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Background:\udRare 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.\ud\udAims\udWe 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.\ud\udMethod:\udWe 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.\ud\udResults:\udMost 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.\ud\udConclusions\udCNVs 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.

Background\ud 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.\ud \ud Aims\ud 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.\ud \ud Method\ud 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.\ud \ud Results\ud 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.\ud \ud Conclusions\ud 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.

Importance: The role of large, rare copy number variants (CNVs) in neuropsychiatric disorders is well established, but their association with common psychiatric disorders, such as depression, remains unclear.Objective: To examine the association of a group of 53 CNVs associated with neurodevelopmental disorders and burden of rare CNVs with risk of depression.Design, Setting, and Participants: This case-control study used data from the UK Biobank study sample, which comprised 502 534 individuals living in the United Kingdom. Individuals with autism spectrum disorder, intellectual disability, attention-deficit/hyperactivity disorder, schizophrenia, or bipolar affective disorder diagnoses were excluded. Analyses were further restricted to individuals of European genetic ancestry (n = 407 074). The study was conducted from January 2017 to September 2018.Exposures: CNV carrier status.Main Outcomes and Measures: For the primary outcome, individuals who reported that a physician had told them they had a depression diagnosis were defined as cases. Analyses were repeated using 2 alternative depression definitions: self-reported lifetime depression with current antidepressant prescription at the time of visit 1, and hospital discharge diagnosis of depression.Results: Copy number variants were identified in 488 366 individuals aged 37 to 73 years. In total, 407 074 individuals with European genetic ancestry (220 201 female [54.1%]; mean [SD] age of 56.9 [8.0] years) were included in the study. Of these individuals, 23 979 (5.9%) had self-reported lifetime depression and 383 095 (94.1%) reported no lifetime depression. The group of 53 neurodevelopmental CNVs was associated with self-reported depression (odds ratio [OR], 1.34; 95% CI, 1.19-1.49, uncorrected P = 1.38 × 10-7), and these results were consistent when using 2 alternative definitions of depression. This association was partially explained by physical health, educational attainment, social deprivation, smoking status, and alcohol consumption. A strong independent association remained between the neurodevelopmental CNVs and depression in analyses that incorporated these other measures (OR, 1.26; 95% CI, 1.11-1.43; P = 2.87 × 10-4). Eight individual CNVs were nominally associated with risk of depression, and 3 of these 8 CNVs (1q21.1 duplication, Prader-Willi syndrome duplication, and 16p11.2 duplication) survived Bonferroni correction for the 53 CNVs tested. After the exclusion of carriers of neurodevelopmental CNVs, no association was found between measures of CNV burden and depression.Conclusions and Relevance: Neurodevelopmental CNVs appear to be associated with depression, extending the spectrum of clinical phenotypes that are associated with CNV carrier status.

Figure S1. Images of the changes in the physical traits (normalised z-score values) associated with each CNV and their 95% confidence intervals (95%CI). (XLSX 335 kb) (DOCX 1040 kb)