Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants With Treatment Resistance in Schizophrenia

Key Points Question Can common genetic variants be used to differentiate between treatment-resistant schizophrenia (TRS) and other forms of this disorder? Findings Data from this genome-wide association study including 85 490 participants were used to estimate genome-wide single-nucleotide variation effect size differences between individuals with and without TRS, which were compatible with a polygenic model of treatment resistance. Results were used to generate a polygenic risk score, which was significantly associated with TRS status in independent incidence and prevalence samples. Meaning Findings of this study based on common genetic variants indicate that TRS is heritable with a modest but significant single-nucleotide variation–based heritability.

[1]  M. Owen,et al.  Pharmacogenomics: A road ahead for precision medicine in psychiatry , 2021, Neuron.

[2]  J. MacCabe,et al.  Rates of treatment-resistant schizophrenia from first-episode cohorts: systematic review and meta-analysis , 2021, The British Journal of Psychiatry.

[3]  I. Pe’er,et al.  Leveraging correlations between variants in polygenic risk scores to detect heterogeneity in GWAS cohorts , 2020, PLoS genetics.

[4]  G. Breen,et al.  Evaluation of polygenic prediction methodology within a reference-standardized framework , 2020, bioRxiv.

[5]  S. Kymes,et al.  A modelling approach to estimate the prevalence of treatment-resistant schizophrenia in the United States , 2020, PloS one.

[6]  D. Weinberger,et al.  Special Article: Translational Science Update. Pharmacological Implications of Emerging Schizophrenia Genetics: Can the Bridge From 'Genomics' to 'Therapeutics' be Defined and Traversed? , 2020, Journal of clinical psychopharmacology.

[7]  M. Owen,et al.  Translating insights from neuropsychiatric genetics and genomics for precision psychiatry , 2020, Genome Medicine.

[8]  A. Price,et al.  Identifying loci with different allele frequencies among cases of eight psychiatric disorders using CC-GWAS , 2020, Nature Genetics.

[9]  Till F. M. Andlauer,et al.  An Investigation of Psychosis Subgroups With Prognostic Validation and Exploration of Genetic Underpinnings: The PsyCourse Study. , 2020, JAMA psychiatry.

[10]  P. Sullivan,et al.  Increased schizophrenia family history burden and reduced premorbid IQ in treatment-resistant schizophrenia: a Swedish National Register and Genomic Study , 2019, Molecular Psychiatry.

[11]  G. Remington,et al.  Clozapine response trajectories and predictors of non-response in treatment-resistant schizophrenia: a chart review study , 2019, European Archives of Psychiatry and Clinical Neuroscience.

[12]  Shing Wan Choi,et al.  PRSice-2: Polygenic Risk Score software for biobank-scale data , 2019, GigaScience.

[13]  G. Kirov,et al.  Clinical indicators of treatment-resistant psychosis , 2019, The British Journal of Psychiatry.

[14]  D. Rujescu,et al.  A genome-wide association study in individuals of African ancestry reveals the importance of the Duffy-null genotype in the assessment of clozapine-related neutropenia , 2019, Molecular Psychiatry.

[15]  A. Malhotra,et al.  Schizophrenia Polygenic Risk Score as a Predictor of Antipsychotic Efficacy in First-Episode Psychosis. , 2019, The American journal of psychiatry.

[16]  T. Werge,et al.  Schizophrenia polygenic risk scores, urbanicity and treatment-resistant schizophrenia , 2019, Schizophrenia Research.

[17]  B. Crespo-Facorro,et al.  Age of onset of Cannabis use and cognitive function in first-episode non-affective psychosis patients: Outcome at three-year follow-up , 2018, Schizophrenia Research.

[18]  Doug Speed,et al.  SumHer better estimates the SNP heritability of complex traits from summary statistics , 2018, Nature Genetics.

[19]  G. Remington,et al.  The impact of delay in clozapine initiation on treatment outcomes in patients with treatment-resistant schizophrenia: A systematic review , 2018, Psychiatry Research.

[20]  I. Melle,et al.  Consequences of persistent depression and apathy in first-episode psychosis - A one-year follow-up study. , 2018, Comprehensive psychiatry.

[21]  T. Ge,et al.  Polygenic prediction via Bayesian regression and continuous shrinkage priors , 2018, bioRxiv.

[22]  N. Kanahara,et al.  First-episode psychosis in treatment-resistant schizophrenia: a cross-sectional study of a long-term follow-up cohort , 2018, BMC Psychiatry.

[23]  A. David,et al.  The dynamic relationship between insight and suicidal behavior in first episode psychosis patients over 3-year follow-up , 2018, European Neuropsychopharmacology.

[24]  Caroline F. Wright,et al.  Common genetic variants contribute to risk of rare severe neurodevelopmental disorders , 2018, Nature.

[25]  Jakob Grove,et al.  Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection , 2018, Nature Genetics.

[26]  W. Fleischhacker,et al.  Why do indiviuals with schizophrenia drop out of observational clinical trials? , 2017, Psychiatry Research.

[27]  P. McGuffin,et al.  Advancing psychiatric genetics through dissecting heterogeneity , 2017, Human molecular genetics.

[28]  C. Gasse,et al.  Polygenic Risk Score for Schizophrenia and Treatment-Resistant Schizophrenia , 2017, Schizophrenia bulletin.

[29]  A. Richards,et al.  The emerging role of the FKBP5 gene polymorphisms in vulnerability-stress model of schizophrenia: further evidence from a Serbian population Author list , 2016 .

[30]  K. Kendler,et al.  The utility of empirically assigning ancestry groups in cross‐population genetic studies of addiction , 2017, The American journal on addictions.

[31]  R. Murray,et al.  Patterns of illness and care over the 5 years following onset of psychosis in different ethnic groups; the GAP-5 study , 2017, Social Psychiatry and Psychiatric Epidemiology.

[32]  A. Tanskanen,et al.  Real-World Effectiveness of Antipsychotic Treatments in a Nationwide Cohort of 29 823 Patients With Schizophrenia , 2017, JAMA psychiatry.

[33]  Abraham Weizman,et al.  Association between serum levels of glutamate and neurotrophic factors and response to clozapine treatment , 2017, Schizophrenia Research.

[34]  G. Davey Smith,et al.  Genetic epidemiology and Mendelian randomization for informing disease therapeutics: Conceptual and methodological challenges , 2017, bioRxiv.

[35]  R. Murray,et al.  Antipsychotic treatment resistance in first-episode psychosis: prevalence, subtypes and predictors , 2017, Psychological Medicine.

[36]  K. Do,et al.  Mild Depressive Symptoms Mediate the Impact of Childhood Trauma on Long-Term Functional Outcome in Early Psychosis Patients , 2017, European Psychiatry.

[37]  H. Möller,et al.  Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology. , 2017, The American journal of psychiatry.

[38]  A. Egerton,et al.  Is treatment-resistant schizophrenia categorically distinct from treatment-responsive schizophrenia? a systematic review , 2017, BMC Psychiatry.

[39]  Tariq Ahmad,et al.  Genome-wide association study identifies distinct genetic contributions to prognosis and susceptibility in Crohn's disease , 2017, Nature Genetics.

[40]  L. Hooft,et al.  A guide to systematic review and meta-analysis of prediction model performance , 2017, British Medical Journal.

[41]  D. Smit,et al.  Heritability of tic disorders: a twin-family study , 2016, Psychological Medicine.

[42]  F. Gaughran,et al.  Treatment-resistant schizophrenia: current insights on the pharmacogenomics of antipsychotics , 2016, Pharmacogenomics and personalized medicine.

[43]  R. Murray,et al.  Two distinct patterns of treatment resistance: clinical predictors of treatment resistance in first-episode schizophrenia spectrum psychoses , 2016, Psychological Medicine.

[44]  Alan M. Kwong,et al.  Next-generation genotype imputation service and methods , 2016, Nature Genetics.

[45]  M. Matějka,et al.  Connectivity of the anterior insula differentiates participants with first-episode schizophrenia spectrum disorders from controls: a machine-learning study , 2016, Psychological Medicine.

[46]  M. Matějka,et al.  Altered Neural Correlate of the Self-Agency Experience in First-Episode Schizophrenia-Spectrum Patients: An fMRI Study. , 2016, Schizophrenia bulletin.

[47]  C. Correll,et al.  Correlates of Clozapine Use after a First Episode of Schizophrenia: Results From a Long-term Prospective Study , 2016, CNS Drugs.

[48]  P. Conus,et al.  Duration of untreated psychosis: Impact of the definition of treatment onset on its predictive value over three years of treatment. , 2016, Journal of psychiatric research.

[49]  Tom R. Gaunt,et al.  LD Hub: a centralized database and web interface to perform LD score regression that maximizes the potential of summary level GWAS data for SNP heritability and genetic correlation analysis , 2016, bioRxiv.

[50]  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.

[51]  B. Misiak,et al.  Profiling cognitive impairment in treatment-resistant schizophrenia patients , 2016, Psychiatry Research.

[52]  Bruce S Weir,et al.  Model-free Estimation of Recent Genetic Relatedness. , 2016, American journal of human genetics.

[53]  C. Eap,et al.  Importance of early weight changes to predict long-term weight gain during psychotropic drug treatment. , 2015, The Journal of clinical psychiatry.

[54]  Z. Kutalik,et al.  Influence of MCHR2 and MCHR2-AS1 Genetic Polymorphisms on Body Mass Index in Psychiatric Patients and In Population-Based Subjects with Present or Past Atypical Depression , 2015, PloS one.

[55]  Andrew K. Martin,et al.  Increased rare duplication burden genomewide in patients with treatment-resistant schizophrenia , 2015, Psychological Medicine.

[56]  R Plomin,et al.  Phenome-wide analysis of genome-wide polygenic scores , 2015, Molecular Psychiatry.

[57]  T. Lehtimäki,et al.  Integrative approaches for large-scale transcriptome-wide association studies , 2015, Nature Genetics.

[58]  Qian Liu,et al.  Systematic assessment of imputation performance using the 1000 Genomes reference panels , 2015, Briefings Bioinform..

[59]  Timothy A Thornton,et al.  Robust Inference of Population Structure for Ancestry Prediction and Correction of Stratification in the Presence of Relatedness , 2015, Genetic epidemiology.

[60]  Z. Kutalik,et al.  Impact of HSD11B1 polymorphisms on BMI and components of the metabolic syndrome in patients receiving psychotropic treatments , 2015, Pharmacogenetics and genomics.

[61]  J. Hlinka,et al.  White matter changes in first episode psychosis and their relation to the size of sample studied: A DTI study , 2015, Schizophrenia Research.

[62]  Paola Dazzan,et al.  Proportion of patients in south London with first-episode psychosis attributable to use of high potency cannabis: a case-control study. , 2015, The lancet. Psychiatry.

[63]  Carson C Chow,et al.  Second-generation PLINK: rising to the challenge of larger and richer datasets , 2014, GigaScience.

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

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

[66]  M. Ron,et al.  A longitudinal study of cortical changes and their cognitive correlates in patients followed up after first-episode psychosis , 2014, Psychological Medicine.

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

[68]  D. Rujescu,et al.  Identification of increased genetic risk scores for schizophrenia in treatment-resistant patients , 2014, Molecular Psychiatry.

[69]  R. Murray,et al.  Reappraising the long-term course and outcome of psychotic disorders: the AESOP-10 study , 2014, Psychological Medicine.

[70]  M. Daly,et al.  LD Score regression distinguishes confounding from polygenicity in genome-wide association studies , 2014, Nature Genetics.

[71]  I. Melle,et al.  One year follow-up of alcohol and illicit substance use in first-episode psychosis: does gender matter? , 2014, Comprehensive psychiatry.

[72]  F. Iasevoli,et al.  Differential cognitive performances between schizophrenic responders and non-responders to antipsychotics: Correlation with course of the illness, psychopathology, attitude to the treatment and antipsychotics doses , 2013, Psychiatry Research.

[73]  I. Melle,et al.  Apathy, poor verbal memory and male gender predict lower psychosocial functioning one year after the first treatment of psychosis , 2013, Psychiatry Research.

[74]  G. Kirov,et al.  Evidence that duplications of 22q11.2 protect against schizophrenia , 2013, Molecular Psychiatry.

[75]  J. Beckmann,et al.  Influence of CRTC1 polymorphisms on body mass index and fat mass in psychiatric patients and the general adult population. , 2013, JAMA psychiatry.

[76]  K. Do,et al.  Treatment and Early Intervention in Psychosis Program (TIPP‐Lausanne): implementation of an early intervention programme for psychosis in Switzerland , 2013, Early intervention in psychiatry.

[77]  S Purcell,et al.  Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC , 2013, Molecular Psychiatry.

[78]  L. Clark,et al.  Reflection impulsivity and response inhibition in first-episode psychosis: relationship to cannabis use , 2013, Psychological Medicine.

[79]  O. Delaneau,et al.  Supplementary Information for ‘ Improved whole chromosome phasing for disease and population genetic studies ’ , 2012 .

[80]  J. Marchini,et al.  Fast and accurate genotype imputation in genome-wide association studies through pre-phasing , 2012, Nature Genetics.

[81]  G. Remington,et al.  Defining treatment-resistant schizophrenia and response to antipsychotics: A review and recommendation , 2012, Psychiatry Research.

[82]  P. Visscher,et al.  A Better Coefficient of Determination for Genetic Profile Analysis , 2012, Genetic epidemiology.

[83]  D. Berardi,et al.  First-episode psychosis at the West Bologna Community Mental Health Centre: results of an 8-year prospective study , 2012, Psychological Medicine.

[84]  N. Wray,et al.  Impact of diagnostic misclassification on estimation of genetic correlations using genome-wide genotypes , 2012, European Journal of Human Genetics.

[85]  A. Üçok,et al.  Remission after first-episode schizophrenia: Results of a long-term follow-up , 2011, Psychiatry Research.

[86]  Sharon R Grossman,et al.  Integrating common and rare genetic variation in diverse human populations , 2010, Nature.

[87]  Elvira Bramon,et al.  Gene variants associated with schizophrenia in a Norwegian genome-wide study are replicated in a large European cohort. , 2010, Journal of psychiatric research.

[88]  A. Morris,et al.  Data quality control in genetic case-control association studies , 2010, Nature Protocols.

[89]  Wolfgang Viechtbauer,et al.  Conducting Meta-Analyses in R with the metafor Package , 2010 .

[90]  Yun Li,et al.  METAL: fast and efficient meta-analysis of genomewide association scans , 2010, Bioinform..

[91]  G. Barker,et al.  Changes in the Frontotemporal Cortex and Cognitive Correlates in First-Episode Psychosis , 2010, Biological Psychiatry.

[92]  A. Mortimer,et al.  Clozapine for treatment-resistant schizophrenia: National Institute of Clinical Excellence (NICE) guidance in the real world. , 2010, Clinical schizophrenia & related psychoses.

[93]  Alessandra Paparelli,et al.  High-potency cannabis and the risk of psychosis , 2009, British Journal of Psychiatry.

[94]  Ofer Harel,et al.  The estimation of R 2 and adjusted R 2 in incomplete data sets using multiple imputation , 2009 .

[95]  S. Cooper,et al.  Impact of persistent substance misuse on 1-year outcome in first-episode psychosis. , 2009, The British journal of psychiatry : the journal of mental science.

[96]  C. Eap,et al.  [Follow-up of the metabolic syndrome induced by atypical antipsychotics: recommendations and pharmacogenetics perspectives]. , 2008, Revue medicale suisse.

[97]  J. Vázquez-Barquero,et al.  Epidemiological factors associated with treated incidence of first‐episode non‐affective psychosis in Cantabria: insights from the Clinical Programme on Early Phases of Psychosis , 2008, Early intervention in psychiatry.

[98]  K. Shianna,et al.  Long-range LD can confound genome scans in admixed populations. , 2008, American journal of human genetics.

[99]  A. Wheeler.  Treatment Pathway and Patterns of Clozapine Prescribing for Schizophrenia in New Zealand , 2008, The Annals of pharmacotherapy.

[100]  S. Kumra,et al.  Clozapine and “High-Dose” Olanzapine in Refractory Early-Onset Schizophrenia: A 12-Week Randomized and Double-Blind Comparison , 2008, Biological Psychiatry.

[101]  I. Melle,et al.  Assessing apathy: The use of the Apathy Evaluation Scale in first episode psychosis , 2008, European Psychiatry.

[102]  J. Vázquez-Barquero,et al.  Predictors of acute treatment response in patients with a first episode of non-affective psychosis: sociodemographics, premorbid and clinical variables. , 2007, Journal of psychiatric research.

[103]  T. Hodgson,et al.  Gaze Strategies During Planning in First-Episode Psychosis , 2007, Journal of abnormal psychology.

[104]  R. Murray,et al.  Grey matter correlates of minor physical anomalies in the ÆSOP first-episode psychosis study , 2006, British Journal of Psychiatry.

[105]  Peter B. Jones,et al.  Incidence of schizophrenia and other psychoses in ethnic minority groups: results from the MRC AESOP Study , 2006, Psychological Medicine.

[106]  Paola Dazzan,et al.  Heterogeneity in incidence rates of schizophrenia and other psychotic syndromes: findings from the 3-center AeSOP study. , 2006, Archives of general psychiatry.

[107]  R. Murray,et al.  First episode psychosis and ethnicity: initial findings from the AESOP study. , 2006, World psychiatry : official journal of the World Psychiatric Association.

[108]  John Suckling,et al.  Different Effects of Typical and Atypical Antipsychotics on Grey Matter in First Episode Psychosis: the ÆSOP Study , 2005, Neuropsychopharmacology.

[109]  D. Weinberger,et al.  Remission in schizophrenia: proposed criteria and rationale for consensus. , 2005, The American journal of psychiatry.

[110]  N. Turan,et al.  Duration of untreated psychosis may predict acute treatment response in first-episode schizophrenia. , 2004, Journal of psychiatric research.

[111]  Douglas G Altman,et al.  Interaction revisited: the difference between two estimates , 2003, BMJ : British Medical Journal.

[112]  C. McMurray,et al.  Genetics and etiopathophysiology of schizophrenia. , 2002, Mayo Clinic proceedings.

[113]  R. Conley,et al.  Management of treatment resistance in schizophrenia , 2001, Biological Psychiatry.

[114]  E. F. Stone-Romero,et al.  Relative power of moderated multiple regression and the comparison of subgroup correlation coefficients for detecting moderating effects. , 1994 .

[115]  Gerome Breen,et al.  Psychiatric Genomics: An Update and an Agenda , 2017, bioRxiv.

[116]  I. Buchan,et al.  Investigating heterogeneity of effects and associations using interaction terms. , 2018, Journal of clinical epidemiology.

[117]  P. Kraft,et al.  Artifact due to differential error when cases and controls are imputed from different platforms , 2011, Human Genetics.

[118]  A. Corvin,et al.  The Clinical Impact of Substance Use in Schizophrenia: A Study in an Irish Population. , 2008 .

[119]  A. Polat,et al.  One year outcome in first episode schizophrenia. Predictors of relapse. , 2006, European archives of psychiatry and clinical neuroscience.

[120]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .