Irritability in young people with copy number variants associated with neurodevelopmental disorders (ND-CNVs).

A range of rare mutations involving micro-deletion or -duplication of genetic material (copy number variants (CNVs)) have been associated with high neurodevelopmental and psychiatric risk (ND-CNVs). Irritability is frequently observed in childhood neurodevelopmental conditions, yet its aetiology is largely unknown. Genetic variation may play a role, but there is a sparsity of studies investigating the presentation of irritability in young people with ND-CNVs. This study aimed to investigate whether there is a difference in irritability in young people with rare ND-CNVs compared to those without ND-CNVs, and to what extent irritability is associated with psychiatric diagnoses and cognitive ability (IQ). Irritability and broader psychopathology were assessed in 485 young people with ND-CNVs and 164 sibling controls, using the child and adolescent psychiatric assessment. Autism was assessed using the social communication questionnaire, and intelligence quotient (IQ) by the Wechsler abbreviated scale of intelligence. Fifty four percent of young people with ND-CNVs met the threshold for irritability; significantly more than controls (OR = 3.77, CI = 3.07-7.90, p = 5.31 × 10-11). When controlling for the presence of other psychiatric comorbidities, ND-CNV status was still associated with irritability. There was no evidence for a relationship between irritability and IQ. Irritability is an important aspect of the clinical picture in young people with ND-CNVs. This work shows that genetic variation is associated with irritability in young people with ND-CNVs, independent of psychiatric comorbidities or IQ impairment. Clinicians should be aware of this increased risk to inform management and interventions.

Severe psychiatric disorders are associated with increased risk of dementia.

BACKGROUND: Individuals with psychiatric disorders have an increased risk of developing dementia. Most cross-sectional studies suffer from selection bias, underdiagnosis and poor population representation, while there is only limited evidence from longitudinal studies on the role of anxiety, bipolar and psychotic disorders. Electronic health records (EHRs) permit large cohorts to be followed across the lifespan and include a wide range of diagnostic information. OBJECTIVE: To assess the association between four groups of psychiatric disorders (schizophrenia, bipolar disorder/mania, depression and anxiety) with dementia in two large population-based samples with EHR. METHODS: Using EHR on nearly 1 million adult individuals in Wales, and from 228 937 UK Biobank participants, we studied the relationships between schizophrenia, mania/bipolar disorder, depression, anxiety and subsequent risk of dementia. FINDINGS: In Secure Anonymised Information Linkage, there was a steep increase in the incidence of a first diagnosis of psychiatric disorder in the years prior to the diagnosis of dementia, reaching a peak in the year prior to dementia diagnosis for all psychiatric diagnoses. Psychiatric disorders, except anxiety, were highly significantly associated with a subsequent diagnosis of dementia: HRs=2.87, 2.80, 1.63 for schizophrenia, mania/bipolar disorder and depression, respectively. A similar pattern was found in the UK Biobank (HRs=4.46, 3.65, 2.39, respectively) and anxiety was also associated with dementia (HR=1.34). Increased risk of dementia was observed for all ages at onset of psychiatric diagnoses when these were divided into 10-year bins. CONCLUSIONS: Psychiatric disorders are associated with an increased risk of subsequent dementia, with a greater risk of more severe disorders. CLINICAL IMPLICATIONS: A late onset of psychiatric disorders should alert clinicians of possible incipient dementia.

Linking haploinsufficiency of the autism- and schizophrenia-associated gene Cyfip1 with striatal-limbic-cortical network dysfunction and cognitive inflexibility.

Impaired behavioural flexibility is a core feature of neuropsychiatric disorders and is associated with underlying dysfunction of fronto-striatal circuitry. Reduced dosage of Cyfip1 is a risk factor for neuropsychiatric disorder, as evidenced by its involvement in the 15q11.2 (BP1-BP2) copy number variant: deletion carriers are haploinsufficient for CYFIP1 and exhibit a two- to four-fold increased risk of schizophrenia, autism and/or intellectual disability. Here, we model the contributions of Cyfip1 to behavioural flexibility and related fronto-striatal neural network function using a recently developed haploinsufficient, heterozygous knockout rat line. Using multi-site local field potential (LFP) recordings during resting state, we show that Cyfip1 heterozygous rats (Cyfip1+/-) harbor disrupted network activity spanning medial prefrontal cortex, hippocampal CA1 and ventral striatum. In particular, Cyfip1+/- rats showed reduced influence of nucleus accumbens and increased dominance of prefrontal and hippocampal inputs, compared to wildtype controls. Adult Cyfip1+/- rats were able to learn a single cue-response association, yet unable to learn a conditional discrimination task that engages fronto-striatal interactions during flexible pairing of different levers and cue combinations. Together, these results implicate Cyfip1 in development or maintenance of cortico-limbic-striatal network integrity, further supporting the hypothesis that alterations in this circuitry contribute to behavioural inflexibility observed in neuropsychiatric diseases including schizophrenia and autism.

Impaired oxysterol-liver X receptor signaling underlies aberrant cortical neurogenesis in a stem cell model of neurodevelopmental disorder.

The mechanisms by which genomic risks contribute to the onset of neuropsychiatric conditions remain a key challenge and a prerequisite for successful development of effective therapies. 15q11.2 copy number variation (CNV) containing the CYFIP1 gene is associated with autism and schizophrenia. Using stem cell models, we show that 15q11.2 deletion (15q11.2del) and CYFIP1 loss of function (CYFIP1-LoF) lead to premature neuronal differentiation, while CYFIP1 gain of function (CYFIP1-GoF) favors neural progenitor maintenance. CYFIP1 dosage changes led to dysregulated cholesterol metabolism and altered levels of 24S,25-epoxycholesterol, which can mimic the 15q11.2del and CYFIP1-LoF phenotypes by promoting cortical neuronal differentiation and can restore the impaired neuronal differentiation of CYFIP1-GoF neural progenitors. Moreover, the neurogenic activity of 24S,25-epoxycholesterol is lost following genetic deletion of liver X receptor (LXRß), while compound deletion of LXRß in CYFIP1-/- background rescued their premature neurogenesis. This work delineates LXR-mediated oxysterol regulation of neurogenesis as a pathological mechanism in neural cells carrying 15q11.2 CNV and provides a potential target for therapeutic strategies for associated disorders.

Using rare genetic mutations to revisit structural brain asymmetry.

Asymmetry between the left and right hemisphere is a key feature of brain organization. Hemispheric functional specialization underlies some of the most advanced human-defining cognitive operations, such as articulated language, perspective taking, or rapid detection of facial cues. Yet, genetic investigations into brain asymmetry have mostly relied on common variants, which typically exert small effects on brain-related phenotypes. Here, we leverage rare genomic deletions and duplications to study how genetic alterations reverberate in human brain and behavior. We designed a pattern-learning approach to dissect the impact of eight high-effect-size copy number variations (CNVs) on brain asymmetry in a multi-site cohort of 552 CNV carriers and 290 non-carriers. Isolated multivariate brain asymmetry patterns spotlighted regions typically thought to subserve lateralized functions, including language, hearing, as well as visual, face and word recognition. Planum temporale asymmetry emerged as especially susceptible to deletions and duplications of specific gene sets. Targeted analysis of common variants through genome-wide association study (GWAS) consolidated partly diverging genetic influences on the right versus left planum temporale structure. In conclusion, our gene-brain-behavior data fusion highlights the consequences of genetically controlled brain lateralization on uniquely human cognitive capacities.

Genetic and Phenotypic Features of Schizophrenia in the UK Biobank.

Importance: Large-scale biobanks provide important opportunities for mental health research, but selection biases raise questions regarding the comparability of individuals with those in clinical research settings. Objective: To compare the genetic liability to psychiatric disorders in individuals with schizophrenia in the UK Biobank with individuals in the Psychiatric Genomics Consortium (PGC) and to compare genetic liability and phenotypic features with participants recruited from clinical settings. Design, Setting, and Participants: This cross-sectional study included participants from the population-based UK Biobank and schizophrenia samples recruited from clinical settings (CLOZUK, CardiffCOGS, Cardiff F-Series, and Cardiff Affected Sib-Pairs). Data were collected between January 1993 and July 2021. Data analysis was conducted between July 2021 and June 2023. Main Outcomes and Measures: A genome-wide association study of UK Biobank schizophrenia case-control status was conducted, and the results were compared with those from the PGC via genetic correlations. To test for differences with the clinical samples, polygenic risk scores (PRS) were calculated for schizophrenia, bipolar disorder, depression, and intelligence using PRS-CS. PRS and phenotypic comparisons were conducted using pairwise logistic regressions. The proportions of individuals with copy number variants associated with schizophrenia were compared using Firth logistic regression. Results: The sample of 517 375 participants included 1438 UK Biobank participants with schizophrenia (550 [38.2%] female; mean [SD] age, 54.7 [8.3] years), 499 475 UK Biobank controls (271 884 [54.4%] female; mean [SD] age, 56.5 [8.1] years), and 4 schizophrenia research samples (4758 [28.9%] female; mean [SD] age, 38.2 [21.0] years). Liability to schizophrenia in UK Biobank was highly correlated with the latest genome-wide association study from the PGC (genetic correlation, 0.98; SE, 0.18) and showed the expected patterns of correlations with other psychiatric disorders. The schizophrenia PRS explained 6.8% of the variance in liability for schizophrenia case status in UK Biobank. UK Biobank participants with schizophrenia had significantly lower schizophrenia PRS than 3 of the clinically ascertained samples and significantly lower rates of schizophrenia-associated copy number variants than the CLOZUK sample. UK Biobank participants with schizophrenia had higher educational attainment and employment rates than the clinically ascertained schizophrenia samples, lower rates of smoking, and a later age of onset of psychosis. Conclusions and Relevance: Individuals with schizophrenia in the UK Biobank, and likely other volunteer-based biobanks, represent those less severely affected. Their inclusion in wider studies should enhance the representation of the full spectrum of illness severity.

Rare variants in pharmacogenes influence clozapine metabolism in individuals with schizophrenia.

Clozapine is the only licensed medication for treatment-resistant schizophrenia (TRS). Few predictors for variation in response to clozapine have been identified, but clozapine metabolism is known to influence therapeutic response and adverse side effects. Here, we expand on genome-wide studies of clozapine metabolism, previously focused on common genetic variation, by analysing whole-exome sequencing data from 2062 individuals with schizophrenia taking clozapine in the UK. We investigated whether rare genomic variation in genes and gene sets involved in the clozapine metabolism pathway influences plasma concentrations of clozapine metabolites, assessed through the longitudinal analysis of 6585 pharmacokinetic assays. We observed a statistically significant association between the burden of rare damaging coding variants (MAF ≤ 1 %) in gene sets broadly related to drug pharmacokinetics and lower clozapine (ß = -0.054, SE = 0.019, P-value = 0.005) concentrations in plasma. We estimate that the effects in clozapine plasma concentrations of a single damaging allele in this gene set are akin to reducing the clozapine dose by about 35 mg/day. The gene-based analysis identified rare variants in CYP1A2, which encodes the enzyme responsible for converting clozapine to norclozapine, as having the strongest effects of any gene on clozapine metabolism (ß = 0.324, SE = 0.124, P = 0.009). Our findings support the hypothesis that rare genetic variants in known drug-metabolising enzymes and transporters can markedly influence clozapine plasma concentrations; these results suggest that pharmacogenomic efforts trying to predict clozapine metabolism and personalise drug therapy could benefit from the inclusion of rare damaging variants in pharmacogenes beyond those already identified and catalogued as PGx star alleles.

Identifying genetic differences between bipolar disorder and major depression through multiple GWAS.

Background: Accurate diagnosis of bipolar disorder (BD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A key reason is that the first manic episode is often preceded by a depressive one, making it difficult to distinguish BD from unipolar major depressive disorder (MDD). Aims: Here, we use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores that may aid early differential diagnosis. Methods: Based on individual genotypes from case-control cohorts of BD and MDD shared through the Psychiatric Genomics Consortium, we compile case-case-control cohorts, applying a careful merging and quality control procedure. In a resulting cohort of 51,149 individuals (15,532 BD cases, 12,920 MDD cases and 22,697 controls), we perform a variety of GWAS and polygenic risk scores (PRS) analyses. Results: While our GWAS is not well-powered to identify genome-wide significant loci, we find significant SNP-heritability and demonstrate the ability of the resulting PRS to distinguish BD from MDD, including BD cases with depressive onset. We replicate our PRS findings, but not signals of individual loci in an independent Danish cohort (iPSYCH 2015 case-cohort study, N=25,966). We observe strong genetic correlation between our case-case GWAS and that of case-control BD. Conclusions: We find that MDD and BD, including BD with a depressive onset, are genetically distinct. Further, our findings support the hypothesis that Controls - MDD - BD primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BD and, importantly, BD with depressive onset from MDD.

Source-based morphometry reveals structural brain pattern abnormalities in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11DS) is the most frequently occurring microdeletion in humans. It is associated with a significant impact on brain structure, including prominent reductions in gray matter volume (GMV), and neuropsychiatric manifestations, including cognitive impairment and psychosis. It is unclear whether GMV alterations in 22q11DS occur according to distinct structural patterns. Then, 783 participants (470 with 22q11DS: 51% females, mean age [SD] 18.2 [9.2]; and 313 typically developing [TD] controls: 46% females, mean age 18.0 [8.6]) from 13 datasets were included in the present study. We segmented structural T1-weighted brain MRI scans and extracted GMV images, which were then utilized in a novel source-based morphometry (SBM) pipeline (SS-Detect) to generate structural brain patterns (SBPs) that capture co-varying GMV. We investigated the impact of the 22q11.2 deletion, deletion size, intelligence quotient, and psychosis on the SBPs. Seventeen GMV-SBPs were derived, which provided spatial patterns of GMV covariance associated with a quantitative metric (i.e., loading score) for analysis. Patterns of topographically widespread differences in GMV covariance, including the cerebellum, discriminated individuals with 22q11DS from healthy controls. The spatial extents of the SBPs that revealed disparities between individuals with 22q11DS and controls were consistent with the findings of the univariate voxel-based morphometry analysis. Larger deletion size was associated with significantly lower GMV in frontal and occipital SBPs; however, history of psychosis did not show a strong relationship with these covariance patterns. 22q11DS is associated with distinct structural abnormalities captured by topographical GMV covariance patterns that include the cerebellum. Findings indicate that structural anomalies in 22q11DS manifest in a nonrandom manner and in distinct covarying anatomical patterns, rather than a diffuse global process. These SBP abnormalities converge with previously reported cortical surface area abnormalities, suggesting disturbances of early neurodevelopment as the most likely underlying mechanism.

Atypical cortical networks in children at high-genetic risk of psychiatric and neurodevelopmental disorders.

Although many genetic risk factors for psychiatric and neurodevelopmental disorders have been identified, the neurobiological route from genetic risk to neuropsychiatric outcome remains unclear. 22q11.2 deletion syndrome (22q11.2DS) is a copy number variant (CNV) syndrome associated with high rates of neurodevelopmental and psychiatric disorders including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD) and schizophrenia. Alterations in neural integration and cortical connectivity have been linked to the spectrum of neuropsychiatric disorders seen in 22q11.2DS and may be a mechanism by which the CNV acts to increase risk. In this study, magnetoencephalography (MEG) was used to investigate electrophysiological markers of local and global network function in 34 children with 22q11.2DS and 25 controls aged 10-17 years old. Resting-state oscillatory activity and functional connectivity across six frequency bands were compared between groups. Regression analyses were used to explore the relationships between these measures, neurodevelopmental symptoms and IQ. Children with 22q11.2DS had altered network activity and connectivity in high and low frequency bands, reflecting modified local and long-range cortical circuitry. Alpha and theta band connectivity were negatively associated with ASD symptoms while frontal high frequency (gamma band) activity was positively associated with ASD symptoms. Alpha band activity was positively associated with cognitive ability. These findings suggest that haploinsufficiency at the 22q11.2 locus impacts short and long-range cortical circuits, which could be a mechanism underlying neurodevelopmental and psychiatric vulnerability in this high-risk group.

Rare genetic brain disorders with overlapping neurological and psychiatric phenotypes.

Understanding rare genetic brain disorders with overlapping neurological and psychiatric phenotypes is of increasing importance given the potential for developing disease models that could help to understand more common, polygenic disorders. However, the traditional clinical boundaries between neurology and psychiatry result in frequent segregation of these disorders into distinct silos, limiting cross-specialty understanding that could facilitate clinical and biological advances. In this Review, we highlight multiple genetic brain disorders in which neurological and psychiatric phenotypes are observed, but for which in-depth, cross-spectrum clinical phenotyping is rarely undertaken. We describe the combined phenotypes observed in association with genetic variants linked to epilepsy, dystonia, autism spectrum disorder and schizophrenia. We also consider common underlying mechanisms that centre on synaptic plasticity, including changes to synaptic and neuronal structure, calcium handling and the balance of excitatory and inhibitory neuronal activity. Further investigation is needed to better define and replicate these phenotypes in larger cohorts, which would help to gain greater understanding of the pathophysiological mechanisms and identify common therapeutic targets.

The schizophrenia syndrome, circa 2024: What we know and how that informs its nature.

With new data about different aspects of schizophrenia being continually generated, it becomes necessary to periodically revisit exactly what we know. Along with a need to review what we currently know about schizophrenia, there is an equal imperative to evaluate the construct itself. With these objectives, we undertook an iterative, multi-phase process involving fifty international experts in the field, with each step building on learnings from the prior one. This review assembles currently established findings about schizophrenia (construct, etiology, pathophysiology, clinical expression, treatment) and posits what they reveal about its nature. Schizophrenia is a heritable, complex, multi-dimensional syndrome with varying degrees of psychotic, negative, cognitive, mood, and motor manifestations. The illness exhibits a remitting and relapsing course, with varying degrees of recovery among affected individuals with most experiencing significant social and functional impairment. Genetic risk factors likely include thousands of common genetic variants that each have a small impact on an individual's risk and a plethora of rare gene variants that have a larger individual impact on risk. Their biological effects are concentrated in the brain and many of the same variants also increase the risk of other psychiatric disorders such as bipolar disorder, autism, and other neurodevelopmental conditions. Environmental risk factors include but are not limited to urban residence in childhood, migration, older paternal age at birth, cannabis use, childhood trauma, antenatal maternal infection, and perinatal hypoxia. Structural, functional, and neurochemical brain alterations implicate multiple regions and functional circuits. Dopamine D-2 receptor antagonists and partial agonists improve psychotic symptoms and reduce risk of relapse. Certain psychological and psychosocial interventions are beneficial. Early intervention can reduce treatment delay and improve outcomes. Schizophrenia is increasingly considered to be a heterogeneous syndrome and not a singular disease entity. There is no necessary or sufficient etiology, pathology, set of clinical features, or treatment that fully circumscribes this syndrome. A single, common pathophysiological pathway appears unlikely. The boundaries of schizophrenia remain fuzzy, suggesting the absence of a categorical fit and need to reconceptualize it as a broader, multi-dimensional and/or spectrum construct.

Rare X-linked variants carry predominantly male risk in autism, Tourette syndrome, and ADHD.

Autism spectrum disorder (ASD), Tourette syndrome (TS), and attention-deficit/hyperactivity disorder (ADHD) display strong male sex bias, due to a combination of genetic and biological factors, as well as selective ascertainment. While the hemizygous nature of chromosome X (Chr X) in males has long been postulated as a key point of "male vulnerability", rare genetic variation on this chromosome has not been systematically characterized in large-scale whole exome sequencing studies of "idiopathic" ASD, TS, and ADHD. Here, we take advantage of informative recombinations in simplex ASD families to pinpoint risk-enriched regions on Chr X, within which rare maternally-inherited damaging variants carry substantial risk in males with ASD. We then apply a modified transmission disequilibrium test to 13,052 ASD probands and identify a novel high confidence ASD risk gene at exome-wide significance (MAGEC3). Finally, we observe that rare damaging variants within these risk regions carry similar effect sizes in males with TS or ADHD, further clarifying genetic mechanisms underlying male vulnerability in multiple neurodevelopmental disorders that can be exploited for systematic gene discovery.

Assessing the validity of a self-reported clinical diagnosis of schizophrenia.

Background: Diagnoses in psychiatric research can be derived from various sources. This study assesses the validity of a self-reported clinical diagnosis of schizophrenia. Methods: The study included 3,029 clinically ascertained participants with schizophrenia or psychotic disorders diagnosed by self-report and/or research interview and 1,453 UK Biobank participants with self-report and/or medical record diagnosis of schizophrenia or schizoaffective disorder depressed-type (SA-D). We assessed positive predictive values (PPV) of self-reported clinical diagnoses against research interview and medical record diagnoses. We compared polygenic risk scores (PRS) and phenotypes across diagnostic groups, and compared the variance explained by schizophrenia PRS to samples in the Psychiatric Genomics Consortium (PGC). Results: In the clinically ascertained sample, the PPV of self-reported schizophrenia to a research diagnosis of schizophrenia was 0.70, which increased to 0.81 when benchmarked against schizophrenia or SA-D. In UK Biobank, the PPV of self-reported schizophrenia to a medical record diagnosis was 0.74. Compared to self-report participants, those with a research diagnosis were younger and more likely to have a high school qualification (clinically ascertained sample) and those with a medical record diagnosis were less likely to be employed or have a high school qualification (UK Biobank). Schizophrenia PRS did not differ between participants that had a diagnosis from self-report, research diagnosis or medical record diagnosis. Polygenic liability r2, for all diagnosis definitions, fell within the distribution of PGC schizophrenia cohorts. Conclusions: Self-report measures of schizophrenia are justified in research to maximise sample size and representativeness, although within sample validation of diagnoses is recommended.

Irritability in young people with copy number variants associated with neurodevelopmental disorders (ND-CNVs).

Background: A range of rare mutations involving micro-deletion or -duplication of genetic material (copy number variants (CNVs)) have been associated with high neurodevelopmental and psychiatric risk (ND-CNVs). Irritability is frequently observed in childhood neurodevelopmental conditions, yet its aetiology is largely unknown. Genetic variation may play a role, but there is a sparsity of studies investigating presentation of irritability in young people with ND-CNVs. Aims: This study aimed to investigate whether there is a difference in irritability in young people with rare ND-CNVs compared to those without ND-CNVs, and to what extent irritability is associated with psychiatric diagnoses and cognitive ability (IQ). Methods: Irritability and broader psychopathology was assessed in 485 young people with ND-CNVs and 164 sibling controls, using the child and adolescent psychiatric assessment (CAPA). Autism was assessed using the Social Communication Questionnaire (SCQ), and Intelligence Quotient (IQ) by the Wechsler Abbreviated Scale of Intelligence (WASI). Results: 54% of young people with ND-CNVs met the threshold for irritability; significantly more than controls (OR = 3.77, CI = 3.07-7.90, p= 5.31 × 10-11). When controlling for the presence of other psychiatric comorbidities, ND-CNV status was still associated with irritability. There was no evidence for a relationship between irritability and IQ. Conclusions: Irritability is an important aspect of the clinical picture in young people with ND-CNVs. This work shows that genetic variation is associated with irritability in young people with ND-CNVs, independent of psychiatric comorbidities or IQ impairment. Clinicians should be aware of this increased risk to inform management and interventions.

Effective synthesis, development and application of a highly fluorescent cyanine dye for antibody conjugation and microscopy imaging.

An asymmetric cyanine-type fluorescent dye was designed and synthesized via a versatile, multi-step process, aiming to conjugate with an Her2+ receptor specific antibody by an azide-alkyne click reaction. The aromaticity and the excitation and relaxation energetics of the fluorophore were characterized by computational methods. The synthesized dye exhibited excellent fluorescence properties for confocal microscopy, offering efficient applicability in in vitro imaging due to its merits such as a high molar absorption coefficient (36 816 M-1 cm-1), excellent brightness, optimal wavelength (627 nm), larger Stokes shift (26 nm) and appropriate photostability compared to cyanines. The conjugated cyanine-trastuzumab was constructed via an effective, metal-free, strain-promoted azide-alkyne click reaction leading to a regulated number of dyes being conjugated. This novel cyanine-labelled antibody was successfully applied for in vitro confocal imaging and flow cytometry of Her2+ tumor cells.

Copy Number Variants Increasing Risk for Schizophrenia: Shared and Distinct Effects on Brain Morphometry and Cognitive Performance.

Background: Copy number variations (CNVs) conferring risk for mental disorders are associated with brain changes and cognitive deficits. However, whether these effects are shared or distinct across CNVs remains untested. Here we compared the effects on brain morphometry and cognitive performance across CNVs with shared psychiatric liability. Methods: Unaffected and unrelated participants of White British and Irish ancestry were drawn from the UK Biobank. After quality control, we retained 31,941 participants not carrying any damaging CNVs and 202 participants carrying one CNV increasing risk for schizophrenia. Using regression analyses, we tested the association between brain morphometry and cognitive performance with CNV carrying status and compared these effect sizes across CNVs using z test for the equality of regression coefficients. Equation modeling was used to examine the mediation of brain phenotypes on the association between CNVs and cognitive performance. Results: We detected different patterns of association between CNVs and brain morphometry and cognitive abilities. Comparing across CNVs, 1q21.1 deletion showed the strongest association with surface area in frontal lobe (ß = -1.03, p = 4 × 10-8; ß = -0.81, p = .00001) and performance in digit memory (ß = -1.58, p = .00003), while 1q21.1 duplication showed the strongest association with volume of the putamen (ß = -0.70, p = .0004) and reaction time (ß = -1.14, p = .000002). We also showed that even when 2 CNVs were associated with performance in the same cognitive ability, these associations were mediated by different brain changes. Conclusions: Despite sharing similar psychiatric liability, the CNVs under study appeared to have different effects on brain morphometry and on performance in cognitive abilities, suggesting the existence of distinctive neurobiological pathways into the same clinical phenotypes.

How can UK public health initiatives support each other to improve the maintenance of physical activity? Evidence from a cross-sectional survey of runners who move from Couch-to-5k to parkrun.

Physical activity improves physical and mental well-being and reduces mortality risk. However, only a quarter of adults globally meet recommended physical activity levels for health. Two common initiatives in the UK are Couch-to-5k (an app-assisted 9-week walk/run programme) and parkrun (a free, weekly, timed 5-km walk/run). It is not known how these initiatives are linked, how Couch-to-5k parkrunners compare to parkrunners, and the extent to which this influences their parkrun performance. The aims were to compare the characteristics and motives and to compare physical activity levels, parkrun performance and the impact of parkrun between Couch-to-5k parkrunners and parkrunners. Three thousand two hundred and ninety six Couch-to-5k parkrunners were compared to 55,923 parkrunners to explore age, sex, ethnicity, employment status, neighbourhood deprivation, motives, physical activity levels, parkrun performance and the impact of parkrun. Couch-to-5k parkrunners were slightly older, more likely to be female and work part-time, but similar in ethnicity, and neighbourhood deprivation compared with other parkrunners. Couch-to-5k parkrunners had different motives for participation and reported high levels of physical activity at registration, which remained to the point of survey completion. This group had slower parkrun times but, when registered for a year, completed a similar number of runs (11) per year. Larger proportions of Couch-to-5k parkrunners perceived positive impacts compared with other parkrunners and 65% of Couch-to-5k parkrunners reported improvements to their lifestyle. parkrun appears to be an effective pathway for those on the Couch-to-5k programme, and the promising positive association between the two initiatives may be effective in assisting previously inactive participants to take part in weekly physical activity.

Mediation and longitudinal analysis to interpret the association between clozapine pharmacokinetics, pharmacogenomics, and absolute neutrophil count.

Clozapine is effective at reducing symptoms of treatment-resistant schizophrenia, but it can also induce several adverse outcomes including neutropenia and agranulocytosis. We used linear mixed-effect models and structural equation modelling to determine whether pharmacokinetic and genetic variables influence absolute neutrophil count in a longitudinal UK-based sample of clozapine users not currently experiencing neutropenia (N = 811). Increased daily clozapine dose was associated with elevated neutrophil count, amounting to a 133 cells/mm3 rise per standard deviation increase in clozapine dose. One-third of the total effect of clozapine dose was mediated by plasma clozapine and norclozapine levels, which themselves demonstrated opposing, independent associations with absolute neutrophil count. Finally, CYP1A2 pharmacogenomic activity score was associated with absolute neutrophil count, supporting lower neutrophil levels in CYP1A2 poor metabolisers during clozapine use. This information may facilitate identifying at-risk patients and then introducing preventative interventions or individualised pharmacovigilance procedures to help mitigate these adverse haematological reactions.