University of Oulu

Cattaneo, A., Cattane, N., Malpighi, C., Czamara, D., Suarez, A., Mariani, N., … Pariante, C. M. (2018). FoxO1, A2M, and TGF-β1: three novel genes predicting depression in gene X environment interactions are identified using cross-species and cross-tissues transcriptomic and miRNomic analyses. Molecular Psychiatry, 23(11), 2192–2208.

FoxO1, A2M, and TGF-β1 : three novel genes predicting depression in gene X environment interactions are identified using cross-species and cross-tissues transcriptomic and miRNomic analyses

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Author: Cattaneo, Annamaria1,2; Cattane, Nadia2; Malpighi, Chiara2;
Organizations: 1Stress, Psychiatry and Immunology Laboratory, Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College, London, UK
2Biological Psychiatry Unit, IRCCS Fatebenefratelli S. Giovanni di Dio, Brescia, Italy
3Department of Translational Research in Psychiatry, Max-Planck Institute of Psychiatry, Munich, Germany
4Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland
5National Institute for Health and Welfare, Helsinki, Finland
6Folkhälsan Research Centre, Helsinki, Finland
7Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
8Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
9Hospital for Children and Adolescents, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
10PEDEGO Research Unit, Oulu University Hospital and University of Oulu, Oulu, Finland
11Helsinki Collegium for Advanced Studies, Helsinki, Finland
12Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
13Department of Psychiatry & Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.9 MB)
Persistent link:
Language: English
Published: Springer Nature, 2018
Publish Date: 2019-09-20


To date, gene-environment (GxE) interaction studies in depression have been limited to hypothesis-based candidate genes, since genome-wide (GWAS)-based GxE interaction studies would require enormous datasets with genetics, environmental, and clinical variables. We used a novel, cross-species and cross-tissues “omics” approach to identify genes predicting depression in response to stress in GxE interactions. We integrated the transcriptome and miRNome profiles from the hippocampus of adult rats exposed to prenatal stress (PNS) with transcriptome data obtained from blood mRNA of adult humans exposed to early life trauma, using a stringent statistical analyses pathway. Network analysis of the integrated gene lists identified the Forkhead box protein O1 (FoxO1), Alpha-2-Macroglobulin (A2M), and Transforming Growth Factor Beta 1 (TGF-β1) as candidates to be tested for GxE interactions, in two GWAS samples of adults either with a range of childhood traumatic experiences (Grady Study Project, Atlanta, USA) or with separation from parents in childhood only (Helsinki Birth Cohort Study, Finland). After correction for multiple testing, a meta-analysis across both samples confirmed six FoxO1 SNPs showing significant GxE interactions with early life emotional stress in predicting depressive symptoms. Moreover, in vitro experiments in a human hippocampal progenitor cell line confirmed a functional role of FoxO1 in stress responsivity. In secondary analyses, A2M and TGF-β1 showed significant GxE interactions with emotional, physical, and sexual abuse in the Grady Study. We therefore provide a successful ‘hypothesis-free’ approach for the identification and prioritization of candidate genes for GxE interaction studies that can be investigated in GWAS datasets.

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Series: Molecular psychiatry
ISSN: 1359-4184
ISSN-E: 1476-5578
ISSN-L: 1359-4184
Volume: 23
Issue: 11
Pages: 2192 - 2208
DOI: 10.1038/s41380-017-0002-4
Type of Publication: A1 Journal article – refereed
Field of Science: 3142 Public health care science, environmental and occupational health
Funding: Professor C.M.P. has received research funding from Johnson & Johnson as part of a program of research on depression and inflammation. In addition, Professor C.M.P. has received research funding from the Medical Research Council (UK) and the Wellcome Trust for research on depression and inflammation as part of two large consortia that also include Johnson & Johnson, GSK, Pfizer and Lundbeck. Prof. M.A.R. has received compensation as speaker/consultant for Lundbeck, Otzuka, Sumitomo Dainippon Pharma and Sunovion, and he has received research grants from Lundbeck, Sumitomo Dainippon Pharma and Sunovion, although none of these had a role in the present study. The remaining authors declare that they have no conflict of interest.
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