University of Leicester
Browse

Research Review: How to interpret associations between polygenic scores, environmental risks, and phenotypes

Download (557.42 kB)
journal contribution
posted on 2022-11-09, 09:50 authored by Jean-Baptiste Pingault, Andrea G Allegrini, Tracy Odigie, Leonard Frach, Jessie R Baldwin, Fruhling Rijsdijk, Frank Dudbridge

Genetic influences are ubiquitous as virtually all phenotypes and most exposures typically classified as environmental have been found to be heritable. A polygenic score summarises the associations between millions of genetic variants and an outcome in a single value for each individual. Ever lowering costs have enabled the genotyping of many samples relevant to child psychology and psychiatry research, including cohort studies, leading to the proliferation of polygenic score studies. It is tempting to assume that associations detected between polygenic scores and phenotypes in those studies only reflect genetic effects. However, such associations can reflect many pathways (e.g. via environmental mediation) and biases.Here, we provide a comprehensive overview of the many reasons why associations between polygenic scores, environmental exposures, and phenotypes exist. We include formal representations of common analyses in polygenic score studies using structural equation modelling. We derive biases, provide illustrative empirical examples and, when possible, mention steps that can be taken to alleviate those biases.Structural equation models and derivations show the many complexities arising from jointly modelling polygenic scores with environmental exposures and phenotypes. Counter-intuitive examples include that: (a) associations between polygenic scores and phenotypes may exist even in the absence of direct genetic effects; (b) associations between child polygenic scores and environmental exposures can exist in the absence of evocative/active gene-environment correlations; and (c) adjusting an exposure-outcome association for a polygenic score can increase rather than decrease bias.Strikingly, using polygenic scores may, in some cases, lead to more bias than not using them. Appropriately conducting and interpreting polygenic score studies thus requires researchers in child psychology and psychiatry and beyond to be versed in both epidemiological and genetic methods or build on interdisciplinary collaborations.

Funding

H2020 European Research Council. Grant Number: 863981 Advanced Medical Research Foundation. Grant Number: MRF-160-0002-ELP-PINGA Wellcome Trust. Grant Number: 215917/Z/19/Z

History

Citation

Pingault, J.-B., Allegrini, A.G., Odigie, T., Frach, L., Baldwin, J.R., Rijsdijk, F. and Dudbridge, F. (2022), Research Review: How to interpret associations between polygenic scores, environmental risks, and phenotypes. J Child Psychol Psychiatr, 63: 1125-1139. https://doi.org/10.1111/jcpp.13607

Author affiliation

Department of Health Sciences

Version

  • VoR (Version of Record)

Published in

Journal of Child Psychology and Psychiatry

Volume

63

Pagination

1125-1139

Publisher

Wiley

issn

0021-9630

eissn

1469-7610

Acceptance date

2022-02-23

Copyright date

2022

Available date

2022-03-28

Spatial coverage

England

Language

English