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Mental health and neurodevelopmental disorders are highly heritable and can affect morbidity and mortality. A large, growing body of evidence has implicated both common and rare variation in the risk of these disorders. Testing for rare variants, such as copy number variants, has been available in clinical practice for some time in the context of developmental disorders. However, until recently, individuals with mental health and neurodevelopmental disorders in the UK have not tended to access genetic counselling and testing. Here, we describe the development of the All Wales Psychiatric Genomics Service, a collaborative effort between psychiatric and clinical genetics services and the first of its kind in the UK. We provide an overview of the structure and function of the service, our referral criteria, a summary of the 40 referrals we have received to date and our future plans. [ABSTRACT FROM AUTHOR]

Background The UK Biobank is a unique resource for biomedical research, with extensive phenotypic and genetic data on half a million adults from the general population. We aimed to examine the effect of neurodevelopmental copy number variants (CNVs) on the cognitive performance of participants. Methods We used Affymetrix Power Tools and PennCNV-Affy software to analyze Affymetrix microarrays of the first 152,728 genotyped individuals. We annotated a list of 93 CNVs and compared their frequencies with control datasets. We analyzed the performance on seven cognitive tests of carriers of 12 CNVs associated with schizophrenia ( n = 1087) and of carriers of another 41 neurodevelopmental CNVs ( n = 484). Results The frequencies of the 93 CNVs in the Biobank subjects were remarkably similar to those among 26,628 control subjects from other datasets. Carriers of schizophrenia-associated CNVs and of the group of 41 other neurodevelopmental CNVs had impaired performance on the cognitive tests, with nine of 14 comparisons remaining statistically significant after correction for multiple testing. They also had lower educational and occupational attainment ( p values between 10 −7 and 10 −18 ). The deficits in cognitive performance were modest ( Z score reductions between 0.01 and 0.51), compared with individuals with schizophrenia in the Biobank ( Z score reductions between 0.35 and 0.90). Conclusions This is the largest study on the cognitive phenotypes of CNVs to date. Adult carriers of neurodevelopmental CNVs from the general population have significant cognitive deficits. The UK Biobank will allow unprecedented opportunities for analysis of further phenotypic consequences of CNVs. [ABSTRACT FROM AUTHOR]

The spectrum of non-motor symptoms in dystonia remains unclear. Using UK Biobank data, we analysed clinical phenotypic and genetic information in the largest dystonia cohort reported to date. Case–control comparison of dystonia and matched control cohort was undertaken to identify domains (psychiatric, pain, sleep and cognition) of increased symptom burden in dystonia. Whole exome data were used to determine the rate and likely pathogenicity of variants in Mendelian inherited dystonia causing genes and linked to clinical data. Within the dystonia cohort, phenotypic and genetic single-nucleotide polymorphism (SNP) data were combined in a mixed model analysis to derive genetically informed phenotypic axes. A total of 1572 individuals with dystonia were identified, including cervical dystonia (n = 775), blepharospasm (n = 131), tremor (n = 488) and dystonia, unspecified (n = 154) groups. Phenotypic patterns highlighted a predominance of psychiatric symptoms (anxiety and depression), excess pain and sleep disturbance. Cognitive impairment was limited to prospective memory and fluid intelligence. Whole exome sequencing identified 798 loss of function variants in dystonia-linked genes, 67 missense variants (MPC > 3) and 305 other forms of non-synonymous variants (including inframe deletion, inframe insertion, stop loss and start loss variants). A single loss of function variant (ANO3) was identified in the dystonia cohort. Combined SNP and clinical data identified multiple genetically informed phenotypic axes with predominance of psychiatric, pain and sleep non-motor domains. An excess of psychiatric, pain and sleep symptoms were evident across all forms of dystonia. Combination with genetic data highlights phenotypic subgroups consistent with the heterogeneity observed in clinical practice. [ABSTRACT FROM AUTHOR]

Highlights from the article: B Background: b Autism Spectrum Disorders (ASD) are lifelong neurodevelopmental conditions characterised by persistent difficulties in reciprocal social interaction, communication, restricted interests, stereotypic behaviours and resistance to change. This study aims to examine i) the rate of rare neurodevelopmental copy number variants (CNVs) and, ii) the polygenic risk scores (PRS) of a cohort of individuals diagnosed with ASD in adulthood. Taken together, these results suggest that adults presenting with ASD may have a lower burden of rare penetrant variants and a higher polygenic contribution of common risk alleles than childhood ASD populations, potentially reflecting less severe neurodevelopmental disability.

NRXN1 deletions are a confirmed risk factor for schizophrenia and ASD. The full phenotypic spectrum of consequences of these deletions has not been established. We tested 140,187 white British or Irish participants in the UK Biobank (aged 40–70) for the presence of deletions that intersect at least one exon of the NRXN1 gene 48 people (30 women and 18 men) carried such deletions (0.03%). Carriers had subtle cognitive deficits: on seven tests they showed differences of between 0 and 1 SD (Z-scores, corrected for age and gender), with only two of these reaching significance: Digit Symbol and Reaction Time tests. Carriers did not differ on their educational qualifications (e.g., 15 carriers went to college or university), their occupational attainment, income or subjective happiness and satisfaction with their health and financial situation. We tested over 30 health outcomes, such as heart attacks, diabetes, cancer or number of hospital admissions. There was no increase in any adverse health outcomes. There was no increase in major psychiatric disorders, and no carrier had developed schizophrenia or mania. There were slight reductions of some measures of physical fitness: carriers had slight increases in hip and waist circumference, and lower peak expiratory volume. Despite the only subtle differences and the lack of adverse health outcomes, NRXN1 deletion carriers had on average 0.7 fewer children than the rest of the participants (on average women in the Biobank had 1.82 children and men had 1.78 children). Nine of the 18 men and 13 of the 30 women had no children. The differences in both men and women were significant, confirming previous suggestions that carriers have reduced fecundity (Rees et al., 2011; Stefansson et al., 2014). Reduced fecundity appears to be present even among overall healthy middle-aged people who have escaped early neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]

Copy number variations at the 15q11.2 BP1-BP2 locus are present in 0.5%–1.0% of the population, and the deletion is associated with several neurodevelopmental disorders. Previously, we showed a reciprocal effect of 15q11.2 copy number variation on fractional anisotropy, with widespread increases in deletion carriers. We aim to expand these findings using a larger sample of participants (N = 29,166) and higher resolution imaging and by examining the implications for cognitive performance. Diffusion tensor imaging measures from participants with no neurological or psychiatric diagnoses were obtained from the UK Biobank database. We compared 15q11.2 BP1-BP2 deletion (n = 102) and duplication (n = 113) carriers to a large cohort of control individuals with no neuropsychiatric copy number variants (n = 28,951). Additionally, we assessed how changes in white matter mediated the association between carrier status and cognitive performance. Deletion carriers showed increases in fractional anisotropy in the internal capsule and cingulum and decreases in the posterior thalamic radiation compared with both duplication carriers and control subjects (who had intermediate values). Compared with control subjects, deletion carriers had lower scores across cognitive tasks, which were partly influenced by white matter. Reduced fractional anisotropy in the posterior thalamic radiation partially contributed to worse cognitive performance in deletion carriers. These results, together with our previous findings, provide convergent evidence for an effect of 15q11.2 BP1-BP2 on white matter microstructure, this being more pronounced in deletion carriers. Additionally, changes in white matter were found to partially mediate cognitive ability in deletion carriers, providing a link between white matter changes in 15q11.2 BP1-BP2 carriers and cognitive function. [ABSTRACT FROM AUTHOR]

Highlights from the article: B Background: b Large, rare copy number variants (CNVs) are associated with neurodevelopmental disorders but it is unclear whether such CNVs also contribute to the risk of depression. Exploratory analyses found neurodevelopmental CNVs to have a stronger effect on risk of depression in females (OR 1.48, 95% CI 1.30 - 1.69, p 3.07 × 10-9) compared to males (OR 1.16, 95% CI 0.96 - 1.39, p 0.12) for the primary depression phenotype. B Discussion: b We report the largest study of CNVs in depression to date and the first to robustly demonstrate association between CNVs and depression.

Background: 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. Methods: 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. Results: Neither genetic measure was associated with season or month of birth within the UKBB sample. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Background The UK Biobank is a unique resource for biomedical research, with extensive phenotypic and genetic data on half a million adults. We wanted to call all pathogenic CNVs in the first 150,000 participants and examine the cognitive performance and phenotypic characteristics of their carriers. Methods We used Affymetrix Power Tools and PennCNV-Affy software to analyse 152,728 Affymetrix microarrays in batches of ~4,600 from the first data release. We annotated a list of 93 CNVs that have been proposed to be pathogenic. Results The frequencies of the 93 CNVs were remarkably similar to those among 26,628 controls from other datasets. Carriers of neurodevelopmental CNVs performed worse on cognitive tests and had lower educational and occupational attainment. Carriers of CNVs with known phenotypes displayed the expected characteristics, e.g. increased or reduced BMI in 16p11.2 deletions and duplications carriers. Discussion The UK Biobank is the largest population study that allows the study of the effect of CNVs on cognitive and physical phenotypes. The set of CNVs will be made available for use by the scientific community. [ABSTRACT FROM AUTHOR]

Background: Copy number variants (CNVs) have been shown to increase risk for physical anomalies, developmental, psychiatric and medical disorders. Some of them have been associated with changes in weight, height, and other physical traits. As most studies have been performed on children and young people, these effects of CNVs in middle-aged and older people are not well established. The UK Biobank recruited half a million adults who provided a variety of physical measurements. We called all CNVs from the Affymetrix microarrays and selected a set of 54 CNVs implicated as pathogenic (including their reciprocal deletions/duplications) and that were found in five or more persons. Linear regression analysis was used to establish their association with 16 physical traits relevant to human health. Results: 396,725 participants of white British or Irish descent (excluding first-degree relatives) passed our quality control filters. Out of the 864 CNV/trait associations, 214 were significant at a false discovery rate of 0.1, most of them novel. Many of these traits increase risk for adverse health outcomes: e.g. increases in weight, waist-to-hip ratio, pulse rate and body fat composition. Deletions at 16p11.2, 16p12.1, NRXN1 and duplications at 16p13.11 and 22q11.2 produced the highest numbers of significant associations. Five CNVs produced average changes of over one standard deviation for the 16 traits, compared to controls: deletions at 16p11.2 and 22q11.2, and duplications at 3q29, the Williams-Beuren and Potocki-Lupski regions. CNVs at 1q21.1, 2q13, 16p11.2 and 16p11.2 distal, 16p12.1, 17p12 and 17q12 demonstrated one or more mirror image effects of deletions versus duplications. Conclusions: Carriers of many CNVs should be monitored for physical traits that increase morbidity and mortality. Genes within these CNVs can give insights into biological processes and therapeutic interventions. [ABSTRACT FROM AUTHOR]

Anxiety and depression are common mental health disorders and have a higher prevalence in females. They are modestly heritable, share genetic liability with other psychiatric disorders, and are highly heterogeneous. There is evidence that genetic liability to neurodevelopmental disorders, such as attention deficit hyperactivity disorder (ADHD) is associated with anxiety and depression, particularly in females. We investigated sex differences in family history for neurodevelopmental and psychiatric disorders and neurodevelopmental genetic risk burden (indexed by ADHD polygenic risk scores (PRS) and rare copy number variants; CNVs) in individuals with anxiety and depression, also taking into account age at onset. We used two complementary datasets: 1) participants with a self-reported diagnosis of anxiety or depression (N = 4,178, 65.5% female; mean age = 41.5 years; N = 1,315 with genetic data) from the National Centre for Mental Health (NCMH) cohort and 2) a clinical sample of 13,273 (67.6% female; mean age = 45.2 years) patients with major depressive disorder (MDD) from the Psychiatric Genomics Consortium (PGC). We tested for sex differences in family history of psychiatric problems and presence of rare CNVs (neurodevelopmental and >500kb loci) in NCMH only and for sex differences in ADHD PRS in both datasets. In the NCMH cohort, females were more likely to report family history of neurodevelopmental and psychiatric disorders, but there were no robust sex differences in ADHD PRS or presence of rare CNVs. There was weak evidence of higher ADHD PRS in females compared to males in the PGC MDD sample, particularly in those with an early onset of MDD. These results do not provide strong evidence of sex differences in neurodevelopmental genetic risk burden in adults with anxiety and depression. This indicates that sex may not be a major index of neurodevelopmental genetic heterogeneity, that is captured by ADHD PRS and rare CNV burden, in adults with anxiety and depression. [ABSTRACT FROM AUTHOR]

People born in winter and early spring are at an elevated risk for schizophrenia [1 – 4]. Although the effect is small, with an increase in risk of about around 10%, this season of birth effect is one of the most robust findings in schizophrenia epidemiology [5]. It has also been influential in developing hypotheses of schizophrenia pathogenesis, forming one of the central planks of the viral infection hypothesis of the disorder [6] as well as other less intensively investigated putative mechanisms including vitamin D deficiency during fetal development [7]. However, at present, the mechanisms underpinning this season of birth effect are unknown. We implement PRS analysis of the UK Biobank (UKBB) to determine whether season of birth is associated with genetic risk for schizophrenia. We generated schizophrenia PRS for every participant in the UKBB (June 2015 release, N=136,538) and tested whether this score is associated with month or season of birth. As a secondary test of the plausibility of season of birth being a genetically correlated confound, we also conducted a GWAS of season of birth as a binary phenotype, comparing winter/spring births with summer/autumn. Our aim was to estimate heritability of season of birth as a phenotype. We found no association between schizophrenia PRS and season of birth in the UK Biobank sample and no differences in schizophrenia risk scores with respect to month of birth. No SNPs were associated with season of birth at genome-wide significance, there was no evidence for inflation in the test statistics indicative of polygenic inheritance and no evidence that SNP heritability contributed to this trait (total liability scale h2=-0.002 SE=0.0052 as estimated by LD-Score regression). In this study, we examined seasonality in regard to genetic risk to schizophrenia within UK Biobank. We used the largest schizophrenia dataset to date for identification of genetic risk loci and one of the largest available population cohorts to generate schizophrenia PRS and test for seasonal differences in genetic liability to schizophrenia. We found no trends of elevated schizophrenia polygenic risk scores in people born in winter or spring. These results were further supported by a lack of evidence that seasonality is a heritable trait. Since the PRS analysis and heritability estimates were based upon common SNPs, we don't exclude a possible role for rare SNPs, however the frequencies of rare CNVs, linked to neurodevelopmental disorders, also did not differ by season of birth. [ABSTRACT FROM AUTHOR]

Highlights from the article: F29investigating supervised machine learning methods for prediction of schizophrenia in uk biobank B Background: b Supervised machine learning encompasses a range of methods for learning patterns from labelled data. This study has developed and tested a machine learning framework for analysis of UK Biobank data and investigated several approaches using genetic variants for prediction.

Highlights from the article: B Results: b In carriers of SZ-CNV, reductions in right thalamus, pallidum, hippocampus and accumbens, and left putamen were associated with schizophrenia CNVs (after correction for multiple comparison). Four of the above FDR corrected brain areas showed a significant association with FI and were included in the mediation analysis - i.e. thalamus, hippocampus and pallidum right and putamen left. B Discussion: b SZ-CNVs are, in non-affected adults, associated with alterations in subcortical brain volumes in a manner consistent with reduced hippocampus, thalamus, amygdala and accumbens being potentially pathogenic, although pleiotropy is also possible.