Synergistic effects of childhood adversity and polygenic risk in first-episode psychosis: the EU-GEI study

Abstract Background A history of childhood adversity is associated with psychotic disorder, with an increase in risk according to the number of exposures. However, it is not known why only some exposed individuals go on to develop psychosis. One possibility is pre-existing polygenic vulnerability. Here, we investigated, in the largest sample of first-episode psychosis (FEP) cases to date, whether childhood adversity and high polygenic risk scores for schizophrenia (SZ-PRS) combine synergistically to increase the risk of psychosis, over and above the effect of each alone. Methods We assigned a schizophrenia-polygenic risk score (SZ-PRS), calculated from the Psychiatric Genomics Consortium (PGC2), to all participants in a sample of 384 FEP patients and 690 controls from the case–control component of the EU-GEI study. Only participants of European ancestry were included in the study. A history of childhood adversity was collected using the Childhood Trauma Questionnaire (CTQ). Synergistic effects were estimated using the interaction contrast ratio (ICR) [odds ratio (OR)exposure and PRS − ORexposure − ORPRS + 1] with adjustment for potential confounders. Results There was some evidence that the combined effect of childhood adversities and polygenic risk was greater than the sum of each alone, as indicated by an ICR greater than zero [i.e. ICR 1.28, 95% confidence interval (CI) −1.29 to 3.85]. Examining subtypes of childhood adversities, the strongest synergetic effect was observed for physical abuse (ICR 6.25, 95% CI −6.25 to 20.88). Conclusions Our findings suggest possible synergistic effects of genetic liability and childhood adversity experiences in the onset of FEP, but larger samples are needed to increase precision of estimates.

[1]  I. Melle,et al.  Childhood maltreatment and polygenic risk in bipolar disorders , 2020, Bipolar disorders.

[2]  Peter B. Jones,et al.  The EUropean Network of National Schizophrenia Networks Studying Gene–Environment Interactions (EU-GEI): Incidence and First-Episode Case–Control Programme , 2020, Social Psychiatry and Psychiatric Epidemiology.

[3]  I. Melle,et al.  Elevated hair cortisol is associated with childhood maltreatment and cognitive impairment in schizophrenia and in bipolar disorders , 2019, Schizophrenia Research.

[4]  Nicole A. Restrepo,et al.  Penetrance and Pleiotropy of Polygenic Risk Scores for Schizophrenia in 106,160 Patients Across Four Health Care Systems. , 2019, The American journal of psychiatry.

[5]  N. Wray,et al.  Publisher Correction: Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection , 2019, Nature Genetics.

[6]  M. O’Donovan,et al.  Examining the independent and joint effects of molecular genetic liability and environmental exposures in schizophrenia: results from the EUGEI study , 2019, World psychiatry : official journal of the World Psychiatric Association.

[7]  Peter B. Jones,et al.  The contribution of cannabis use to variation in the incidence of psychotic disorder across Europe (EU-GEI): a multicentre case-control study , 2019, The lancet. Psychiatry.

[8]  A. Danese,et al.  Agreement Between Prospective and Retrospective Measures of Childhood Maltreatment , 2019, JAMA psychiatry.

[9]  J. Os,et al.  Evidence that the association of childhood trauma with psychosis and related psychopathology is not explained by gene-environment correlation: A monozygotic twin differences approach , 2019, Schizophrenia Research.

[10]  R. Murray,et al.  Interaction between childhood adversity and functional polymorphisms in the dopamine pathway on first-episode psychosis , 2019, Schizophrenia Research.

[11]  C. Teufel,et al.  Association of Trauma Type, Age of Exposure, and Frequency in Childhood and Adolescence With Psychotic Experiences in Early Adulthood , 2018, JAMA psychiatry.

[12]  James G. Scott,et al.  Global Epidemiology and Burden of Schizophrenia: Findings From the Global Burden of Disease Study 2016 , 2018, Schizophrenia bulletin.

[13]  Peter B. Jones,et al.  Transdiagnostic dimensions of psychopathology at first episode psychosis: findings from the multinational EU-GEI study , 2018, Psychological Medicine.

[14]  A. Caspi,et al.  Measuring childhood maltreatment to predict early-adult psychopathology: Comparison of prospective informant-reports and retrospective self-reports , 2018, Journal of psychiatric research.

[15]  Alice Mulè,et al.  Treated Incidence of Psychotic Disorders in the Multinational EU-GEI Study , 2017, JAMA psychiatry.

[16]  E. Vassos,et al.  Prospects for using risk scores in polygenic medicine , 2017, Genome Medicine.

[17]  John P. Rice,et al.  Does Childhood Trauma Moderate Polygenic Risk for Depression? A Meta-analysis of 5765 Subjects From the Psychiatric Genomics Consortium , 2017, Biological Psychiatry.

[18]  Kaare Christensen,et al.  Heritability of Schizophrenia and Schizophrenia Spectrum Based on the Nationwide Danish Twin Register , 2017, Biological Psychiatry.

[19]  I. Melle,et al.  Childhood Trauma and Minimization/Denial in People with and without a Severe Mental Disorder , 2017, Front. Psychol..

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

[21]  E. Walker,et al.  The neural diathesis-stress model of schizophrenia revisited: An update on recent findings considering illness stage and neurobiological and methodological complexities , 2017, Neuroscience & Biobehavioral Reviews.

[22]  C. Arango,et al.  Candidate gene associations studies in psychiatry: time to move forward , 2017, European Archives of Psychiatry and Clinical Neuroscience.

[23]  R. Murray,et al.  Interplay between Schizophrenia Polygenic Risk Score and Childhood Adversity in First-Presentation Psychotic Disorder: A Pilot Study , 2016, PloS one.

[24]  Sandhya Ramrakha,et al.  Lest we forget: comparing retrospective and prospective assessments of adverse childhood experiences in the prediction of adult health. , 2016, Journal of child psychology and psychiatry, and allied disciplines.

[25]  R. Murray,et al.  Adversity in childhood linked to elevated striatal dopamine function in adulthood , 2016, Schizophrenia Research.

[26]  Ole A. Andreassen,et al.  The role of childhood trauma in bipolar disorders , 2016, International Journal of Bipolar Disorders.

[27]  J. Potash,et al.  Polygenic interactions with environmental adversity in the aetiology of major depressive disorder , 2015, Psychological Medicine.

[28]  Tyler J. VanderWeele,et al.  A Tutorial on Interaction , 2014 .

[29]  S. Djurovic,et al.  Interplay between childhood trauma and BDNF val66met variants on blood BDNF mRNA levels and on hippocampus subfields volumes in schizophrenia spectrum and bipolar disorders. , 2014, Journal of psychiatric research.

[30]  S. Djurovic,et al.  Polygenic risk score and the psychosis continuum model , 2014, Acta psychiatrica Scandinavica.

[31]  R. Rajkumar.  Childhood attachment and schizophrenia: the "attachment-developmental-cognitive" (ADC) hypothesis. , 2014, Medical hypotheses.

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

[33]  P. Sullivan,et al.  Effect of polygenic risk scores on depression in childhood trauma , 2014, British Journal of Psychiatry.

[34]  R. Murray,et al.  Schizophrenia: an integrated sociodevelopmental-cognitive model , 2014, The Lancet.

[35]  P. Sham,et al.  Molecular genetic gene–environment studies using candidate genes in schizophrenia: A systematic review , 2013, Schizophrenia Research.

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

[37]  I. Myin-Germeys,et al.  Childhood Trauma as a Cause of Psychosis: Linking Genes, Psychology, and Biology , 2013, Canadian journal of psychiatry. Revue canadienne de psychiatrie.

[38]  Tyler J VanderWeele,et al.  Recommendations for presenting analyses of effect modification and interaction. , 2012, International journal of epidemiology.

[39]  J. Read,et al.  Childhood Adversities Increase the Risk of Psychosis: A Meta-analysis of Patient-Control, Prospective- and Cross-sectional Cohort Studies , 2012, Schizophrenia bulletin.

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

[41]  D. Grobbee,et al.  Estimating interaction on an additive scale between continuous determinants in a logistic regression model. , 2007, International journal of epidemiology.

[42]  M. Shevlin,et al.  Cumulative traumas and psychosis: an analysis of the national comorbidity survey and the British Psychiatric Morbidity Survey. , 2007, Schizophrenia bulletin.

[43]  E. Kuipers,et al.  Implications for neurobiological research of cognitive models of psychosis: a theoretical paper , 2007, Psychological Medicine.

[44]  S. Kapur,et al.  From dopamine to salience to psychosis—linking biology, pharmacology and phenomenology of psychosis , 2005, Schizophrenia Research.

[45]  T. Suppes,et al.  Early physical and sexual abuse associated with an adverse course of bipolar illness , 2002, Biological Psychiatry.

[46]  D. Bhugra,et al.  Social environment, ethnicity and schizophrenia , 2002, Social Psychiatry and Psychiatric Epidemiology.

[47]  J. Golding,et al.  Child maltreatment in the "children of the nineties" a longitudinal study of parental risk factors. , 2001, Child abuse & neglect.

[48]  D. Diforio,et al.  Schizophrenia: a neural diathesis-stress model. , 1997, Psychological review.

[49]  J Foote,et al.  Initial reliability and validity of a new retrospective measure of child abuse and neglect. , 1994, The American journal of psychiatry.

[50]  S Lemeshow,et al.  Confidence interval estimation of interaction. , 1992, Epidemiology.

[51]  A. Farmer,et al.  A polydiagnostic application of operational criteria in studies of psychotic illness. Development and reliability of the OPCRIT system. , 1991, Archives of general psychiatry.

[52]  Ariel Y. Deutch,et al.  Prefrontal cortical dopamine depletion enhances the responsiveness of mesolimbic dopamine neurons to stress , 1990, Brain Research.