Polygenic risk for schizophrenia and season of birth within the UK Biobank cohort

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

Conformational Locking upon Cooperative Assembly of Notch Transcription Complexes

SummaryThe Notch intracellular domain (NICD) forms a transcriptional activation complex with the DNA-binding factor CSL and a transcriptional co-activator of the Mastermind family (MAML). The “RAM” region of NICD recruits Notch to CSL, facilitating the binding of MAML at the interface between the ankyrin (ANK) repeat domain of NICD and CSL. Here, we report the X-ray structure of a human MAML1/RAM/ANK/CSL/DNA complex, and probe changes in component dynamics upon stepwise assembly of a MAML1/NICD/CSL complex using HX-MS. Association of CSL with NICD exerts remarkably little effect on the exchange kinetics of the ANK domain, whereas MAML1 binding greatly retards the exchange kinetics of ANK repeats 2-3. These exchange patterns identify critical features contributing to the cooperative assembly of Notch transcription complexes (NTCs), highlight the importance of MAML recruitment in rigidifying the ANK domain and stabilizing its interface with CSL, and rationalize the requirement for MAML1 in driving cooperative dimerization of NTCs on paired-site DNA

Genome-wide analysis in UK Biobank identifies four loci associated with mood instability and genetic correlation with MDD, anxiety disorder and schizophrenia

Mood instability is a core clinical feature of affective and psychotic disorders. In keeping with the Research Domain Criteria approach, it may be a useful construct for identifying biology that cuts across psychiatric categories. We aimed to investigate the biological validity of a simple measure of mood instability and evaluate its genetic relationship with several psychiatric disorders, including major depressive disorder (MDD), bipolar disorder (BD), schizophrenia, attention deficit hyperactivity disorder (ADHD), anxiety disorder and post-traumatic stress disorder (PTSD). We conducted a genome-wide association study (GWAS) of mood instability in 53,525 cases and 60,443 controls from UK Biobank, identifying four independently associated loci (on chromosomes 8, 9, 14 and 18), and a common single-nucleotide polymorphism (SNP)-based heritability estimate of ~8%. We found a strong genetic correlation between mood instability and MDD (r g = 0.60, SE = 0.07, p = 8.95 × 10−17) and a small but significant genetic correlation with both schizophrenia (r g = 0.11, SE = 0.04, p = 0.01) and anxiety disorders (r g = 0.28, SE = 0.14, p = 0.04), although no genetic correlation with BD, ADHD or PTSD was observed. Several genes at the associated loci may have a role in mood instability, including the DCC netrin 1 receptor (DCC) gene, eukaryotic translation initiation factor 2B subunit beta (eIF2B2), placental growth factor (PGF) and protein tyrosine phosphatase, receptor type D (PTPRD). Strengths of this study include the very large sample size, but our measure of mood instability may be limited by the use of a single question. Overall, this work suggests a polygenic basis for mood instability. This simple measure can be obtained in very large samples; our findings suggest that doing so may offer the opportunity to illuminate the fundamental biology of mood regulation

Retroperitoneal Compared to Transperitoneal Approach for Open Abdominal Aortic Aneurysm Repair Is Associated with Reduced Systemic Inflammation and Postoperative Morbidity

Background  In the United Kingdom, the most common surgical approach for repair of open abdominal aortic aneurysms (AAAs) is transperitoneal (TP). However, retroperitoneal (RP) approach is favored in those with more complex vascular anatomy often requiring a cross-clamp on the aorta superior to the renal arteries. This study compared these approaches in patients matched on all major demographic, comorbid, anatomic, and physiological variables. Methods  Fifty-seven patients (TP: n  = 24; RP: n  = 33) unsuitable for endovascular aneurysm repair underwent preoperative cardiopulmonary exercise testing prior to open AAA repair. The surgical approach undertaken was dictated by individual surgeon preference. Postoperative mortality, complications, and length of hospital stay (LoS) were recorded. Patients were further stratified according to infrarenal (IR) or suprarenal/supraceliac (SR/SC) surgical clamping. Systemic inflammation (C-reactive protein) and renal function (serum creatinine and estimated glomerular filtration rate) were recorded. Results  Twenty-three (96%) of TP patients only required an IR clamp compared with 12 (36%) in the RP group. Postoperative systemic inflammation was lower in RP patients ( p  = 0.002 vs. TP) and fewer reported pulmonary/gastrointestinal complications whereas renal impairment was more marked in those receiving SR/SC clamps ( p  < 0.001 vs. IR clamp). RP patients were defined by lower LoS ( p  = 0.001), while mid-/long-term mortality was low/comparable with TP, resulting in considerable cost savings. Conclusion  Despite the demands of more complicated vascular anatomy, the clinical and economic benefits highlighted by these findings justify the more routine adoption of the RP approach for complex AAA repair

Associations between schizophrenia genetic risk, anxiety disorders and manic/hypomanic episode in a longitudinal population cohort study.

BACKGROUND: Studies involving clinically recruited samples show that genetic liability to schizophrenia overlaps with that for several psychiatric disorders including bipolar disorder, major depression and, in a population study, anxiety disorder and negative symptoms in adolescence.AimsWe examined whether, at a population level, association between schizophrenia liability and anxiety disorders continues into adulthood, for specific anxiety disorders and as a group. We explored in an epidemiologically based cohort the nature of adult psychopathology sharing liability to schizophrenia. METHOD: Schizophrenia polygenic risk scores (PRSs) were calculated for 590 European-descent individuals from the Christchurch Health and Development Study. Logistic regression was used to examine associations between schizophrenia PRS and four anxiety disorders (social phobia, specific phobia, panic disorder and generalised anxiety disorder), schizophrenia/schizophreniform disorder, manic/hypomanic episode, alcohol dependence, major depression, and - using linear regression - total number of anxiety disorders. A novel population-level association with hypomania was tested in a UK birth cohort (Avon Longitudinal Study of Parents and Children). RESULTS: Schizophrenia PRS was associated with total number of anxiety disorders and with generalised anxiety disorder and panic disorder. We show a novel population-level association between schizophrenia PRS and manic/hypomanic episode. CONCLUSIONS: The relationship between schizophrenia liability and anxiety disorders is not restricted to psychopathology in adolescence but is present in adulthood and specifically linked to generalised anxiety disorder and panic disorder. We suggest that the association between schizophrenia liability and hypomanic/manic episodes found in clinical samples may not be due to bias.Declarations of interestNone

Genome-wide analysis of self-reported risk-taking behaviour and cross-disorder genetic correlations in the UK Biobank cohort

Risk-taking behaviour is a key component of several psychiatric disorders and could influence lifestyle choices such as smoking, alcohol use, and diet. As a phenotype, risk-taking behaviour therefore fits within a Research Domain Criteria (RDoC) approach, whereby identifying genetic determinants of this trait has the potential to improve our understanding across different psychiatric disorders. Here we report a genome-wide association study in 116,255 UK Biobank participants who responded yes/no to the question “Would you consider yourself a risk taker?” Risk takers (compared with controls) were more likely to be men, smokers, and have a history of psychiatric disorder. Genetic loci associated with risk-taking behaviour were identified on chromosomes 3 (rs13084531) and 6 (rs9379971). The effects of both lead SNPs were comparable between men and women. The chromosome 3 locus highlights CADM2, previously implicated in cognitive and executive functions, but the chromosome 6 locus is challenging to interpret due to the complexity of the HLA region. Risk-taking behaviour shared significant genetic risk with schizophrenia, bipolar disorder, attention-deficit hyperactivity disorder, and post-traumatic stress disorder, as well as with smoking and total obesity. Despite being based on only a single question, this study furthers our understanding of the biology of risk-taking behaviour, a trait that has a major impact on a range of common physical and mental health disorders

Capturing health and eating status through a nutritional perception screening questionnaire (NPSQ9) in a randomised internet-based personalised nutrition intervention : the Food4Me study

BACKGROUND: National guidelines emphasize healthy eating to promote wellbeing and prevention of non-communicable diseases. The perceived healthiness of food is determined by many factors affecting food intake. A positive perception of healthy eating has been shown to be associated with greater diet quality. Internet-based methodologies allow contact with large populations. Our present study aims to design and evaluate a short nutritional perception questionnaire, to be used as a screening tool for assessing nutritional status, and to predict an optimal level of personalisation in nutritional advice delivered via the Internet. METHODS: Data from all participants who were screened and then enrolled into the Food4Me proof-of-principle study (n = 2369) were used to determine the optimal items for inclusion in a novel screening tool, the Nutritional Perception Screening Questionnaire-9 (NPSQ9). Exploratory and confirmatory factor analyses were performed on anthropometric and biochemical data and on dietary indices acquired from participants who had completed the Food4Me dietary intervention (n = 1153). Baseline and intervention data were analysed using linear regression and linear mixed regression, respectively. RESULTS: A final model with 9 NPSQ items was validated against the dietary intervention data. NPSQ9 scores were inversely associated with BMI (β = -0.181, p < 0.001) and waist circumference (Β = -0.155, p < 0.001), and positively associated with total carotenoids (β = 0.198, p < 0.001), omega-3 fatty acid index (β = 0.155, p < 0.001), Healthy Eating Index (HEI) (β = 0.299, p < 0.001) and Mediterranean Diet Score (MDS) (β = 0. 279, p < 0.001). Findings from the longitudinal intervention study showed a greater reduction in BMI and improved dietary indices among participants with lower NPSQ9 scores. CONCLUSIONS: Healthy eating perceptions and dietary habits captured by the NPSQ9 score, based on nine questionnaire items, were associated with reduced body weight and improved diet quality. Likewise, participants with a lower score achieved greater health improvements than those with higher scores, in response to personalised advice, suggesting that NPSQ9 may be used for early evaluation of nutritional status and to tailor nutritional advice. TRIAL REGISTRATION: NCT01530139 .Peer reviewedFinal Published versio

Five Kepler target stars that show multiple transiting exoplanet candidates

We present and discuss five candidate exoplanetary systems identified with the Kepler spacecraft. These five systems show transits from multiple exoplanet candidates. Should these objects prove to be planetary in nature, then these five systems open new opportunities for the field of exoplanets and provide new insights into the formation and dynamical evolution of planetary systems. We discuss the methods used to identify multiple transiting objects from the Kepler photometry as well as the false-positive rejection methods that have been applied to these data. One system shows transits from three distinct objects while the remaining four systems show transits from two objects. Three systems have planet candidates that are near mean motion commensurabilities---two near 2:1 and one just outside 5:2. We discuss the implications that multitransiting systems have on the distribution of orbital inclinations in planetary systems, and hence their dynamical histories; as well as their likely masses and chemical compositions. A Monte Carlo study indicates that, with additional data, most of these systems should exhibit detectable transit timing variations (TTV) due to gravitational interactions---though none are apparent in these data. We also discuss new challenges that arise in TTV analyses due to the presence of more than two planets in a system.Comment: Accepted to Ap

The genomic basis of mood instability:identification of 46 loci in 363,705 UK Biobank participants, genetic correlation with psychiatric disorders, and association with gene expression and function

Genome-wide association studies (GWAS) of psychiatric phenotypes have tended to focus on categorical diagnoses, but to understand the biology of mental illness it may be more useful to study traits which cut across traditional boundaries. Here, we report the results of a GWAS of mood instability as a trait in a large population cohort (UK Biobank, n = 363,705). We also assess the clinical and biological relevance of the findings, including whether genetic associations show enrichment for nervous system pathways. Forty six unique loci associated with mood instability were identified with a SNP heritability estimate of 9%. Linkage Disequilibrium Score Regression (LDSR) analyses identified genetic correlations with Major Depressive Disorder (MDD), Bipolar Disorder (BD), Schizophrenia, anxiety, and Post Traumatic Stress Disorder (PTSD). Gene-level and gene set analyses identified 244 significant genes and 6 enriched gene sets. Tissue expression analysis of the SNP-level data found enrichment in multiple brain regions, and eQTL analyses highlighted an inversion on chromosome 17 plus two brain-specific eQTLs. In addition, we used a Phenotype Linkage Network (PLN) analysis and community analysis to assess for enrichment of nervous system gene sets using mouse orthologue databases. The PLN analysis found enrichment in nervous system PLNs for a community containing serotonin and melatonin receptors. In summary, this work has identified novel loci, tissues and gene sets contributing to mood instability. These findings may be relevant for the identification of novel trans-diagnostic drug targets and could help to inform future stratified medicine innovations in mental health

Modeling Kepler transit light curves as false positives: Rejection of blend scenarios for Kepler-9, and validation of Kepler-9d, a super-Earth-size planet in a multiple system

Light curves from the Kepler Mission contain valuable information on the nature of the phenomena producing the transit-like signals. To assist in exploring the possibility that they are due to an astrophysical false positive, we describe a procedure (BLENDER) to model the photometry in terms of a "blend" rather than a planet orbiting a star. A blend may consist of a background or foreground eclipsing binary (or star-planet pair) whose eclipses are attenuated by the light of the candidate and possibly other stars within the photometric aperture. We apply BLENDER to the case of Kepler-9, a target harboring two previously confirmed Saturn-size planets (Kepler-9b and Kepler-9c) showing transit timing variations, and an additional shallower signal with a 1.59-day period suggesting the presence of a super-Earth-size planet. Using BLENDER together with constraints from other follow-up observations we are able to rule out all blends for the two deeper signals, and provide independent validation of their planetary nature. For the shallower signal we rule out a large fraction of the false positives that might mimic the transits. The false alarm rate for remaining blends depends in part (and inversely) on the unknown frequency of small-size planets. Based on several realistic estimates of this frequency we conclude with very high confidence that this small signal is due to a super-Earth-size planet (Kepler-9d) in a multiple system, rather than a false positive. The radius is determined to be 1.64 (+0.19/-0.14) R(Earth), and current spectroscopic observations are as yet insufficient to establish its mass.Comment: 20 pages in emulateapj format, including 8 tables and 16 figures. To appear in ApJ, 1 January 2010. Accepted versio