2021
An interesting inference drawn by some COVID-19 epidemiological models is that there exists a pro... more An interesting inference drawn by some COVID-19 epidemiological models is that there exists a proportion of the population who are not susceptible to infection—even at the start of the current pandemic. This paper introduces a model of the immune response to a virus. This is based upon the same sort of mean-field dynamics as used in epidemiology. However, in place of the location, clinical status, and other attributes of people in an epidemiological model, we consider the state of a virus, B and T-lymphocytes, and the antibodies they generate. Our aim is to formalise some key hypotheses as to the mechanism of resistance. We present a series of simple simulations illustrating changes to the dynamics of the immune response under these hypotheses. These include attenuated viral cell entry, pre-existing cross-reactive humoral (antibody-mediated) immunity, and enhanced T-cell dependent immunity. Finally, we illustrate the potential application of this sort of model by illustrating variat...
European Neuropsychopharmacology, 2021
European Neuropsychopharmacology, 2021
Neuroscience & Biobehavioral Reviews, 2021
Recent characterisations of self-organising systems depend upon the presence of a 'Markov blanket... more Recent characterisations of self-organising systems depend upon the presence of a 'Markov blanket': a statistical boundary that mediates the interactions between what is inside of and outside of a system. We leverage this idea to provide an analysis of partitions in neuronal systems. This is applicable to brain architectures at multiple scales, enabling partitions into single neurons, brain regions, and brain-wide networks. This treatment is based upon the canonical micro-circuitry used in empirical studies of effective connectivity, so as to speak directly to practical applications. This depends upon the dynamic coupling between functional units, whose form recapitulates that of a Markov blanket at each level. The nuance afforded by partitioning neural systems in this way highlights certain limitations of 'modular' perspectives of brain function that only consider a single level of description.
Molecular Psychiatry, 2020
The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs... more The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, <1% MAF) as well as known schizophrenia-associated CNVs in patients with psychotic disorders, their unaffected relatives and controls (N = 3428) from the Psychosis Endophenotypes International Consortium (PEIC). The carriers of specific schizophreni...
The Pharmacogenomics Journal, 2020
Hyperprolactinemia is a known adverse drug reaction to antipsychotic treatment. Antipsychotic blo... more Hyperprolactinemia is a known adverse drug reaction to antipsychotic treatment. Antipsychotic blood levels are influenced by cytochrome P450 enzymes, primarily CYP2D6. Variation in CYP450 genes may affect the risk of antipsychotic-induced hyperprolactinemia. We undertook a systematic review and meta-analysis to assess whether CYP2D6 functional genetic variants are associated with antipsychoticinduced hyperprolactinemia. The systematic review identified sixteen relevant papers, seven of which were suitable for the meta-analysis (n=303 participants including 134 extreme metabolisers). Participants were classified into four phenotype groups as poor, intermediate, extensive and ultrarapid metabolisers. A random effects meta-analysis was used and Cohen's d calculated as the effect size for each primary study. We found no significant differences in prolactin levels between CYP2D6 metabolic groups. Current evidence does not support using CYP2D6 genotyping to reduce risk of antipsychotic-induced hyperprolactinemia. However, statistical power is limited. Future studies with larger samples and including a range of prolactin-elevating drugs are needed.
European Neuropsychopharmacology, 2019
tomic Wide Analysis, and eQTL mapping, as well as more recently developed methods that integrate ... more tomic Wide Analysis, and eQTL mapping, as well as more recently developed methods that integrate GWAS and eQTL data via mendelian randomization [SMR] and linkage methods [HEIDI] (PMID 29500431& 27019110). Available, brainspecific eQTL databases included GTEXv7, BrainEAC, Com-monMind, ROSMAP, and PsychEncode. Intersecting credible genes were then annotated against multiple chemoinformatic databases (DGI, KI, and a review on 'druggability' (PMID 28356508)). Results: A total of 239 independent cognition-associated loci (39 novel) were identified by MTAG, encompassing 652 Bonferroni-significant genes identified in the MAGMA analysis. Incorporating brain-specific expression data, TWAS and eQTL mapping yielded 444 genes and 588 genes, respectively. By contrast, the more conservative SMR approach identified 166 cognitive genes, while the use of the HEIDI test permitted the identification of additional TWASnominated genes that did not demonstrate direct causal effects. Of the genes nominated by any method, 81 were identified as 'Tier 1' candidates, which included efficacy targets of approved small molecules and clinical-phase drug candidates. Of these, 14 were consistently supported by MAGMA, TWAS, eQTL mapping, SMR, and HEIDI analysis. Discussion: Converging results across multiple data analytic approaches suggest that the following genes-ALMS1,
European Neuropsychopharmacology, 2019
European Neuropsychopharmacology, 2019
Maternal immune activation (MIA) during prenatal development is an environmental risk factor for ... more Maternal immune activation (MIA) during prenatal development is an environmental risk factor for psychiatric disorders including schizophrenia (SZ). This link is particularly well established in the case of schizophrenia. Converging lines of evidence from human and animal model studies have suggested that elevated cytokine levels in the maternal and fetal compartments are an important indication of the mechanisms driving this association. However, there is variability in susceptibility to the psychiatric risk conferred by MIA, likely influenced by genetic factors. How MIA interacts with a genetic profile susceptible to SZ is challenging to test in animal models. To address this gap, we examined whether differential gene expression responses occur in forebrain-lineage neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (hiPSC) generated from three individuals with a diagnosis of schizophrenia and three healthy controls. Following acute (24 hour) treatment...
Biology & Philosophy, 2021
There is a steadily growing literature on the role of the immune system in psychiatric disorders.... more There is a steadily growing literature on the role of the immune system in psychiatric disorders. So far, these advances have largely taken the form of correlations between specific aspects of inflammation (e.g. blood plasma levels of inflammatory markers, genetic mutations in immune pathways, viral or bacterial infection) with the development of neuropsychiatric conditions such as autism, bipolar disorder, schizophrenia and depression. A fundamental question remains open:whyare psychiatric disorders and immune responses intertwined? To address this would require a step back from a historical mind–body dualism that has created such a dichotomy. We propose three contributions of active inference when addressing this question:translation,unification, andsimulation.To illustrate these contributions, we consider the following questions. Is there an immunological analogue of sensory attenuation? Is there a common generative model that the brain and immune system jointly optimise? Can the...
Genes, 2021
CYP2D6 and CYP2C19 enzymes are essential in the metabolism of antidepressants and antipsychotics.... more CYP2D6 and CYP2C19 enzymes are essential in the metabolism of antidepressants and antipsychotics. Genetic variation in these genes may increase risk of adverse drug reactions. Antidepressants and antipsychotics have previously been associated with risk of diabetes. We examined whether individual genetic differences in CYP2D6 and CYP2C19 contribute to these effects. We identified 31,579 individuals taking antidepressants and 2699 taking antipsychotics within UK Biobank. Participants were classified as poor, intermediate, or normal metabolizers of CYP2D6, and as poor, intermediate, normal, rapid, or ultra-rapid metabolizers of CYP2C19. Risk of diabetes mellitus represented by HbA1c level was examined in relation to the metabolic phenotypes. CYP2D6 poor metabolizers taking paroxetine had higher Hb1Ac than normal metabolizers (mean difference: 2.29 mmol/mol; p < 0.001). Among participants with diabetes who were taking venlafaxine, CYP2D6 poor metabolizers had higher HbA1c levels comp...
European Neuropsychopharmacology, 2021
European Neuropsychopharmacology, 2019
Journal of Biosciences, 2016
But my eyes and my feelings don't agree, and I must believe my feelings. I know [my left arm and ... more But my eyes and my feelings don't agree, and I must believe my feelings. I know [my left arm and leg] look like mine, but I can feel they are not, and I can't believe my eyes.
Journal of Biosciences, 2015
Neuron
In vitro neurons learn and exhibit sentience when embodied in a simulated game-world Graphical ab... more In vitro neurons learn and exhibit sentience when embodied in a simulated game-world Graphical abstract Highlights d Improvements in performance or ''learning'' over time following closed-loop feedback d Learning observed from both human and primary mouse cortical neurons d Systems with stimulus but no feedback show no learning d Dynamic changes observed in neural electrophysiological activity during embodiment
Frontiers in Psychology
BackgroundAntipsychotic-induced weight gain is a contributing factor in the reduced life expectan... more BackgroundAntipsychotic-induced weight gain is a contributing factor in the reduced life expectancy reported amongst people with psychotic disorders. CYP2D6 is a liver enzyme involved in the metabolism of many commonly used antipsychotic medications. We investigated if CYP2D6 genetic variation influenced weight or BMI among people taking antipsychotic treatment.MethodsWe conducted a systematic review and a random effects meta-analysis of publications in Pubmed, Embase, PsychInfo, and CENTRAAL that had BMI and/or weight measurements of patients on long-term antipsychotics by their CYP2D6-defined metabolic groups (poor, intermediate, normal/extensive, and ultra-rapid metabolizers, UMs).ResultsTwelve studies were included in the systematic review. All cohort studies suggested that the presence of reduced-function or non-functional alleles for CYP2D6 was associated with greater antipsychotic-induced weight gain, whereas most cross-sectional studies did not find any significant associati...
Genes, 2022
Verbal memory impairment is one of the most prominent cognitive deficits in psychosis. However, f... more Verbal memory impairment is one of the most prominent cognitive deficits in psychosis. However, few studies have investigated the genetic basis of verbal memory in a neurodevelopmental context, and most genome-wide association studies (GWASs) have been conducted in European-ancestry populations. We conducted a GWAS on verbal memory in a maximum of 11,017 participants aged 8.9 to 11.1 years in the Adolescent Brain Cognitive Development Study®, recruited from a diverse population in the United States. Verbal memory was assessed by the Rey Auditory Verbal Learning Test, which included three measures of verbal memory: immediate recall, short-delay recall, and long-delay recall. We adopted a mixed-model approach to perform a joint GWAS of all participants, adjusting for ancestral background and familial relatedness. The inclusion of participants from all ancestries increased the power of the GWAS. Two novel genome-wide significant associations were found for short-delay and long-delay re...
Scientific Reports, 2021
An interesting inference drawn by some COVID-19 epidemiological models is that there exists a pro... more An interesting inference drawn by some COVID-19 epidemiological models is that there exists a proportion of the population who are not susceptible to infection—even at the start of the current pandemic. This paper introduces a model of the immune response to a virus. This is based upon the same sort of mean-field dynamics as used in epidemiology. However, in place of the location, clinical status, and other attributes of people in an epidemiological model, we consider the state of a virus, B and T-lymphocytes, and the antibodies they generate. Our aim is to formalise some key hypotheses as to the mechanism of resistance. We present a series of simple simulations illustrating changes to the dynamics of the immune response under these hypotheses. These include attenuated viral cell entry, pre-existing cross-reactive humoral (antibody-mediated) immunity, and enhanced T-cell dependent immunity. Finally, we illustrate the potential application of this sort of model by illustrating variat...
European Neuropsychopharmacology, 2021
European Neuropsychopharmacology, 2021
Neuroscience & Biobehavioral Reviews, 2021
Recent characterisations of self-organising systems depend upon the presence of a 'Markov blanket... more Recent characterisations of self-organising systems depend upon the presence of a 'Markov blanket': a statistical boundary that mediates the interactions between what is inside of and outside of a system. We leverage this idea to provide an analysis of partitions in neuronal systems. This is applicable to brain architectures at multiple scales, enabling partitions into single neurons, brain regions, and brain-wide networks. This treatment is based upon the canonical micro-circuitry used in empirical studies of effective connectivity, so as to speak directly to practical applications. This depends upon the dynamic coupling between functional units, whose form recapitulates that of a Markov blanket at each level. The nuance afforded by partitioning neural systems in this way highlights certain limitations of 'modular' perspectives of brain function that only consider a single level of description.
Molecular Psychiatry, 2020
The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs... more The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, <1% MAF) as well as known schizophrenia-associated CNVs in patients with psychotic disorders, their unaffected relatives and controls (N = 3428) from the Psychosis Endophenotypes International Consortium (PEIC). The carriers of specific schizophreni...
The Pharmacogenomics Journal, 2020
Hyperprolactinemia is a known adverse drug reaction to antipsychotic treatment. Antipsychotic blo... more Hyperprolactinemia is a known adverse drug reaction to antipsychotic treatment. Antipsychotic blood levels are influenced by cytochrome P450 enzymes, primarily CYP2D6. Variation in CYP450 genes may affect the risk of antipsychotic-induced hyperprolactinemia. We undertook a systematic review and meta-analysis to assess whether CYP2D6 functional genetic variants are associated with antipsychoticinduced hyperprolactinemia. The systematic review identified sixteen relevant papers, seven of which were suitable for the meta-analysis (n=303 participants including 134 extreme metabolisers). Participants were classified into four phenotype groups as poor, intermediate, extensive and ultrarapid metabolisers. A random effects meta-analysis was used and Cohen's d calculated as the effect size for each primary study. We found no significant differences in prolactin levels between CYP2D6 metabolic groups. Current evidence does not support using CYP2D6 genotyping to reduce risk of antipsychotic-induced hyperprolactinemia. However, statistical power is limited. Future studies with larger samples and including a range of prolactin-elevating drugs are needed.
European Neuropsychopharmacology, 2019
tomic Wide Analysis, and eQTL mapping, as well as more recently developed methods that integrate ... more tomic Wide Analysis, and eQTL mapping, as well as more recently developed methods that integrate GWAS and eQTL data via mendelian randomization [SMR] and linkage methods [HEIDI] (PMID 29500431& 27019110). Available, brainspecific eQTL databases included GTEXv7, BrainEAC, Com-monMind, ROSMAP, and PsychEncode. Intersecting credible genes were then annotated against multiple chemoinformatic databases (DGI, KI, and a review on 'druggability' (PMID 28356508)). Results: A total of 239 independent cognition-associated loci (39 novel) were identified by MTAG, encompassing 652 Bonferroni-significant genes identified in the MAGMA analysis. Incorporating brain-specific expression data, TWAS and eQTL mapping yielded 444 genes and 588 genes, respectively. By contrast, the more conservative SMR approach identified 166 cognitive genes, while the use of the HEIDI test permitted the identification of additional TWASnominated genes that did not demonstrate direct causal effects. Of the genes nominated by any method, 81 were identified as 'Tier 1' candidates, which included efficacy targets of approved small molecules and clinical-phase drug candidates. Of these, 14 were consistently supported by MAGMA, TWAS, eQTL mapping, SMR, and HEIDI analysis. Discussion: Converging results across multiple data analytic approaches suggest that the following genes-ALMS1,
European Neuropsychopharmacology, 2019
European Neuropsychopharmacology, 2019