Individuals with psychosis experience impairments in real-world functional outcomes such as employment and health. Rare copy number variants (CNVs) are established risk factors for psychosis, neurodevelopmental disorders and cognitive impairment. However, little is known about their effect on real-world functional outcomes in individuals with psychosis.

I aimed to establish the effect of rare neurodevelopmental CNVs on real-world functioning in individuals with psychosis.

I identified 1,932 individuals with psychotic disorders (ICD–10 F20–F29) in the UK Biobank using first-occurrence data (from primary care, hospital inpatient and death register records and self-reported conditions). I mapped UK Biobank data to two domains of real-world functional outcomes – health deficits and vocational outcomes. We previously called CNVs using PennCNV, annotating them with 53 CNVs associated with autism spectrum disorder and developmental delay. I conducted regression analyses with neurodevelopmental CNVs as the predictor, real-world functioning as outcomes and with relevant covariates (e.g. age and sex).

Out of 1,932 individuals with psychotic disorders, 2.5% (n = 49) carried a neurodevelopmental CNV.

Health Deficits

I used first-occurrence diagnosis data to establish comorbid psychiatric diagnoses. I summed these diagnoses and dichotomised them into one or more comorbid diagnoses versus no comorbid psychiatric diagnoses. I conducted a logistic regression analysis – neurodevelopmental CNV carrier status was associated with having at least one psychiatric diagnosis in addition to a psychosis diagnosis (OR 2.1, 95% CI 1.1 - 4.1, p 0.034). Post-hoc analyses revealed an increased rate of dissociative and conversion disorders in CNV carriers (OR 4.5, 95% CI 1.26 - 15.99, p 0.021).

I used first-occurrence physical health diagnosis data to establish the burden of the 20 most prevalent chronic non-cancer illnesses. Neurodevelopmental CNV carrier status was associated with chronic physical health multimorbidity in individuals with psychosis (59.2% vs 43.5%, OR 2.30, 95% CI 1.27–4.17, p 0.006), defined as the presence of two or more chronic physical health conditions.

Vocational Outcomes

I conducted an ordinal regression analysis, establishing that among individuals with psychosis, CNV carriers had a lower likelihood of achieving a higher qualification (OR 0.45, 95% CI 0.27–0.77, p 0.003).

Neurodevelopmental CNVs are associated with important real-world functional outcomes in individuals with psychosis. This work provides information that can guide the assessment and management of individuals with both psychosis and neurodevelopmental CNVs.

Individuals with schizophrenia, schizoaffective disorder, and bipolar affective disorder have higher rates of cardiometabolic disease and have a reduced life expectancy compared with healthy controls. These mental health conditions are highly heritable and neurodevelopmental copy number variants (CNVs) are known to increase the risk of these disorders. Neurodevelopmental CNVs have also been associated with a range of cardiometabolic disorders. The aim of this research was to examine the relationship between neurodevelopmental CNVs and cardiometabolic disease in individuals with schizophrenia, schizoaffective disorder, and bipolar disorder.

Using data from the UK Biobank, a group of individuals with schizophrenia, schizoaffective disorder and bipolar affective disorder was defined (n = 2,611) based on first-occurrence data. CNVs had previously been called using PennCNV and a set of 53 neurodevelopmental loci annotated. I carried out association analyses between neurodevelopmental CNVs and cardiometabolic disease phenotypes using logistic regression with age and sex as covariates.

There was a higher frequency of ischaemic heart disease, hypertension, obesity, and type 2 diabetes mellitus in individuals with schizophrenia, schizoaffective disorder and bipolar disorder than in controls. 2.1% of individuals with these mental health conditions carried a neurodevelopmental CNV. Carrying a neurodevelopmental CNV was significantly associated with type 2 diabetes mellitus (OR = 1.94, 95% CI 1.09–3.57, p = 0.025). However, this result did not survive Bonferroni correction for four tests (p value threshold 0.0125). I did not find any mediators of the neurodevelopmental CNV – type 2 diabetes mellitus association (of obesity, hypertension, cognition, smoking and socioeconomic status).

The relationship between neurodevelopmental CNVs and type 2 diabetes mellitus should be examined in independent samples.

In the United Kingdom, 14.6 million people reported having a disability in the year 2020–2021. Cognition may be one factor that contributes to disability, as previous studies have shown that cognitive abilities predict later health outcomes and prevalence of disability increases with decreasing cognitive function. Furthermore, studies have demonstrated a link between cognition and common psychiatric disorders, such as depression and anxiety. To our knowledge, no studies have examined the role of current mental health in the association between cognition and disability in a general population sample. The aim of this study was to examine the relationship between cognition, mental health and measures of disability/daily functioning in an online population sample. Our hypotheses were: 1) that lower cognitive performance would be associated with increased reported disability, and 2) that this association would be partly explained by current depression and anxiety symptoms.

The sample consisted of 3679 participants recruited from HealthWise Wales. Participants completed the Cardiff ONline Cognitive Assessment, a web-based battery of five tasks assessing processing speed, working memory, vocabulary, reasoning, and emotion identification. Disability was assessed using the World Health Organisation Disability Assessment Schedule (WHODAS). Real world measures of functioning were also included (currently employed, living with a partner, children and ever married). Current depression and anxiety symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS). Linear and logistic regressions were conducted to assess the associations between cognitive performance and measures of disability/functioning. Structural equation modelling was performed to assess whether these associations could be partially explained by HADS scores, as well as measures of education and health/lifestyle factors.

Higher cognitive performance was associated with lower overall WHODAS scores (B=−0.1, SE = 0.01, P = 1 × 10–13), living with a partner (OR = 1.13, 95% CIs = 1.06–1.21, P = 4.3 × 10–4) and being in employment or education (OR = 1.22, 95% CIs = 1.13–1.33, P = 2.1 × 10-6). HADS scores partially explained the relationship between cognition and: 1) WHODAS (80%), 2) employment (63%) and 3) living with a partner (37%). In addition, smoking status explained 3% of the relationship between cognition and WHODAS.

Current symptoms of depression and anxiety partially explained the relationship between cognition and three measures of disability/functioning. Alleviating these symptoms may improve patients’ daily difficulties. Future research should establish the direction of causality of these associations.

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.

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.

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.

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.

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.

Schizophrenia is a highly heritable disorder with undetermined neurobiological causes. Understanding the impact on brain anatomy of carrying genetic risk for the disorder will contribute to uncovering its neurobiological underpinnings.

To examine the effect of rare copy number variants (CNVs) associated with schizophrenia on brain cortical anatomy in a sample of unaffected participants from the UK Biobank.

We used regression analyses to compare cortical thickness and surface area (total and across gyri) between 120 unaffected carriers of rare CNVs associated with schizophrenia and 16 670 participants without any pathogenic CNV. A measure of cortical thickness and surface area covariance across gyri was also compared between groups.

Carrier status was associated with reduced surface area (β = −0.020 mm2, P < 0.001) and less robustly with increased cortical thickness (β = 0.015 mm, P = 0.035), and with increased covariance in thickness (carriers z = 0.31 v. non-carriers z = 0.22, P < 0.0005). Associations were mainly present in frontal and parietal areas and driven by a limited number of rare risk alleles included in our analyses (mainly 15q11.2 deletion for surface area and 16p13.11 duplication for thickness covariance).

Results for surface area conformed with previous clinical findings, supporting surface area reductions as an indicator of genetic liability for schizophrenia. Results for cortical thickness, though, argued against its validity as a potential risk marker. Increased structural thickness covariance across gyri also appears related to risk for schizophrenia. The heterogeneity found across the effects of rare risk alleles suggests potential different neurobiological gateways into schizophrenia's phenotype.

The past decade has seen the development of services for adults presenting with symptoms of autism spectrum disorder (ASD) in the UK. Compared with children, little is known about the phenotypic and genetic characteristics of these patients.

This e-cohort study aimed to examine the phenotypic and genetic characteristics of a clinically presenting sample of adults diagnosed with ASD by specialist services.

Individuals diagnosed with ASD as adults were recruited by the National Centre for Mental Health and completed self-report questionnaires, interviews and provided DNA; 105 eligible individuals were matched to 76 healthy controls. We investigated demographics, social history and comorbid psychiatric and physical disorders. Samples were genotyped, copy number variants (CNVs) were called and polygenic risk scores were calculated.

Of individuals with ASD, 89.5% had at least one comorbid psychiatric diagnosis, with depression (62.9%) and anxiety (55.2%) being the most common. The ASD group experienced more neurological comorbidities than controls, particularly migraine headache. They were less likely to have married or be in work, and had more alcohol-related problems. There was a significantly higher load of autism common genetic variants in the adult ASD group compared with controls, but there was no difference in the rate of rare CNVs.

This study provides important information about psychiatric comorbidity in adult ASD, which may inform clinical practice and patient counselling. It also suggests that the polygenic load of common ASD-associated variants may be important in conferring risk within the non-intellectually disabled population of adults with ASD.

None.

Rare copy number variants (CNVs) are associated with risk of neurodevelopmental disorders characterised by varying degrees of cognitive impairment, including schizophrenia, autism spectrum disorder and intellectual disability. However, the effects of many individual CNVs in carriers without neurodevelopmental disorders are not yet fully understood, and little is known about the effects of reciprocal copy number changes of known pathogenic loci.

We aimed to analyse the effect of CNV carrier status on cognitive performance and measures of occupational and social outcomes in unaffected individuals from the UK Biobank.

We called CNVs in the full UK Biobank sample and analysed data from 420 247 individuals who passed CNV quality control, reported White British or Irish ancestry and were not diagnosed with neurodevelopmental disorders. We analysed 33 pathogenic CNVs, including their reciprocal deletions/duplications, for association with seven cognitive tests and four general measures of functioning: academic qualifications, occupation, household income and Townsend Deprivation Index.

Most CNVs (24 out of 33) were associated with reduced performance on at least one cognitive test or measure of functioning. The changes on the cognitive tests were modest (average reduction of 0.13 s.d.) but varied markedly between CNVs. All 12 schizophrenia-associated CNVs were associated with significant impairments on measures of functioning.

CNVs implicated in neurodevelopmental disorders, including schizophrenia, are associated with cognitive deficits, even among unaffected individuals. These deficits may be subtle but CNV carriers have significant disadvantages in educational attainment and ability to earn income in adult life.

None.

There is strong evidence that people born in winter and in spring have a small increased risk of schizophrenia. As this ‘season of birth’ effect underpins some of the most influential hypotheses concerning potentially modifiable risk exposures, it is important to exclude other possible explanations for the phenomenon.

Here we sought to determine whether the season of birth effect reflects gene-environment confounding rather than a pathogenic process indexing environmental exposure. We directly measured, in 136 538 participants from the UK Biobank (UKBB), the burdens of common schizophrenia risk alleles and of copy number variants known to increase the risk for the disorder, and tested whether these were correlated with a season of birth.

Neither genetic measure was associated with season or month of birth within the UKBB sample.

As our study was highly powered to detect small effects, we conclude that the season of birth effect in schizophrenia reflects a true pathogenic effect of environmental exposure.