Publications by authors named "Michael J Owen"

431 Publications

Effects of eight neuropsychiatric copy number variants on human brain structure.

Transl Psychiatry 2021 Jul 20;11(1):399. Epub 2021 Jul 20.

Douglas Research Centre, McGill University, Montréal, QC, Canada.

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen's d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions.
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http://dx.doi.org/10.1038/s41398-021-01490-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292542PMC
July 2021

Using induced pluripotent stem cells to investigate human neuronal phenotypes in 1q21.1 deletion and duplication syndrome.

Mol Psychiatry 2021 Jun 10. Epub 2021 Jun 10.

Neuroscience and Mental Health Research Institute, Hadyn Ellis Building, Cardiff University, Cardiff, United Kingdom.

Copy Number Variation (CNV) at the 1q21.1 locus is associated with a range of neurodevelopmental and psychiatric disorders in humans, including abnormalities in head size and motor deficits. Yet, the functional consequences of these CNVs (both deletion and duplication) on neuronal development remain unknown. To determine the impact of CNV at the 1q21.1 locus on neuronal development, we generated induced pluripotent stem cells from individuals harbouring 1q21.1 deletion or duplication and differentiated them into functional cortical neurons. We show that neurons with 1q21.1 deletion or duplication display reciprocal phenotype with respect to proliferation, differentiation potential, neuronal maturation, synaptic density and functional activity. Deletion of the 1q21.1 locus was also associated with an increased expression of lower cortical layer markers. This difference was conserved in the mouse model of 1q21.1 deletion, which displayed altered corticogenesis. Importantly, we show that neurons with 1q21.1 deletion and duplication are associated with differential expression of calcium channels and demonstrate that physiological deficits in neurons with 1q21.1 deletion or duplication can be pharmacologically modulated by targeting Ca channel activity. These findings provide biological insight into the neuropathological mechanism underlying 1q21.1 associated brain disorder and indicate a potential target for therapeutic interventions.
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http://dx.doi.org/10.1038/s41380-021-01182-2DOI Listing
June 2021

Haploinsufficiency of the schizophrenia and autism risk gene Cyfip1 causes abnormal postnatal hippocampal neurogenesis through microglial and Arp2/3 mediated actin dependent mechanisms.

Transl Psychiatry 2021 05 24;11(1):313. Epub 2021 May 24.

Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, UK.

Genetic risk factors can significantly increase chances of developing psychiatric disorders, but the underlying biological processes through which this risk is effected remain largely unknown. Here we show that haploinsufficiency of Cyfip1, a candidate risk gene present in the pathogenic 15q11.2(BP1-BP2) deletion may impact on psychopathology via abnormalities in cell survival and migration of newborn neurons during postnatal hippocampal neurogenesis. We demonstrate that haploinsufficiency of Cyfip1 leads to increased numbers of adult-born hippocampal neurons due to reduced apoptosis, without altering proliferation. We show this is due to a cell autonomous failure of microglia to induce apoptosis through the secretion of the appropriate factors, a previously undescribed mechanism. Furthermore, we show an abnormal migration of adult-born neurons due to altered Arp2/3 mediated actin dynamics. Together, our findings throw new light on how the genetic risk candidate Cyfip1 may influence the hippocampus, a brain region with strong evidence for involvement in psychopathology.
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http://dx.doi.org/10.1038/s41398-021-01415-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144403PMC
May 2021

Explaining the missing heritability of psychiatric disorders.

World Psychiatry 2021 Jun;20(2):294-295

MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.

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http://dx.doi.org/10.1002/wps.20870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129850PMC
June 2021

Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology.

Nat Genet 2021 06 17;53(6):817-829. Epub 2021 May 17.

Department of Neuroscience, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
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http://dx.doi.org/10.1038/s41588-021-00857-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192451PMC
June 2021

Lack of Support for the Genes by Early Environment Interaction Hypothesis in the Pathogenesis of Schizophrenia.

Schizophr Bull 2021 May 14. Epub 2021 May 14.

Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.

Ursini et al reported recently that the liability of schizophrenia explained by a polygenic risk score (PRS) derived from the variants most associated with schizophrenia was increased 5-fold in individuals who experienced complications during pregnancy or birth. Follow-up gene expression analysis showed that the genes mapping to the most associated genetic variants are highly expressed in placental tissues. If confirmed, these findings will have major implications in our understanding of the joint effect of genes and environment in the pathogenesis of schizophrenia. We examined the interplay between PRS and obstetric complications (OCs) in 5 independent samples (effective N = 2110). OCs were assessed with the full or modified Lewis-Murray scale, or with birth weight < 2.5 kg as a proxy. In a large cohort we tested whether the pathways from placenta-relevant variants in the original report were associated with case-control status. Unlike in the original study, we did not find significant effect of PRS on the presence of OCs in cases, nor a substantial difference in the association of PRS with case-control status in samples stratified by the presence of OCs. Furthermore, none of the PRS by OCs interactions were significant, nor were any of the biological pathways, examined in the Swedish cohort. Our study could not support the hypothesis of a mediating effect of placenta biology in the pathway from genes to schizophrenia. Methodology differences, in particular the different scales measuring OCs, as well as power constraints for interaction analyses in both studies, may explain this discrepancy.
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http://dx.doi.org/10.1093/schbul/sbab052DOI Listing
May 2021

Striatal dopaminergic alterations in individuals with copy number variants at the 22q11.2 genetic locus and their implications for psychosis risk: a [18F]-DOPA PET study.

Mol Psychiatry 2021 May 12. Epub 2021 May 12.

Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, UK.

Dopaminergic dysregulation is one of the leading hypotheses for the pathoetiology underlying psychotic disorders such as schizophrenia. Molecular imaging studies have shown increased striatal dopamine synthesis capacity (DSC) in schizophrenia and people in the prodrome of psychosis. However, it is unclear if genetic risk for psychosis is associated with altered DSC. To investigate this, we recruited healthy controls and two antipsychotic naive groups of individuals with copy number variants, one with a genetic deletion at chromosome 22q11.2, and the other with a duplication at the same locus, who are at increased and decreased risk for psychosis, respectively. Fifty-nine individuals (21 with 22q11.2 deletion, 12 with the reciprocal duplication and 26 healthy controls) received clinical measures and [18F]-DOPA PET imaging to index striatal Ki. There was an inverse linear effect of copy number variant number on striatal Ki value (B = -1.2 × 10, SE = 2 × 10, p < 0.001), with controls showing levels intermediate between the two variant groups. Striatal Ki was significantly higher in the 22q11.2 deletion group compared to the healthy control (p < 0.001, Cohen's d = 1.44) and 22q11.2 duplication (p < 0.001, Cohen's d = 2) groups. Moreover, Ki was positively correlated with the severity of psychosis-risk symptoms (B = 730.5, SE = 310.2, p < 0.05) and increased over time in the subject who went on to develop psychosis, but was not associated with anxiety or depressive symptoms. Our findings suggest that genetic risk for psychosis is associated with dopaminergic dysfunction and identify dopamine synthesis as a potential target for treatment or prevention of psychosis in 22q11.2 deletion carriers.
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http://dx.doi.org/10.1038/s41380-021-01108-yDOI Listing
May 2021

Mental Health Research, shared goals.

J Ment Health 2021 May 9. Epub 2021 May 9.

Cardiff University School of Medicine, Cardiff, UK.

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http://dx.doi.org/10.1080/09638237.2021.1898562DOI Listing
May 2021

Developmental Profile of Psychiatric Risk Associated With Voltage-Gated Cation Channel Activity.

Biol Psychiatry 2021 Mar 13. Epub 2021 Mar 13.

Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom; MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom.

Background: Recent breakthroughs in psychiatric genetics have implicated biological pathways onto which genetic risk for psychiatric disorders converges. However, these studies do not reveal the developmental time point(s) at which these pathways are relevant.

Methods: We aimed to determine the relationship between psychiatric risk and developmental gene expression relating to discrete biological pathways. We used postmortem RNA sequencing data (BrainSeq and BrainSpan) from brain tissue at multiple prenatal and postnatal time points, with summary statistics from recent genome-wide association studies of schizophrenia, bipolar disorder, and major depressive disorder. We prioritized gene sets for overall enrichment of association with each disorder and then tested the relationship between the association of their constituent genes with their relative expression at each developmental stage.

Results: We observed relationships between the expression of genes involved in voltage-gated cation channel activity during early midfetal, adolescence, and early adulthood time points and association with schizophrenia and bipolar disorder, such that genes more strongly associated with these disorders had relatively low expression during early midfetal development and higher expression during adolescence and early adulthood. The relationship with schizophrenia was strongest for the subset of genes related to calcium channel activity, while for bipolar disorder, the relationship was distributed between calcium and potassium channel activity genes.

Conclusions: Our results indicate periods during development when biological pathways related to the activity of calcium and potassium channels may be most vulnerable to the effects of genetic variants conferring risk for psychiatric disorders. Furthermore, they indicate key time points and potential targets for disorder-specific therapeutic interventions.
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http://dx.doi.org/10.1016/j.biopsych.2021.03.009DOI Listing
March 2021

Clozapine Metabolism is Associated With Absolute Neutrophil Count in Individuals With Treatment-Resistant Schizophrenia.

Front Pharmacol 2021 16;12:658734. Epub 2021 Apr 16.

MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom.

Up to one-third of those with schizophrenia fail to respond to standard antipsychotics and are considered to have treatment-resistant schizophrenia, a condition for which clozapine is the only evidence-based medication. While up to 60% of treated individuals obtain therapeutic benefits from clozapine, it is currently underprescribed worldwide, partly because of concerns related to its broad adverse effect profile. In particular, the potential effects of clozapine on the immune system have gained relevance after a recent study showed that drug plasma concentrations were inversely correlated with neutrophil counts in individuals routinely undergoing treatment. Seeking to investigate this relationship in more detail, we extracted metabolic, immune, and genetic data from a UK cohort of long-term clozapine users linked to a clozapine monitoring service, CLOZUK2 ( = 208). Whilst a correlation analysis was compatible with the original results, a multiple linear regression accounting for dose and other confounding factors additionally allowed us to estimate the decrease in absolute neutrophil counts to approximately 141 cells/mm for every 0.1 mg/L increase in clozapine concentration. However, this association was attenuated after controlling for the metabolic ratio between clozapine and its main metabolite, norclozapine, which was itself negatively associated with neutrophil concentrations. Further analyses revealed that these relationships are likely moderated by genetic factors, as three pharmacogenomic SNPs previously associated to norclozapine plasma concentrations and the metabolic ratio (rs61750900, rs2011425 and rs1126545) were shown to be independently associated with a variation in neutrophil counts of about 400 cells/mm per effect allele. Such results are compatible with an effect of norclozapine, but not necessarily clozapine, on immune cell counts, and highlight the need for further investigations into the potential role of genetic determinants of clozapine pharmacokinetics in the occurrence of adverse effects during treatment.
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http://dx.doi.org/10.3389/fphar.2021.658734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094024PMC
April 2021

Risk Factors, Clinical Features, and Polygenic Risk Scores in Schizophrenia and Schizoaffective Disorder Depressive-Type.

Schizophr Bull 2021 Apr 10. Epub 2021 Apr 10.

MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK.

There is controversy about the status of schizoaffective disorder depressive-type (SA-D), particularly whether it should be considered a form of schizophrenia or a distinct disorder. We aimed to determine whether individuals with SA-D differ from individuals with schizophrenia in terms of demographic, premorbid, and lifetime clinical characteristics, and genetic liability to schizophrenia, depression, and bipolar disorder. Participants were from the CardiffCOGS sample and met ICD-10 criteria for schizophrenia (n = 713) or SA-D (n = 151). Two samples, Cardiff Affected-sib (n = 354) and Cardiff F-series (n = 524), were used for replication. For all samples, phenotypic data were ascertained through structured interview, review of medical records, and an ICD-10 diagnosis made by trained researchers. Univariable and multivariable logistic regression models were used to compare individuals with schizophrenia and SA-D for demographic and clinical characteristics, and polygenic risk scores (PRS). In the CardiffCOGS, SA-D, compared to schizophrenia, was associated with female sex, childhood abuse, history of alcohol dependence, higher functioning Global Assessment Scale (GAS) score in worst episode of psychosis, lower functioning GAS score in worst episode of depression, and reduced lifetime severity of disorganized symptoms. Individuals with SA-D had higher depression PRS compared to those with schizophrenia. PRS for schizophrenia and bipolar disorder did not significantly differ between SA-D and schizophrenia. Compared to individuals with schizophrenia, individuals with SA-D had higher rates of environmental and genetic risk factors for depression and a similar genetic liability to schizophrenia. These findings are consistent with SA-D being a sub-type of schizophrenia resulting from elevated liability to both schizophrenia and depression.
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http://dx.doi.org/10.1093/schbul/sbab036DOI Listing
April 2021

Association of genetic liability for psychiatric disorders with accelerometer-assessed physical activity in the UK Biobank.

PLoS One 2021 26;16(3):e0249189. Epub 2021 Mar 26.

MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychiatry and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom.

Levels of activity are often affected in psychiatric disorders and can be core symptoms of illness. Advances in technology now allow the accurate assessment of activity levels but it remains unclear whether alterations in activity arise from shared risk factors for developing psychiatric disorders, such as genetics, or are better explained as consequences of the disorders and their associated factors. We aimed to examine objectively-measured physical activity in individuals with psychiatric disorders, and assess the role of genetic liability for psychiatric disorders on physical activity. Accelerometer data were available on 95,529 UK Biobank participants, including measures of overall mean activity and minutes per day of moderate activity, walking, sedentary activity, and sleep. Linear regressions measured associations between psychiatric diagnosis and activity levels, and polygenic risk scores (PRS) for psychiatric disorders and activity levels. Genetic correlations were calculated between psychiatric disorders and different types of activity. Having a diagnosis of schizophrenia, bipolar disorder, depression, or autism spectrum disorders (ASD) was associated with reduced overall activity compared to unaffected controls. In individuals without a psychiatric disorder, reduced overall activity levels were associated with PRS for schizophrenia, depression, and ASD. ADHD PRS was associated with increased overall activity. Genetic correlations were consistent with PRS findings. Variation in physical activity is an important feature across psychiatric disorders. Whilst levels of activity are associated with genetic liability to psychiatric disorders to a very limited extent, the substantial differences in activity levels in those with psychiatric disorders most likely arise as a consequences of disorder-related factors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249189PLOS
March 2021

1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans.

Transl Psychiatry 2021 03 22;11(1):182. Epub 2021 Mar 22.

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
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http://dx.doi.org/10.1038/s41398-021-01213-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985307PMC
March 2021

Genome-wide analyses of smoking behaviors in schizophrenia: Findings from the Psychiatric Genomics Consortium.

J Psychiatr Res 2021 05 18;137:215-224. Epub 2021 Feb 18.

Department of Psychiatry and Behavioral Sciences, State University of New York Downstate Medical Center, Brooklyn, NY, USA; VA New York Harbor Healthcare System, Brooklyn, NY, USA. Electronic address:

While 17% of US adults use tobacco regularly, smoking rates among persons with schizophrenia are upwards of 60%. Research supports a shared etiological basis for smoking and schizophrenia, including findings from genome-wide association studies (GWAS). However, few studies have directly tested whether the same or distinct genetic variants also influence smoking behavior among schizophrenia cases. Using data from the Psychiatric Genomics Consortium (PGC) study of schizophrenia (35476 cases, 46839 controls), we estimated genetic correlations between these traits and tested whether polygenic risk scores (PRS) constructed from the results of smoking behaviors GWAS were associated with schizophrenia risk or smoking behaviors among schizophrenia cases. Results indicated significant genetic correlations of schizophrenia with smoking initiation (r = 0.159; P = 5.05 × 10), cigarettes-smoked-per-day (r = 0.094; P = 0.006), and age-of-onset of smoking (r = 0.10; P = 0.009). Comparing smoking behaviors among schizophrenia cases to the general population, we observe positive genetic correlations for smoking initiation (r = 0.624, P = 0.002) and cigarettes-smoked-per-day (r = 0.689, P = 0.120). Similarly, TAG-based PRS for smoking initiation and cigarettes-smoked-per-day were significantly associated with smoking initiation (P = 3.49 × 10) and cigarettes-smoked-per-day (P = 0.007) among schizophrenia cases. We performed the first GWAS of smoking behavior among schizophrenia cases and identified a novel association with cigarettes-smoked-per-day upstream of the TMEM106B gene on chromosome 7p21.3 (rs148253479, P = 3.18 × 10, n = 3520). Results provide evidence of a partially shared genetic basis for schizophrenia and smoking behaviors. Additionally, genetic risk factors for smoking behaviors were largely shared across schizophrenia and non-schizophrenia populations. Future research should address mechanisms underlying these associations to aid both schizophrenia and smoking treatment and prevention efforts.
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http://dx.doi.org/10.1016/j.jpsychires.2021.02.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096167PMC
May 2021

Rare Copy Number Variants Are Associated With Poorer Cognition in Schizophrenia.

Biol Psychiatry 2021 07 19;90(1):28-34. Epub 2020 Dec 19.

MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom. Electronic address:

Background: Cognitive impairment in schizophrenia is a major contributor to poor outcomes, yet its causes are poorly understood. Some rare copy number variants (CNVs) are associated with schizophrenia risk and affect cognition in healthy populations, but their contribution to cognitive impairment in schizophrenia has not been investigated. We examined the effect of 12 schizophrenia CNVs on cognition in those with schizophrenia.

Methods: General cognitive ability was measured using the Measurement and Treatment Research to Improve Cognition in Schizophrenia composite z score in 875 patients with schizophrenia and in a replication sample of 519 patients with schizophrenia using Wechsler Adult Intelligence Scale Full Scale IQ. Using linear regression, we tested for association between cognition and schizophrenia CNV status, covarying for age and sex. In addition, we tested whether CNVs hitting genes in schizophrenia-enriched gene sets (loss-of-function intolerant and synaptic gene sets) were associated with cognitive impairment.

Results: A total of 23 schizophrenia CNV carriers were identified. Schizophrenia CNV carriers had lower general cognitive ability than nonschizophrenia CNV carriers in discovery (β = -0.66, 95% confidence interval [CI] = -1.31 to -0.01) and replication samples (β = -0.91, 95% CI = -1.71 to -0.11) and after meta-analysis (β = -0.76, 95% CI = -1.26 to -0.25, p = .003). CNVs hitting loss-of-function intolerant genes were associated with lower cognition (β = -0.15, 95% CI = -0.29 to -0.001, p = .048).

Conclusions: In those with schizophrenia, cognitive ability in schizophrenia CNV carriers is 0.5-1.0 standard deviations below non-CNV carriers, which may have implications for clinical assessment and management. We also demonstrate that rare CNVs hitting genes intolerant to loss-of-function variation lead to more severe cognitive impairment, above and beyond the effect of known schizophrenia CNVs.
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http://dx.doi.org/10.1016/j.biopsych.2020.11.025DOI Listing
July 2021

Neurotrophin receptor activation rescues cognitive and synaptic abnormalities caused by hemizygosity of the psychiatric risk gene Cacna1c.

Mol Psychiatry 2021 Feb 17. Epub 2021 Feb 17.

Neuroscience and Mental Health Research Institute, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.

Genetic variation in CACNA1C, which encodes the alpha-1 subunit of Ca1.2 L-type voltage-gated calcium channels, is strongly linked to risk for psychiatric disorders including schizophrenia and bipolar disorder. To translate genetics to neurobiological mechanisms and rational therapeutic targets, we investigated the impact of mutations of one copy of Cacna1c on rat cognitive, synaptic and circuit phenotypes implicated by patient studies. We show that rats hemizygous for Cacna1c harbour marked impairments in learning to disregard non-salient stimuli, a behavioural change previously associated with psychosis. This behavioural deficit is accompanied by dys-coordinated network oscillations during learning, pathway-selective disruption of hippocampal synaptic plasticity, attenuated Ca signalling in dendritic spines and decreased signalling through the Extracellular-signal Regulated Kinase (ERK) pathway. Activation of the ERK pathway by a small-molecule agonist of TrkB/TrkC neurotrophin receptors rescued both behavioural and synaptic plasticity deficits in Cacna1c rats. These results map a route through which genetic variation in CACNA1C can disrupt experience-dependent synaptic signalling and circuit activity, culminating in cognitive alterations associated with psychiatric disorders. Our findings highlight targeted activation of neurotrophin signalling pathways with BDNF mimetic drugs as a genetically informed therapeutic approach for rescuing behavioural abnormalities in psychiatric disorder.
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http://dx.doi.org/10.1038/s41380-020-01001-0DOI Listing
February 2021

The psychiatric phenotypes of 1q21 distal deletion and duplication.

Transl Psychiatry 2021 02 4;11(1):105. Epub 2021 Feb 4.

Division of Psychological Medicine and Clinical Neurosciences, Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.

Copy number variants are amongst the most highly penetrant risk factors for psychopathology and neurodevelopmental deficits, but little information about the detailed clinical phenotype associated with particular variants is available. We present the largest study of the microdeletion and -duplication at the distal 1q21 locus, which has been associated with schizophrenia and intellectual disability, in order to investigate the range of psychiatric phenotypes. Clinical and cognitive data from 68 deletion and 55 duplication carriers were analysed with logistic regression analysis to compare frequencies of mental disorders between carrier groups and controls, and linear mixed models to compare quantitative phenotypes. Both children and adults with copy number variants at 1q21 had high frequencies of psychopathology. In the children, neurodevelopmental disorders were most prominent (56% for deletion, 68% for duplication carriers). Adults had increased prevalence of mood (35% for deletion [OR = 6.6 (95% CI: 1.4-40.1)], 55% for duplication carriers [8.3 (1.4-55.5)]) and anxiety disorders (24% [1.8 (0.4-8.4)] and 55% [10.0 (1.9-71.2)]). The adult group, which included mainly genetically affected parents of probands, had an IQ in the normal range. These results confirm high prevalence of neurodevelopmental disorders associated with CNVs at 1q21 but also reveal high prevalence of mood and anxiety disorders in a high-functioning adult group with these CNVs. Because carriers of neurodevelopmental CNVs who show relevant psychopathology but no major cognitive impairment are not currently routinely receiving clinical genetic services widening of genetic testing in psychiatry may be considered.
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http://dx.doi.org/10.1038/s41398-021-01226-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862693PMC
February 2021

Global Brain Flexibility During Working Memory Is Reduced in a High-Genetic-Risk Group for Schizophrenia.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 Jan 29. Epub 2021 Jan 29.

Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom; Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, Cardiff, United Kingdom; MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff School of Medicine, Cardiff University, Cardiff, United Kingdom; School for Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands.

Background: Altered functional brain connectivity has been proposed as an intermediate phenotype between genetic risk loci and clinical expression of schizophrenia. Genetic high-risk groups of healthy subjects are particularly suited for the investigation of this proposition because they can be tested in the absence of medication or other secondary effects of schizophrenia.

Methods: Here, we applied dynamic functional connectivity analysis to functional magnetic resonance imaging data to reveal the reconfiguration of brain networks during a cognitive task. We recruited healthy carriers of common risk variants using the recall-by-genotype design. We assessed 197 individuals: 99 individuals (52 female, 47 male) with low polygenic risk scores (schizophrenia risk profile scores [SCZ-PRSs]) and 98 individuals (52 female, 46 male) with high SCZ-PRSs from both tails of the SCZ-PRS distribution from a genotyped population cohort, the Avon Longitudinal Study of Parents and Children (N = 8169). We compared groups both on conventional brain activation profiles, using the general linear model of the experiment, and on the neural flexibility index, which quantifies how frequent a brain region's community affiliation changes over experimental time.

Results: Behavioral performance and standard brain activation profiles did not differ significantly between groups. High SCZ-PRS was associated with reduced flexibility index and network modularity across n-back levels. The whole-brain flexibility index and that of the frontoparietal working memory network was associated with n-back performance. We identified a dynamic network phenotype related to high SCZ-PRS.

Conclusions: Such neurophysiological markers can become important for the elucidation of biological mechanisms of schizophrenia and, particularly, the associated cognitive deficit.
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http://dx.doi.org/10.1016/j.bpsc.2021.01.007DOI Listing
January 2021

Clinical evaluation of patients with a neuropsychiatric risk copy number variant.

Curr Opin Genet Dev 2021 Jun 15;68:26-34. Epub 2021 Jan 15.

MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, UK. Electronic address:

Several copy number variants (CNVs) have been identified to confer high risk for a range of neuropsychiatric conditions. Because of advances in genetic testing within clinical settings, patients are increasingly receiving diagnoses of copy number variant genomic disorders. However, clinical guidelines surrounding assessment and management are limited. This review synthesises recent research and makes preliminary recommendations regarding the clinical evaluation of patients with neuropsychiatric risk CNVs. We recommend multi-system assessment beyond the initial referral reason, recognition of the potential need for co-ordinated multidisciplinary care, and that interventions take account of relevant multimorbidity. The frequently complex needs of patients with CNVs across the life-course pose challenges for many health care systems and may be best provided for by the establishment of specialist clinics.
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http://dx.doi.org/10.1016/j.gde.2020.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219523PMC
June 2021

A Genetics-First Approach to Dissecting the Heterogeneity of Autism: Phenotypic Comparison of Autism Risk Copy Number Variants.

Am J Psychiatry 2021 01;178(1):77-86

MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom (Chawner, Doherty, Anney, Moss, Hall, Owen, van den Bree); Cardiff University Centre for Human Developmental Science, School of Psychology, Cardiff University, Cardiff, United Kingdom (Chawner); Department of Psychology, Syracuse University, Syracuse, N.Y. (Antshel); Department of Psychiatry and Behavioral Sciences and Psychology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles (Bearden, Kushan); Departments of Psychiatry and Behavioral Sciences, University of Washington, Seattle (Bernier); Departments of Pediatrics and Medicine, Columbia University Irving Medical Center, New York (Chung); Center for Autism Research, Children's Hospital of Philadelphia (Clements, Miller, Schultz); Department of Psychology, University of Pennsylvania, Philadelphia (Clements); South West London and St. George's Mental Health National Health Service Foundation Trust, London (Curran); University Children's Hospital, Belgrade, Serbia; Faculty of Medicine, University of Belgrade, Serbia (Cuturilo); Department of Psychiatry, Brain Center, University Medical Center Utrecht, the Netherlands (Fiksinski, Vorstman); Clinical Genetics Research Program, Centre for Addiction and Mental Health, and the Dalglish Family 22q Clinic for 22q11.2 Deletion Syndrome, Toronto General Hospital, University Health Network, Toronto (Fiksinski); Department of Psychiatry, Trinity College Dublin, Ireland (Gallagher); Department of Pediatrics, Baylor College of Medicine, Houston (Goin-Kochel); Lifespan Brain Institute, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia (Gur); Department of Psychiatry, Neurodevelopment and Psychosis Section, Perelman School of Medicine, University of Pennsylvania, Philadelphia (Gur); Department of Child and Adolescent Psychiatry, Children's Hospital of Philadelphia (Gur, Schultz); Developmental Medicine, Children's Hospital Boston/Harvard Medical School, Boston (Hanson); Department of Pediatrics, University of Montreal (Jacquemont, Maillard); Centre de recherche, Centre Hospitalier Universitaire Sainte Justine, Montreal (Jacquemont); Department of Psychiatry and Behavioral Sciences, State University of New York at Upstate Medical University, Syracuse (Kates); Service des Troubles du Spectre de l'Autisme et Apparentés, Lausanne University Hospital, Lausanne, Switzerland (Maillard); Division of Human Genetics and Molecular Biology, Children's Hospital of Philadelphia (McDonald-McGinn); 22q and You Center, Children's Hospital of Philadelphia (McDonald-McGinn); Department of Pediatrics, University of Pennsylvania, Philadelphia (McDonald-McGinn, Schultz); Clinic for Psychiatry, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Serbia (Mihaljevic); Institute of Mental Health, Belgrade, Serbia, Faculty of Medicine, University of Belgrade, Serbia (Pejovic-Milovancevic); Simons Foundation, New York (Green-Snyder); Program in Genetics and Genome Biology, SickKids Research Institute, Toronto (Vorstman); Department of Psychiatry, Hospital for Sick Children, University of Toronto (Vorstman); Department of Pediatrics, Seattle Children's Hospital, Seattle (Wenger); and Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom (Hall, Owen, van den Bree).

Objective: Certain copy number variants (CNVs) greatly increase the risk of autism. The authors conducted a genetics-first study to investigate whether heterogeneity in the clinical presentation of autism is underpinned by specific genotype-phenotype relationships.

Methods: This international study included 547 individuals (mean age, 12.3 years [SD=4.2], 54% male) who were ascertained on the basis of having a genetic diagnosis of a rare CNV associated with high risk of autism (82 16p11.2 deletion carriers, 50 16p11.2 duplication carriers, 370 22q11.2 deletion carriers, and 45 22q11.2 duplication carriers), as well as 2,027 individuals (mean age, 9.1 years [SD=4.9], 86% male) with autism of heterogeneous etiology. Assessments included the Autism Diagnostic Interview-Revised and IQ testing.

Results: The four genetic variant groups differed in autism symptom severity, autism subdomain profile, and IQ profile. However, substantial variability was observed in phenotypic outcome in individual genetic variant groups (74%-97% of the variance, depending on the trait), whereas variability between groups was low (1%-21%, depending on the trait). CNV carriers who met autism criteria were compared with individuals with heterogeneous autism, and a range of profile differences were identified. When clinical cutoff scores were applied, 54% of individuals with one of the four CNVs who did not meet full autism diagnostic criteria had elevated levels of autistic traits.

Conclusions: Many CNV carriers do not meet full diagnostic criteria for autism but nevertheless meet clinical cutoffs for autistic traits. Although profile differences between variants were observed, there is considerable variability in clinical symptoms in the same variant.
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http://dx.doi.org/10.1176/appi.ajp.2020.20010015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022239PMC
January 2021

Large-Scale Genomics: A Paradigm Shift in Psychiatry?

Biol Psychiatry 2021 01 31;89(1):5-7. Epub 2020 Jan 31.

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom.

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http://dx.doi.org/10.1016/j.biopsych.2020.01.017DOI Listing
January 2021

Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 deletion syndrome.

Nat Med 2020 12 9;26(12):1912-1918. Epub 2020 Nov 9.

Centro de Genética y Genómica, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile.

The 22q11.2 deletion syndrome (22q11DS) is associated with a 20-25% risk of schizophrenia. In a cohort of 962 individuals with 22q11DS, we examined the shared genetic basis between schizophrenia and schizophrenia-related early trajectory phenotypes: sub-threshold symptoms of psychosis, low baseline intellectual functioning and cognitive decline. We studied the association of these phenotypes with two polygenic scores, derived for schizophrenia and intelligence, and evaluated their use for individual risk prediction in 22q11DS. Polygenic scores were not only associated with schizophrenia and baseline intelligence quotient (IQ), respectively, but schizophrenia polygenic score was also significantly associated with cognitive (verbal IQ) decline and nominally associated with sub-threshold psychosis. Furthermore, in comparing the tail-end deciles of the schizophrenia and IQ polygenic score distributions, 33% versus 9% of individuals with 22q11DS had schizophrenia, and 63% versus 24% of individuals had intellectual disability. Collectively, these data show a shared genetic basis for schizophrenia and schizophrenia-related phenotypes and also highlight the future potential of polygenic scores for risk stratification among individuals with highly, but incompletely, penetrant genetic variants.
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http://dx.doi.org/10.1038/s41591-020-1103-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7975627PMC
December 2020

Impact of schizophrenia genetic liability on the association between schizophrenia and physical illness: data-linkage study.

BJPsych Open 2020 Nov 10;6(6):e139. Epub 2020 Nov 10.

MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, UK.

Background: Individuals with schizophrenia are at higher risk of physical illnesses, which are a major contributor to their 20-year reduced life expectancy. It is currently unknown what causes the increased risk of physical illness in schizophrenia.

Aims: To link genetic data from a clinically ascertained sample of individuals with schizophrenia to anonymised National Health Service (NHS) records. To assess (a) rates of physical illness in those with schizophrenia, and (b) whether physical illness in schizophrenia is associated with genetic liability.

Method: We linked genetic data from a clinically ascertained sample of individuals with schizophrenia (Cardiff Cognition in Schizophrenia participants, n = 896) to anonymised NHS records held in the Secure Anonymised Information Linkage (SAIL) databank. Physical illnesses were defined from the General Practice Database and Patient Episode Database for Wales. Genetic liability for schizophrenia was indexed by (a) rare copy number variants (CNVs), and (b) polygenic risk scores.

Results: Individuals with schizophrenia in SAIL had increased rates of epilepsy (standardised rate ratio (SRR) = 5.34), intellectual disability (SRR = 3.11), type 2 diabetes (SRR = 2.45), congenital disorders (SRR = 1.77), ischaemic heart disease (SRR = 1.57) and smoking (SRR = 1.44) in comparison with the general SAIL population. In those with schizophrenia, carrier status for schizophrenia-associated CNVs and neurodevelopmental disorder-associated CNVs was associated with height (P = 0.015-0.017), with carriers being 7.5-7.7 cm shorter than non-carriers. We did not find evidence that the increased rates of poor physical health outcomes in schizophrenia were associated with genetic liability for the disorder.

Conclusions: This study demonstrates the value of and potential for linking genetic data from clinically ascertained research studies to anonymised health records. The increased risk for physical illness in schizophrenia is not caused by genetic liability for the disorder.
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http://dx.doi.org/10.1192/bjo.2020.42DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745237PMC
November 2020

Genetic association of FMRP targets with psychiatric disorders.

Mol Psychiatry 2020 Oct 19. Epub 2020 Oct 19.

MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.

Genes encoding the mRNA targets of fragile X mental retardation protein (FMRP) are enriched for genetic association with psychiatric disorders. However, many FMRP targets possess functions that are themselves genetically associated with psychiatric disorders, including synaptic transmission and plasticity, making it unclear whether the genetic risk is truly related to binding by FMRP or is alternatively mediated by the sampling of genes better characterised by another trait or functional annotation. Using published common variant, rare coding variant and copy number variant data, we examined the relationship between FMRP binding and genetic association with schizophrenia, major depressive disorder and bipolar disorder. High-confidence targets of FMRP, derived from studies of multiple tissue types, were enriched for common schizophrenia risk alleles, as well as rare loss-of-function and de novo nonsynonymous variants in schizophrenia cases. Similarly, through common variation, FMRP targets were associated with major depressive disorder, and we present novel evidence of association with bipolar disorder. These relationships could not be explained by other functional annotations known to be associated with psychiatric disorders, including those related to synaptic structure and function. This study reinforces the evidence that targeting by FMRP captures a subpopulation of genes enriched for genetic association with a range of psychiatric disorders.
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http://dx.doi.org/10.1038/s41380-020-00912-2DOI Listing
October 2020

The Duffy-null genotype and risk of infection.

Hum Mol Genet 2020 12;29(20):3341-3349

MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK.

Many medical treatments, from oncology to psychiatry, can lower white blood cell counts and thus access to these treatments can be restricted to individuals with normal levels of white blood cells, principally in order to minimize risk of serious infection. This adversely affects individuals of African or Middle Eastern ancestries who have on average a reduced number of circulating white blood cells, because of the Duffy-null (CC) genotype at rs2814778 in the ACKR1 gene. Here, we investigate whether the Duffy-null genotype is associated with the risk of infection using the UK Biobank sample and the iPSYCH Danish case-cohort study, two population-based samples from different countries and age ranges. We found that a high proportion of those with the Duffy-null genotype (21%) had a neutrophil count below the threshold often used as a cut-off for access to relevant treatments, compared with 1% of those with the TC/TT genotype. In addition we found that despite its strong association with lower average neutrophil counts, the Duffy-null genotype was not associated with an increased risk of infection, viral or bacterial. These results have widespread implications for the clinical treatment of individuals of African ancestry and indicate that neutrophil thresholds to access treatments could be lowered in individuals with the Duffy-null genotype without an increased risk of infection.
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http://dx.doi.org/10.1093/hmg/ddaa208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906776PMC
December 2020

Electrophysiological network alterations in adults with copy number variants associated with high neurodevelopmental risk.

Transl Psychiatry 2020 09 21;10(1):324. Epub 2020 Sep 21.

Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, Maindy Road, Cardiff, CF24 4HQ, UK.

Rare copy number variants associated with increased risk for neurodevelopmental and psychiatric disorders (referred to as ND-CNVs) are characterized by heterogeneous phenotypes thought to share a considerable degree of overlap. Altered neural integration has often been linked to psychopathology and is a candidate marker for potential convergent mechanisms through which ND-CNVs modify risk; however, the rarity of ND-CNVs means that few studies have assessed their neural correlates. Here, we used magnetoencephalography (MEG) to investigate resting-state oscillatory connectivity in a cohort of 42 adults with ND-CNVs, including deletions or duplications at 22q11.2, 15q11.2, 15q13.3, 16p11.2, 17q12, 1q21.1, 3q29, and 2p16.3, and 42 controls. We observed decreased connectivity between occipital, temporal, and parietal areas in participants with ND-CNVs. This pattern was common across genotypes and not exclusively characteristic of 22q11.2 deletions, which were present in a third of our cohort. Furthermore, a data-driven graph theory framework enabled us to successfully distinguish participants with ND-CNVs from unaffected controls using differences in node centrality and network segregation. Together, our results point to alterations in electrophysiological connectivity as a putative common mechanism through which genetic factors confer increased risk for neurodevelopmental and psychiatric disorders.
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http://dx.doi.org/10.1038/s41398-020-00998-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506525PMC
September 2020
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