Abstract
BACKGROUND: Several nonpsychotic psychiatric disorders in childhood and adolescence can precede the onset of schizophrenia, but the etiology of this relationship remains unclear. We investigated to what extent the association between schizophrenia and psychiatric disorders in childhood is explained by correlated genetic risk factors.
METHODS: Polygenic risk scores (PRS), reflecting an individual's genetic risk for schizophrenia, were constructed for 2588 children from the Netherlands Twin Register (NTR) and 6127 from the Avon Longitudinal Study of Parents And Children (ALSPAC). The associations between schizophrenia PRS and measures of anxiety, depression, attention deficit hyperactivity disorder (ADHD), and oppositional defiant disorder/conduct disorder (ODD/CD) were estimated at age 7, 10, 12/13, and 15 years in the 2 cohorts. Results were then meta-analyzed, and a meta-regression analysis was performed to test differences in effects sizes over, age and disorders.
RESULTS: Schizophrenia PRS were associated with childhood and adolescent psychopathology. Meta-regression analysis showed differences in the associations over disorders, with the strongest association with childhood and adolescent depression and a weaker association for ODD/CD at age 7. The associations increased with age and this increase was steepest for ADHD and ODD/CD. Genetic correlations varied between 0.10 and 0.25.
CONCLUSION: By optimally using longitudinal data across diagnoses in a multivariate meta-analysis this study sheds light on the development of childhood disorders into severe adult psychiatric disorders. The results are consistent with a common genetic etiology of schizophrenia and developmental psychopathology as well as with a stronger shared genetic etiology between schizophrenia and adolescent onset psychopathology.
| Original language | English |
|---|---|
| Pages (from-to) | 1197-1207 |
| Number of pages | 11 |
| Journal | Schizophrenia Bulletin |
| Volume | 43 |
| Issue number | 6 |
| Early online date | 11 Mar 2017 |
| DOIs | |
| Publication status | Published - Nov 2017 |
Funding
The UK Medical Research Council and the Wellcome Trust (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. This work was supported in part by the Medical Research Council Integrative Epidemiology Unit at the University of Bristol (MC_UU_12013/6). This publication is the work of the authors and M.G.N. will serve as guarantor for the contents of this article. ALSPAC GWAS data was generated by Sample Logistics and Genotyping Facilities at the Wellcome Trust Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. The NTR gratefully acknowledges support from “Genetic influences on stability and change in psychopathology from childhood to young adulthood” (ZonMW 912-10-020) and “Genetics of Mental Illness” (ERC-230374), The Netherlands Organization for Scientific Research (NWO) and MagW/ZonMW grants Middelgroot-911-09-032, Center for Medical Systems Biology (CSMB, NWO Genomics), NBIC/BioAssist/ RK (2008.024), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI–NL, 184.021.007), VU University’s Institute for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam (NCA). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health, Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH R01 HD042157-01A1, MH081802, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995) M.G.N. is supported by Royal Netherlands Academy of Science Professor Award (PAH/6635). The Netherlands Twin Register (NTR) (www.tweelin-genregister.org) follows newborn and adult twins. In the Young NTR (YNTR), twins are registered by their parents and followed from birth onwards. Until age 12, parents complete surveys to report on their twins. From age 14 onwards, information is collected by means of self-report.34 In the current study, maternal ratings of childhood psychopathology collected at age 7, 10, and 12 years were analyzed as well as self-report data collected between ages 14–16 years. The number of genotyped children with scores available varied between 1223 and 2588 depending on age group (supplementary table S1). Informed consent was obtained from all participants. The study was approved by the Central Ethics Committee on Research Involving Human Subjects of the VU University Medical Centre, Amsterdam, an Institutional Review Board certified by the US Office of Human Research Protections (IRB number IRB-2991 under Federal-wide Assurance-3703; IRB/institute codes, NTR 03-180).
| Funders | Funder number |
|---|---|
| Avera Institute | |
| Center for Medical Systems Biology | |
| Genetic Association Information Network | |
| Medical Research Council Integrative Epidemiology Unit | MC_UU_12013/6 |
| NIMH U24 MH068457-06 | U24 MH068457-06 |
| NWO Genomics | 2008.024, 184.021.007 |
| Netherlands Organization for Scientific Research | |
| US Office of Human Research Protections | IRB-2991, NTR 03-180 |
| VU University | |
| VU University’s | |
| Wellcome Trust Sanger Institute | ZonMW 912-10-020, ERC-230374 |
| National Institutes of Health | 1RC2 MH089951, MH081802, R01 HD042157-01A1 |
| Foundation for the National Institutes of Health | |
| National Institute of Mental Health | RC2MH089995 |
| Center for Outcomes Research and Evaluation, Yale School of Medicine | |
| Wellcome Trust | 102215/2/13/2 |
| Research Councils UK | |
| University of Bristol | |
| Royal Swedish Academy of Sciences | PAH/6635 |
| Nederlandse Organisatie voor Wetenschappelijk Onderzoek | Middelgroot-911-09-032 |
Keywords
- Journal Article
Cohort Studies
- Netherlands Twin Register (NTR)