Genome-wide interaction study of a proxy for stress-sensitivity and its prediction of major depressive disorder
Year: 2018
Type: review
Study design: Observational Study
Abstract: Individual response to stress is correlated with neuroticism and is an important predictor of both neuroticism and the onset of major depressive disorder (MDD). Identification of the genetics underpinning individual differences in response to negative events (stress-sensitivity) may improve our understanding of the molecular pathways involved, and its association with stress-related illnesses. We sought to generate a proxy for stress-sensitivity through modelling the interaction between SNP allele and MDD status on neuroticism score in order to identify genetic variants that contribute to the higher neuroticism seen in individuals with a lifetime diagnosis of depression compared to unaffected individuals. Meta-analysis of genome-wide interaction studies (GWIS) in UK Biobank (N = 23,092) and Generation Scotland: Scottish Family Health Study (N = 7,155) identified no genome-wide significance SNP interactions. However, gene-based tests identified a genome-wide significant gene, ZNF366, a negative regulator of glucocorticoid receptor function implicated in alcohol dependence (p = 1.48x10-7; Bonferroni-corrected significance threshold p < 2.79x10-6). Using summary statistics from the stress-sensitivity term of the GWIS, SNP heritability for stress-sensitivity was estimated at 5.0%. In models fitting polygenic risk scores of both MDD and neuroticism derived from independent GWAS, we show that polygenic risk scores derived from the UK Biobank stress-sensitivity GWIS significantly improved the prediction of MDD in Generation Scotland. This study may improve interpretation of larger genome-wide association studies of MDD and other stress-related illnesses, and the understanding of the etiological mechanisms underpinning stress-sensitivity.
Source: PLoS ONE
Authors: Aleix Arnau-Soler, Mark J. Adams, Generation Scotland, Caroline Hayward, Pippa A. Thomson
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $1,549
Funders: Amgen, Pfizer, Brigham and Women's Hospital, Massachusetts General Hospital, University of Southern California, Kaiser Permanente, Massachusetts Institute of Technology, Emory University, F. Hoffmann-La Roche, Aarhus Universitet, Aarhus Universitetshospital, Johns Hopkins University, Universität Basel, Harvard T.H. Chan School of Public Health, Virginia Commonwealth University, Wellcome Trust, Deutsches Zentrum für Herz-Kreislaufforschung, Scottish Government, European Bioinformatics Institute, QIMR Berghofer Medical Research Institute, Broad Institute, National Institute for Health and Care Research, Scottish Funding Council, King's College London, University College London, University of Oxford, Newcastle University, University of Glasgow, Cardiff University, Trinity College Dublin, Universiteit Leiden, Rijksuniversiteit Groningen, James Cook University, Queensland University of Technology, University of Queensland, Vrije Universiteit Amsterdam, Albert-Ludwigs-Universität Freiburg, Dalhousie University, GGZ inGeest, Lundbeckfonden, University of Toronto, Università degli Studi di Trento, Karolinska Institutet, Westfälische Wilhelms-Universität Münster, Leids Universitair Medisch Centrum, Universitair Medisch Centrum Groningen, Rigshospitalet, Region Hovedstaden, Háskóli Íslands, Dokuz Eylül Üniversitesi, Universidad de Granada, Office of the Chief Scientist, Ministry of Health, Tartu Ülikool, Rheinische Friedrich-Wilhelms-Universität Bonn, H. Lundbeck A/S, Centre for Cognitive Ageing and Cognitive Epidemiology, School of Medicine, Emory University, University of North Carolina at Chapel Hill, University of California, San Diego, McDonnell Center for Systems Neuroscience, Stanley Center for Psychiatric Research, Broad Institute, Chief Scientist Office, Scottish Government Health and Social Care Directorate, Department of Psychiatry, University of Toronto, Medical Research Council, Menzies Centre for Australian Studies, King's College London, University of London, Queensland Brain Institute, Institute of Molecular and Cell Biology, Statens Serum Institut, Medizinische Fakultät der Albert-Ludwigs-Universität Freiburg, National Institute of Mental Health, National Institute on Drug Abuse, National Cancer Institute, Janssen Research and Development, Institute of Genetics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NHLBI Division of Intramural Research
Awards: UK Dementias Platform, G2437620908, G259633682, 1/7 Psychiatric Genomics Consortium: Finding actionable variation, UK Health Informatics Research Network, MICA: The Scottish eHealth Informatics Research Centre, Stratifying Resilience and Depression Longitudinally (STRADL), 3/7 Psychiatric Genomics Consortium: Finding actionable variation, G4524926127, HSM Polygenic score methodology in the emerging field of Polygenic Epidemiology, UK Biobank (core renewal), G5429586119, MRC Centre for Neuropsychiatric Genetics and Genomics, G5981938709, Quantitative Traits in Health and Disease, Stratifying Resilience and Depression Longitudinally (STRADL), G7304791810, 7/7 Psychiatric Genomics Consortium: Finding actionable variation
OpenAlex ID: W2904951921