Improving Genetic Prediction by Leveraging Genetic Correlations Among Human Diseases and Traits

Genomic prediction has the potential to contribute to precision medicine. However, to date, the utility of such predictors is limited due to low accuracy for most traits. Here theory and simulation study are used to demonstrate that widespread pleiotropy among phenotypes can be utilised to improve genomic risk prediction. We show how a genetic predictor can be created as a weighted index that combines published genome-wide association study (GWAS) summary statistics across many different traits. We apply this framework to predict risk of schizophrenia and bipolar disorder in the Psychiatric Genomics consortium data, finding substantial heterogeneity in prediction accuracy increases across cohorts. For six additional phenotypes in the UK Biobank data, we find increases in prediction accuracy ranging from 0.7 for height to 47 for type 2 diabetes, when using a multi-trait predictor that combines published summary statistics from multiple traits, as compared to a predictor based only on one trait. © 2018 The Author(s)

Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder

This paper is dedicated to the memory of Psychiatric Genomics Consortium (PGC) founding member and Bipolar disorder working group co-chair Pamela Sklar. We thank the participants who donated their time, experiences and DNA to this research, and to the clinical and scientific teams that worked with them. We are deeply indebted to the investigators who comprise the PGC. The views expressed are those of the authors and not necessarily those of any funding or regulatory body. Analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org ) hosted by SURFsara, and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu).Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P<1x10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (GWS, p < 5x10-8) in the discovery GWAS were not GWS in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis 30 loci were GWS including 20 novel loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene-sets including regulation of insulin secretion and endocannabinoid signaling. BDI is strongly genetically correlated with schizophrenia, driven by psychosis, whereas BDII is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential new biological mechanisms for BD.This work was funded in part by the Brain and Behavior Research Foundation, Stanley Medical Research Institute, University of Michigan, Pritzker Neuropsychiatric Disorders Research Fund L.L.C., Marriot Foundation and the Mayo Clinic Center for Individualized Medicine, the NIMH Intramural Research Program; Canadian Institutes of Health Research; the UK Maudsley NHS Foundation Trust, NIHR, NRS, MRC, Wellcome Trust; European Research Council; German Ministry for Education and Research, German Research Foundation IZKF of Münster, Deutsche Forschungsgemeinschaft, ImmunoSensation, the Dr. Lisa-Oehler Foundation, University of Bonn; the Swiss National Science Foundation; French Foundation FondaMental and ANR; Spanish Ministerio de Economía, CIBERSAM, Industria y Competitividad, European Regional Development Fund (ERDF), Generalitat de Catalunya, EU Horizon 2020 Research and Innovation Programme; BBMRI-NL; South-East Norway Regional Health Authority and Mrs. Throne-Holst; Swedish Research Council, Stockholm County Council, Söderström Foundation; Lundbeck Foundation, Aarhus University; Australia NHMRC, NSW Ministry of Health, Janette M O'Neil and Betty C Lynch

Low self-recognition and awareness of past hypomanic and manic episodes in the general population

Background Bipolar disorder is often underdiagnosed and undertreated. Its detection and correct diagnosis highly relies on the report of past hypomanic or manic episodes. We investigated the recognition and awareness of past hypomanic and manic episodes in a sample of respondents with bipolar disorder selected from a general population study. Methods In a reappraisal study from the Netherlands Mental Health Survey and Incidence Study (NEMESIS), we further investigated 40 respondents with lifetime bipolar disorder confirmed by the structured clinical interview for DSM-IV (SCID). Respondents were asked about awareness of past depressive, manic and hypomanic episodes, illness characteristics and treatment history. Results Most respondents (82.5 %) recognized that they had experienced a depressive episode while 75 % had consulted a health professional for a depressive episode. Only a minority (22.5 %) recognized that they had experienced a (hypo)manic episode and only 17.5 % had consulted a health professional for a (hypo)manic episode. Only 12.5 % of the respondents reported having received a diagnosis of bipolar disorder. Recognition of previous (hypo)manic episodes was not related to severity of bipolar disorder. Conclusions In routine clinical practice history-taking on a syndromal level, i.e., only inquiring whether a patient presenting with depression ever experienced a hypomanic or manic episode or received treatment for such an episode, is not sufficient to confirm or exclude a diagnosis of bipolar disorder. Other efforts, such as an interview with a significant other and the use of self report questionnaires or (semi-)structured interviews may be needed to recognize previous manic symptoms in patients with depression

Prevalence of bipolar disorder: a further study in The Netherlands

Item does not contain fulltex

Guideline concordance and outcome in long-term naturalistic treatment of bipolar disorder-a one-year longitudinal study using latent change models

Contains fulltext : 231938.pdf (Publisher’s version ) (Open Access)Background: Only few studies investigated the relation between concordance with treatment guidelines and treatment outcome in everyday treatment of bipolar disorder (BD). Prospective studies are scarce. Methods: A nationwide, naturalistic, prospective study on the relation between guideline concordance and treatment outcome in the long-term outpatient treatment of patients with BD. Participants completed a survey on treatments received and various outcome measures at baseline and after one year. Results: Of 839 patients who completed the baseline survey, 615 (73.3%) also completed the follow-up survey. Consistent with our a priori hypothesis, cross-sectional analyses at baseline showed correlations between guideline concordance with quality of life (r = .17, p < .001), treatment satisfaction (r = .17, p <.001), and impaired functioning (r = -.10, p = .04). At follow-up, guideline concordance was correlated with severity of illness (r = -.10, p = .05), quality of life (r = .18, p < .001), and treatment satisfaction (r = .15, p < .001). Concerning three additional hypotheses on longitudinal relations between concordance and outcome measures, only a positive relation was found between change in guideline concordance and change in quality of life. Limitations: Selection bias may have occurred by inclusion of patients with neither a very severe nor a very mild course of illness. Conclusions: Although guideline concordance was high throughout the study, change in guideline concordance was positively associated with change in quality of life, suggesting that especially in long-term treatment, continuous efforts to optimize ongoing treatment is essential.7 p

Prevalence of bipolar disorder in the general population: A Reappraisal Study of the Netherlands Mental Health Survey and Incidence Study

Item does not contain fulltextObjective: The Netherlands Mental Health Survey and Incidence Study (NEMESIS) is a Dutch population study using a fully structured interview (Composite International Diagnostic Interview, CIDI), administered by trained interviewers. Based on all three assessments of NEMESIS, 2.4% of the respondents were identified with lifetime bipolar disorder (DSM-III-R). The primary aim of the study was to estimate the prevalence of bipolar disorder in the same population based on a semistructured interview administered by clinicians. Method: Seventy-four persons identified with a lifetime CIDI/DSM-III-R bipolar disorder and 40 persons with a major depressive disorder (MDD) were reinterviewed with the Structured Clinical Interview for DSM (SCID). Results: Based on the SCID, 30 of 74 respondents with a CIDI/DSM-III-R bipolar disorder and eight of 40 respondents with MDD met DSM-IV criteria for bipolar disorder or cyclothymia, corresponding with an adjusted lifetime prevalence in these groups of 1% (95% CI: 0.7-1.3%) and 4.2% (95% CI: 1.6-6.9%) respectively. Conclusion: Compared with the SCID, the CIDI on the one hand overdiagnoses bipolar disorder but on the other hand underdiagnoses bipolar disorder

Hypercalcemia in patients with bipolar disorder treated with lithium: a cross-sectional study

BACKGROUND: Lithium-induced hyperparathyroidism (LIH) is a relative underrecognized complication of long-term lithium treatment. Hypercalcemia may be the first, but often overlooked, sign of LIH. Symptoms of LIH can be similar to the underlying psychiatric illness, which may cause a significant doctor’s delay in diagnosing LIH. The aim of this study was to determine the prevalence of hypercalcemia in a cohort of psychiatric patients. METHODS: In this cross-sectional study, we collected data from 314 patients treated with lithium in an outpatient clinic for bipolar disorder. Patients with bipolar disorder from the same clinics, who had never been treated with lithium and of whom serum calcium levels were available, were included as controls (n = 15). Patient characteristics and laboratory results were collected during the period of June 2010 till June 2011. RESULTS: The mean serum calcium level was 2.49 (SD 0.11) mmol/l. The point prevalence of hypercalcemia (>2.60 mmol/l) was 15.6%. In a comparable group of psychiatric patients not using lithium, the mean serum calcium level was 2.37 mmol/l, and none of these patients had hypercalcemia (p = 0.001). The duration of lithium treatment was the only significant predictor for the development of hypercalcemia (p = 0.002). DISCUSSION: The prevalence of hypercalcemia in lithium-treated patients was significantly higher than that in non-lithium treated controls and correlated to the cumulative time lithium was used in this cross-sectional study. We recommend that serum calcium levels should be routinely tested in patients using lithium for timely detection of LIH or hypercalcemia due to other causes

Exploring aspects of self-reported emotional mental imagery in patients with bipolar disorder

Background and objectives: CBT for patients with bipolar disorder has modest effects. Across disorders, mental imagery has been used to update CBT to increase effectiveness. In order to enhance CBT for bipolar disorder with imagery techniques, research is needed into emotional imagery quality and, related appraisals of imagery and their relationships with mood instability and subsequent behaviour in bipolar disorder. Methods: Patients with bipolar disorder (n = 106), unipolar depression (n = 51), creative imagery prone participants (n = 53) and participants without a history of a mood disorder (n = 135) completed the Dutch Imagery Survey (DImS), an online imagery survey, adapted from the Imagery Interview, assessing self-reported emotional imagery aspects. Imagery quality, appraisals and their self-perceived effects on emotion and behaviour were compared between groups. As unexpected differences within the bipolar group appeared, these were additionally explored. Results: Imagery appraisals but not imagery quality discriminated between the patient groups and non-patient groups Imagery was perceived as an emotional amplifier in all groups, but this was specifically apparent in bipolar manic and bipolar depressed groups. Only in the bipolar group imagery was experienced to amplify behavioural tendencies. Limitations Results need to be replicated using a larger sample of patients with BD who are currently manic or depressed. Conclusions; Not only quality of imagery, but especially appraisals associated with imagery are differentiating between imagery prone people with and without mood disorder. Imagery amplifies emotion in all groups, but only in those patients with bipolar disorder currently manic or depressed did this influence behaviour

The feasibility of mindfulness-based cognitive therapy for people with bipolar disorder: a qualitative study

Contains fulltext : 226809.pdf (publisher's version ) (Open Access