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

Carmine Maria Pariante; Annamaria Cattaneo; Nadia Cattane; Chiara Malpighi; Darina Czamara; Nicole Mariani; Alessia  Luoni; Erik Johnsson; Valeria Mondelli; Paola Dazzan; Katri Raikkonen; Eero Kajantie; Marco Riva

doi:10.1038/s41380-017-0002-4

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

Carmine Maria Pariante, Annamaria Cattaneo, Nadia Cattane, Chiara Malpighi, Darina Czamara, Nicole Mariani, Alessia Luoni, Erik Johnsson, Valeria Mondelli, Paola Dazzan, Katri Raikkonen, Eero Kajantie, Marco Riva

Research output: Contribution to journal › Article › peer-review

74 Citations (Scopus)

165 Downloads (Pure)

Abstract

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.

Original language	English
Pages (from-to)	2192–2208
Journal	Molecular Psychiatry
Volume	23
Issue number	11
Early online date	4 Jan 2018
DOIs	https://doi.org/10.1038/s41380-017-0002-4
Publication status	Published - 1 Nov 2018

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41380-017-0002-4Licence: CC BY-NC-ND

FoxO1, A2M, and TGF-β1 three_CATTANEO_Acc16Oct2017Epub4Jan2018_GOLD VoR(CC BY)Final published version, 2.93 MBLicence: CC BY-NC-ND

Cite this

Pariante, C. M., Cattaneo, A., Cattane, N., Malpighi, C., Czamara, D., Mariani, N., Luoni, A., Johnsson, E., Mondelli, V., Dazzan, P., Raikkonen, K., Kajantie, E., & Riva, 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. https://doi.org/10.1038/s41380-017-0002-4

@article{2c3aafd5d9d94028b97a4ad5c5aebff6,

title = "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",

abstract = "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 {\textquoteleft}hypothesis-free{\textquoteright} approach for the identification and prioritization of candidate genes for GxE interaction studies that can be investigated in GWAS datasets.",

author = "Pariante, {Carmine Maria} and Annamaria Cattaneo and Nadia Cattane and Chiara Malpighi and Darina Czamara and Nicole Mariani and Alessia Luoni and Erik Johnsson and Valeria Mondelli and Paola Dazzan and Katri Raikkonen and Eero Kajantie and Marco Riva",

year = "2018",

month = nov,

day = "1",

doi = "10.1038/s41380-017-0002-4",

language = "English",

volume = "23",

pages = "2192–2208",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Springer Nature [academic journals on nature.com]",

number = "11",

}

Pariante, CM , Cattaneo, A, Cattane, N, Malpighi, C, Czamara, D, Mariani, N, Luoni, A, Johnsson, E, Mondelli, V , Dazzan, P, Raikkonen, K, Kajantie, E & Riva, 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, vol. 23, no. 11, pp. 2192–2208. https://doi.org/10.1038/s41380-017-0002-4

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. / Pariante, Carmine Maria ; Cattaneo, Annamaria; Cattane, Nadia et al.
In: Molecular Psychiatry, Vol. 23, No. 11, 01.11.2018, p. 2192–2208.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - FoxO1, A2M and TGF-β1

T2 - three novel genes predicting depression in gene X environment interactions are identified using cross-species and cross-tissues transcriptomic and miRNomic analyses

AU - Pariante, Carmine Maria

AU - Cattaneo, Annamaria

AU - Cattane, Nadia

AU - Malpighi, Chiara

AU - Czamara, Darina

AU - Mariani, Nicole

AU - Luoni, Alessia

AU - Johnsson, Erik

AU - Mondelli, Valeria

AU - Dazzan, Paola

AU - Raikkonen, Katri

AU - Kajantie, Eero

AU - Riva, Marco

PY - 2018/11/1

Y1 - 2018/11/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85040045279&partnerID=8YFLogxK

U2 - 10.1038/s41380-017-0002-4

DO - 10.1038/s41380-017-0002-4

M3 - Article

SN - 1359-4184

VL - 23

SP - 2192

EP - 2208

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 11

ER -

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

Abstract

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this