Genome-wide gene-environment interactions in neuroticism: an exploratory study across 25 environments

Josefin Werme,Sophie Van Der Sluis,Christiaan A De Leeuw,Danielle Posthuma

doi:10.1038/s41398-021-01288-9

Josefin Werme, Sophie Van Der Sluis + Show 2 more

Open Access

https://doi.org/10.1038/s41398-021-01288-9

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Abstract

Gene-environment interactions (GxE) are often suggested to play an important role in the aetiology of psychiatric phenotypes, yet so far, only a handful of genome-wide environment interaction studies (GWEIS) of psychiatric phenotypes have been conducted. Representing the most comprehensive effort of its kind to date, we used data from the UK Biobank to perform a series of GWEIS for neuroticism across 25 broadly conceptualised environmental risk factors (trauma, social support, drug use, physical health). We investigated interactions on the level of SNPs, genes, and gene-sets, and computed interaction-based polygenic risk scores (PRS) to predict neuroticism in an independent sample subset (N = 10,000). We found that the predictive ability of the interaction-based PRSs did not significantly improve beyond that of a traditional PRS based on SNP main effects from GWAS, but detected one variant and two gene-sets showing significant interaction signal after correction for the number of analysed environments. This study illustrates the possibilities and limitations of a comprehensive GWEIS in currently available sample sizes.

Highlights

Neuroticism is a personality trait that is characterised by emotion dysregulation and negative affect
We evaluated the predictive ability of SNP-interaction effects across the genome by constructing interaction-based polygenic scores for each environment and used these to predict neuroticism in an independent subset of the UKB sample (N = 10,000)
Gene sets enriched by the most interactable genes In order to determine whether the most strongly associated genes for any environment tended to be overrepresented within particular pathways, cellular locations, or implicated in particular tissue-specific gene expression patterns, we performed competitive gene-set and gene-property analyses in MAGMA using the results from the 25 GWEISbased gene analyses as input

Summary

Introduction

Neuroticism is a personality trait that is characterised by emotion dysregulation and negative affect. It has been thought to confer a general susceptibility to mental health problems, resulting in the frequent experience of negative emotions such as worry, sadness, self-consciousness, or anger[1,2,3]. High neuroticism is associated with increased psychiatric comorbidity, and there is a substantial overlap between neuroticism and a wide range of psychiatric disorders, depression and anxiety[4,5,6]. The associated societal costs of neuroticism are substantial[7], leading to increased use of both mental and physical health services due to poorer overall health and quality of life[8]. The genetic aetiology of neuroticism has been studied using large-scale genome-wide association studies (GWAS) which have uncovered more than a hundred genomic loci that point towards genes and pathways involved in brain functioning[14,15]

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