Use of schizophrenia and bipolar disorder polygenic risk scores to identify psychotic disorders

Background There is increasing evidence for shared genetic susceptibility between schizophrenia and bipolar disorder. Although genetic variants only convey subtle increases in risk individually, their combination into a polygenic risk score constitutes a strong disease predictor. Aims To investigate whether schizophrenia and bipolar disorder polygenic risk scores can distinguish people with broadly defined psychosis and their unaffected relatives from controls. Method Using the latest Psychiatric Genomics Consortium data, we calculated schizophrenia and bipolar disorder polygenic risk scores for 1168 people with psychosis, 552 unaffected relatives and 1472 controls. Results Patients with broadly defined psychosis had dramatic increases in schizophrenia and bipolar polygenic risk scores, as did their relatives, albeit to a lesser degree. However, the accuracy of predictive models was modest. Conclusions Although polygenic risk scores are not ready for clinical use, it is hoped that as they are refined they could help towards risk reduction advice and early interventions for psychosis. Declaration of interest R.M.M. has received honoraria for lectures from Janssen, Lundbeck, Lilly, Otsuka and Sunovian.

[1]  David J. Porteous,et al.  Association Between Schizophrenia-Related Polygenic Liability and the Occurrence and Level of Mood-Incongruent Psychotic Symptoms in Bipolar Disorder , 2017, JAMA psychiatry.

[2]  P. O’Reilly,et al.  An Examination of Polygenic Score Risk Prediction in Individuals With First-Episode Psychosis , 2017, Biological Psychiatry.

[3]  R. Murray,et al.  Meta-analysis of the Association Between the Level of Cannabis Use and Risk of Psychosis. , 2016, Schizophrenia bulletin.

[4]  Stephan Ripke,et al.  Genome‐wide association study reveals greater polygenic loading for schizophrenia in cases with a family history of illness , 2016, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[5]  C. Spencer,et al.  A contribution of novel CNVs to schizophrenia from a genome-wide study of 41,321 subjects: CNV Analysis Group and the Schizophrenia Working Group of the Psychiatric Genomics Consortium , 2016, bioRxiv.

[6]  Pak Chung Sham,et al.  Local True Discovery Rate Weighted Polygenic Scores Using GWAS Summary Data , 2016, Behavior genetics.

[7]  Daniel H. Geschwind,et al.  Genetics and genomics of psychiatric disease , 2015, Science.

[8]  Esben Agerbo,et al.  Polygenic Risk Score, Parental Socioeconomic Status, Family History of Psychiatric Disorders, and the Risk for Schizophrenia: A Danish Population-Based Study and Meta-analysis. , 2015, JAMA psychiatry.

[9]  Paul J. Harrison,et al.  Recent genetic findings in schizophrenia and their therapeutic relevance , 2015, Journal of psychopharmacology.

[10]  B. Neale,et al.  Genetic analysis of schizophrenia and bipolar disorder reveals polygenicity but also suggests new directions for molecular interrogation , 2015, Current Opinion in Neurobiology.

[11]  Jack Euesden,et al.  PRSice: Polygenic Risk Score software , 2014, Bioinform..

[12]  B. Stephan,et al.  Cardiovascular Disease Risk Models and Longitudinal Changes in Cognition: A Systematic Review , 2014, PloS one.

[13]  N. Wray,et al.  Novel directions for G × E analysis in psychiatry , 2014, Epidemiology and Psychiatric Sciences.

[14]  N. Wray,et al.  Research review: Polygenic methods and their application to psychiatric traits. , 2014, Journal of child psychology and psychiatry, and allied disciplines.

[15]  J. Kirkbride The emerging molecular architecture of schizophrenia, polygenic risk scores and the clinical implications for gXe research , 2014, Social Psychiatry and Psychiatric Epidemiology.

[16]  C. Spencer,et al.  Biological Insights From 108 Schizophrenia-Associated Genetic Loci , 2014, Nature.

[17]  D. Rujescu,et al.  Identifying gene-environment interactions in schizophrenia: contemporary challenges for integrated, large-scale investigations. , 2014, Schizophrenia bulletin.

[18]  Peter M Visscher,et al.  Large-scale genomics unveils the genetic architecture of psychiatric disorders , 2014, Nature Neuroscience.

[19]  M. Owen,et al.  Genetic relationships between schizophrenia, bipolar disorder, and schizoaffective disorder. , 2014, Schizophrenia bulletin.

[20]  M. Owen,et al.  Genomic insights into the overlap between psychiatric disorders: implications for research and clinical practice , 2014, Genome Medicine.

[21]  M. Pirinen,et al.  A Genome-wide Association Analysis of a Broad Psychosis Phenotype Identifies Three Loci for Further Investigation , 2014, Biological Psychiatry.

[22]  Eric S. Lander,et al.  A polygenic burden of rare disruptive mutations in schizophrenia , 2014, Nature.

[23]  P. Sham,et al.  The emerging molecular architecture of schizophrenia, polygenic risk scores and the clinical implications for GxE research , 2014, Social Psychiatry and Psychiatric Epidemiology.

[24]  S. Djurovic,et al.  Polygenic dissection of diagnosis and clinical dimensions of bipolar disorder and schizophrenia , 2013, Molecular Psychiatry.

[25]  P. Visscher,et al.  Where GWAS and epidemiology meet: opportunities for the simultaneous study of genetic and environmental risk factors in schizophrenia. , 2013, Schizophrenia bulletin.

[26]  Simon C. Potter,et al.  Genome-wide Association Analysis Identifies 14 New Risk Loci for Schizophrenia , 2013, Nature Genetics.

[27]  M. Daly,et al.  Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis , 2013, The Lancet.

[28]  F. Dudbridge Correction: Power and Predictive Accuracy of Polygenic Risk Scores , 2013, PLoS Genetics.

[29]  F. Dudbridge Power and Predictive Accuracy of Polygenic Risk Scores , 2013, PLoS genetics.

[30]  Stephan Ripke,et al.  Investigation of the Genetic Association between Quantitative Measures of Psychosis and Schizophrenia: A Polygenic Risk Score Analysis , 2012, PloS one.

[31]  Manuel A. R. Ferreira,et al.  Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4 , 2011, Nature Genetics.

[32]  E. Walker,et al.  Diagnostic and Statistical Manual of Mental Disorders , 2013 .

[33]  Jung-Ying Tzeng,et al.  Studying gene and gene-environment effects of uncommon and common variants on continuous traits: a marker-set approach using gene-trait similarity regression. , 2011, American journal of human genetics.

[34]  Xavier Robin,et al.  pROC: an open-source package for R and S+ to analyze and compare ROC curves , 2011, BMC Bioinformatics.

[35]  R. Murray,et al.  Migration, ethnicity, and psychosis: toward a sociodevelopmental model. , 2010, Schizophrenia bulletin.

[36]  T. Suppes,et al.  Genetics and intermediate phenotypes of the schizophrenia—bipolar disorder boundary , 2010, Neuroscience & Biobehavioral Reviews.

[37]  P. Visscher,et al.  Narrowing the Boundaries of the Genetic Architecture of Schizophrenia , 2009, Schizophrenia bulletin.

[38]  Peter M Visscher,et al.  Harnessing the information contained within genome-wide association studies to improve individual prediction of complex disease risk. , 2009, Human molecular genetics.

[39]  P. Visscher,et al.  Common polygenic variation contributes to risk of schizophrenia and bipolar disorder , 2009, Nature.

[40]  Tyrone D. Cannon,et al.  Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study , 2009, The Lancet.

[41]  M. Bogren,et al.  How common are psychotic and bipolar disorders? A 50-year follow-up of the Lundby population , 2009, Nordic journal of psychiatry.

[42]  K. Zou,et al.  Receiver-Operating Characteristic Analysis for Evaluating Diagnostic Tests and Predictive Models , 2007, Circulation.

[43]  D. Reich,et al.  Population Structure and Eigenanalysis , 2006, PLoS genetics.

[44]  D. Reich,et al.  Principal components analysis corrects for stratification in genome-wide association studies , 2006, Nature Genetics.

[45]  Shah Ebrahim,et al.  JOINT ESC GUIDELINES 2016 European Guidelines on cardiovascular disease prevention in clinical practice – Web Addenda , 2016 .

[46]  L. Petrangeli,et al.  Schedules for Clinical Assessment in Neuropsychiatry , 1997, Epidemiologia e Psichiatria Sociale.

[47]  J. Younger,et al.  Statistical methodology: III. Receiver operating characteristic (ROC) curves. , 1997, Academic emergency medicine : official journal of the Society for Academic Emergency Medicine.

[48]  K. Kendler,et al.  Schizophreniform disorder, delusional disorder and psychotic disorder not otherwise specified: clinical features, outcome and familial psychopathology , 1995, Acta psychiatrica Scandinavica.

[49]  M. First,et al.  The Structured Clinical Interview for DSM-III-R (SCID). I: History, rationale, and description. , 1992, Archives of general psychiatry.

[50]  T. Brugha,et al.  SCAN. Schedules for Clinical Assessment in Neuropsychiatry. , 1990, Archives of general psychiatry.

[51]  J A Swets,et al.  Measuring the accuracy of diagnostic systems. , 1988, Science.

[52]  J. Endicott,et al.  A diagnostic interview: the schedule for affective disorders and schizophrenia. , 1978, Archives of general psychiatry.

[53]  S. E. Stewart,et al.  Cross-disorder genome-wide analyses suggest a complex genetic relationship between Tourette's syndrome and OCD. , 2015, The American journal of psychiatry.

[54]  A. Fanous,et al.  Molecular validation of the schizophrenia spectrum. , 2014, Schizophrenia bulletin.

[55]  K. Hajian‐Tilaki,et al.  Receiver Operating Characteristic (ROC) Curve Analysis for Medical Diagnostic Test Evaluation. , 2013, Caspian journal of internal medicine.

[56]  N. Cook Statistical evaluation of prognostic versus diagnostic models: beyond the ROC curve. , 2008, Clinical chemistry.

[57]  A. Hoes,et al.  [Guidelines on cardiovascular disease prevention in clinical practice]. , 2005, Revue medicale de Liege.