Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
30877270
TITLE
Using genetic drug-target networks to develop new drug hypotheses for major depressive disorder.
ABSTRACT
The major depressive disorder (MDD) working group of the Psychiatric Genomics Consortium (PGC) has published a genome-wide association study (GWAS) for MDD in 130,664 cases, identifying 44 risk variants. We used these results to investigate potential drug targets and repurposing opportunities. We built easily interpretable bipartite drug-target networks integrating interactions between drugs and their targets, genome-wide association statistics, and genetically predicted expression levels in different tissues, using the online tool Drug Targetor ( drugtargetor.com ). We also investigated drug-target relationships that could be impacting MDD. MAGMA was used to perform pathway analyses and S-PrediXcan to investigate the directionality of tissue-specific expression levels in patients vs. controls. Outside the major histocompatibility complex (MHC) region, 153 protein-coding genes are significantly associated with MDD in MAGMA after multiple testing correction; among these, five are predicted to be down or upregulated in brain regions and 24 are known druggable genes. Several drug classes were significantly enriched, including monoamine reuptake inhibitors, sex hormones, antipsychotics, and antihistamines, indicating an effect on MDD and potential repurposing opportunities. These findings not only require validation in model systems and clinical examination, but also show that GWAS may become a rich source of new therapeutic hypotheses for MDD and other psychiatric disorders that need new-and better-treatment options.
DATE PUBLISHED
2019 03 15
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2018/06/05
accepted 2019/02/12
revised 2019/01/28
entrez 2019/03/17 06:00
pubmed 2019/03/17 06:00
medline 2020/01/10 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Gaspar HA Gaspar Héléna A HA National Institute for Health Research Biomedical Research Centre, South London and Maudsley National Health Service Trust, London, EC1V 2PD, UK. helena.gaspar@kcl.ac.uk.
Gerring Z Gerring Zachary Z Translational Neurogenomics Laboratory, QIMR Berghofer Institute of Medical Research, Brisbane City, QLD 4006, Australia.
Hübel C Hübel Christopher C Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
Middeldorp CM Middeldorp Christel M CM Biological Psychology, Vrije Universiteit Amsterdam, 1081 HV, Amsterdam, Netherlands.
Derks EM Derks Eske M EM Translational Neurogenomics Laboratory, QIMR Berghofer Institute of Medical Research, Brisbane City, QLD 4006, Australia.
Breen G Breen Gerome G National Institute for Health Research Biomedical Research Centre, South London and Maudsley National Health Service Trust, London, EC1V 2PD, UK.
INVESTIGATORS
JOURNAL
VOLUME: 9
ISSUE: 1
TITLE: Translational psychiatry
ISOABBREVIATION: Transl Psychiatry
YEAR: 2019
MONTH: 03
DAY: 15
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 2158-3188
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Transl Psychiatry
COUNTRY: United States
ISSNLINKING: 2158-3188
NLMUNIQUEID: 101562664
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
GRANTS
GRANTID AGENCY COUNTRY
U01 MH109536 NIMH NIH HHS United States
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Antipsychotic Agents therapeutic use
Brain metabolism
Case-Control Studies metabolism
Depressive Disorder, Major genetics
Drug Delivery Systems genetics
Drug Discovery methods
Gene Regulatory Networks methods
Genome-Wide Association Study methods
Humans methods
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 Antipsychotic Agents
OTHER ID's