Combined polygenic risk scores of different psychiatric traits predict general and specific psychopathology in childhood

Alexander Neumann, Alexia Jolicoeur-Martineau, Eszter Szekely, Hannah M Sallis, Kieran J O'Donnell, Celia M T Greenwood, Robert D. Levitan, Ashley Wazana, Jonathan Evans, Henning Tiemeier*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Abstract

Background: Polygenic risk scores (PRSs) operationalize genetic propensity towards a particular mental disorder and hold promise as early predictors of psychopathology, but before a PRS can be used clinically, explanatory power must be increased and the specificity for a psychiatric domain established. To enable early detection it is crucial to study these psychometric properties in childhood. We examined whether PRSs associate more with general or with specific psychopathology in school-aged children. Additionally, we tested whether psychiatric PRSs can be combined into a multi-PRS score for improved performance.

Methods: We computed 16 PRSs based on GWASs of psychiatric phenotypes, but also neuroticism and cognitive ability, in mostly adult populations. Study participants were 9247 school-aged children from three population-based cohorts of the DREAM-BIG consortium: ALSPAC (UK), The Generation R Study (Netherlands) and MAVAN (Canada). We associated each PRS with general and specific psychopathology factors, derived from a bifactor model based on self-, parental-, teacher-, and observer reports. After fitting each PRS in separate models, we also tested a multi-PRS model, in which all PRSs are entered simultaneously as predictors of the general psychopathology factor.
Results: Seven PRSs were associated with the general psychopathology factor after multiple testing adjustment, two with specific externalizing and five with specific internalizing psychopathology. PRSs predicted general psychopathology independently of each other, with the exception of depression and depressive symptom PRSs. Most PRSs associated with a specific psychopathology domain, were also associated with general child psychopathology.

Conclusions: The results suggest that PRSs based on current GWASs of psychiatric phenotypes tend to be associated with general psychopathology, or both general and
3 specific psychiatric domains, but not with one specific psychopathology domain only. Furthermore, PRSs can be combined to improve predictive ability. PRS users should therefore be conscious of non-specificity and consider using multiple PRSs simultaneously, when predicting psychiatric disorders.
Original languageEnglish
Number of pages10
JournalJournal of Child Psychology and Psychiatry
Early online date13 Aug 2021
DOIs
Publication statusE-pub ahead of print - 13 Aug 2021

Bibliographical note

Funding Information:
The Generation R Study is conducted by the Erasmus Medical Center in close collaboration with the Erasmus University Rotterdam, Faculty of Social Sciences, the Municipal Health Service Rotterdam area, and the Stichting Trombosedienst and Artsenlaboratorium Rijnmond. The authors gratefully acknowledge the contribution of general practitioners, hospitals, midwives, and pharmacies in Rotterdam. GenR is financially supported by Erasmus Medical Center and the Netherlands Organization for Health Research and Development. A.N. and H.T. are supported by a grant of the Dutch Ministry of Education, Culture, and Science and the Netherlands Organization for Scientific Research (024.001.003, Consortium on Individual Development). The work of H.T. is further supported by a European Union’s Horizon 2020 research and innovation program (633595, DynaHealth) and a NWO‐VICI grant (016.VICI.170.200).

Funding Information:
The MAVAN Research Team sincerely thanks the families that have participated in the MAVAN project for so generously giving their time as well as their ongoing support. MAVAN was funded by a Canadian Institutes of Health Research (CIHR) trajectory grant (191827). Private support was received from the McGill University Faculty of Medicine, the Norlien Foundation, and the Woco Foundation. This study was made possible by the CHIR (359912, 365309, and 231614), the Fonds de la recherche en santé du Québec (22418), and the March of Dimes Foundation (12‐FY12‐198). R.L. is supported by the Cameron Parker Holcombe Wilson Chair in Depression Studies, University of Toronto and the Centre for Addiction and Mental Health. The authors have declared that they have no competing or potential conflicts of interest. Key points

Funding Information:
The authors are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. The UK Medical Research Council MRC and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC, see http://www.bristol.ac.uk/alspac/external/documents/grant‐acknowledgements.pdf . This publication is the work of the authors, who serve as guarantors for the contents of this paper. GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. This work was supported by the MRC and the University of Bristol (MC_UU_00011/7). H.M.S. is also supported by the European Research Council (758813 MHINT).

Publisher Copyright:
© 2021 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.

Keywords

  • Genetics
  • molecular
  • Comorbidity
  • Internalising disorder
  • Externalising disorder
  • Meta- analysis

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