Genetic liability for schizophrenia and childhood psychopathology in the general population
Authors: Hannigan Laurie J. , Askeland Ragna Bugge , Ask Helga , Tesli Martin , Corfield Elizabeth , Ayorech Ziada , Helgeland Øyvind , Magnus Per , Njølstad Pål Rasmus , Øyen Anne-Siri , Stoltenberg Camilla , Andreassen Ole A. , Smith George Davey , Reichborn-Kjennerud Ted , Havdahl Alexandra 
Published: May 2020

AbstractBackgroundGenetic liability for schizophrenia is associated with psychopathology in early life. It is not clear if these associations are time-dependent during childhood, nor if they are specific across different forms of psychopathology.MethodsUsing genotype and questionnaire data on children (N = 15,105) from the Norwegian Mother, Father, and Child Cohort Study (MoBa), we tested associations between schizophrenia polygenic risk scores and measures of childhood emotional and behavioural problems for developmental stability and domain specificity. We then sought to identify symptom profiles – across development and domains – associated with elevated schizophrenia polygenic liability.OutcomesWe found evidence for developmental stability in associations between schizophrenia polygenic risk scores and emotional and behavioural problems, with the latter being mediated via the rate of change in symptoms between 18 months and 5 years specifically (βslope = 0.032; 95% CI 0.007 – 0.057). At age 8, associations with emotional and behavioural psychopathology were found to be better explained by a model of symptom-specific polygenic risk score effects, rather than effects mediated via a general “p” factor or by domain-specific factors. Overall, individuals with higher schizophrenia polygenic risk scores were more likely (OR= 1.310 [95% CIs: 1.122-1.528]) to have increasing behavioural and emotional symptoms in early childhood, followed by relatively elevated symptoms of conduct disorder, oppositional defiant disorder, hyperactivity and inattention in middle childhood.InterpretationSchizophrenia-associated alleles are linked to specific patterns of early-life psychopathology. The associations are small, but findings of this nature can help us better understand the developmental emergence of schizophrenia.FundingLaurie Hannigan, Ziada Ayorech, and Alexandra Havdahl were supported by grants from the South-Eastern Norway Regional Health Authority (2018059, 2019097 and 2018058, respectively). Ragna Bugge Askeland and Elizabeth Corfield were supported by a grant from the Norwegian Research Council (274611). Ted Reichborn-Kjennerud was supported by a grant from the Research Council of Norway (274611). Pål Rasmus Njølstad was funded by the ERC AdG SELECTionPREDISPOSED (#293574), the Stiftelsen Kristian Gerhard Jebsen, the Trond Mohn Foundation, the Norwegian Research Council (#240413/F20), the Novo Nordisk Foundation (#54741), the University of Bergen, and the Western Norway health Authorities (Helse Vest; PERSON-MED-DIA and #911745). Ole A. Andreassen was supported the Research Council of Norway (229129; 213837; 248778; 223273; 249711); the South-East Norway Regional Health Authority (2017-112); KG Jebsen Stiftelsen (SKGJ) and H2020 grant # 847776 CoMorMent. George Davey Smith works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC_UU_00011/1). This work was partly supported by the Research Council of Norway through its Centre of Excellence funding scheme, project number 262700.Research in contextEvidence before this studyGenetic liability to schizophrenia, conferred incrementally by many genetic variants of small effect, is associated with various forms of psychopathology – both symptoms and diagnoses – in the general population during adulthood. To get an overview of the relevant evidence for how genetic liability to schizophrenia manifests in psychopathology in childhood, we performed a systematic search of the published literature using the Ovid MEDLINE and PsychINFO databases, for English-language peer-reviewed journal articles published prior to 28 January 2020. We found 7 studies of core relevance (i.e., containing assessment of symptoms or diagnoses of psychopathology in pre-adolescent children), with a further 9 studies examining outcomes potentially related to psychopathology (such as brain structure, cognitive performance, and social functioning). Of the 7 core studies, 3 used clinical samples to demonstrate that polygenic risk scores for schizophrenia are higher among children with ADHD diagnoses than controls, and among cases of the rare child-onset form of schizophrenia than their healthy siblings. The remainder of studies all examined symptoms of psychopathology among children in the general population, finding modest but robust associations of schizophrenia polygenic risk scores with emotional and behavioural problems measured from 3 years of age, as well as with symptoms of depression, ADHD, anxiety, oppositional defiant disorder and conduct disorder in middle childhood.Added value of this studyIn this study, we present a set of analyses designed to improve our understanding of the nature of associations between schizophrenia risk alleles and childhood psychopathology. Specifically, we employ an approach that aims not just to quantify, but also to explore how the effects of schizophrenia risk manifest across childhood, and across different domains of psychopathology. We find evidence that effects of schizophrenia polygenic risk scores on symptoms of emotional and behavioural problems in early childhood are stable, influencing the overall level and rates of change in symptoms, rather than age-specific (i.e., transient or developmental). We also find evidence of specificity in the effects of schizophrenia polygenic risk scores on different domains of psychopathology in 8-year-old children. Overall, we find that higher schizophrenia polygenic risk scores are associated with a developmental symptom profile comprising elevated and increasing symptoms of behavioural problems and increasing levels of emotional problems in early childhood, as well as particularly elevated symptoms of conduct disorder, inattention, hyperactivity, and oppositional defiant disorder in middle childhood.Implications of all the available evidenceFindings of our study align with a growing body of evidence that the effects of schizophrenia risk alleles on psychopathology begin early in life, and influence the likelihood of children experiencing difficulties across development. While previous work has largely found similar effects of schizophrenia polygenic risk scores across different domains of childhood psychopathology, indicating that such effects may be mediated by a hypothetical latent ‘general psychopathology’ or ‘p’ factor, our results suggest that domain- and even symptom-level specificity may emerge by middle childhood. We may be able to improve our understanding of processes underpinning the emergence of schizophrenia later in life by paying attention to nuances in the ways that genetic risk for schizophrenia manifests across childhood and into adolescence.