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
23149448
TITLE
Multi-locus genome-wide association analysis supports the role of glutamatergic synaptic transmission in the etiology of major depressive disorder.
ABSTRACT
Major depressive disorder (MDD) is a common psychiatric illness characterized by low mood and loss of interest in pleasurable activities. Despite years of effort, recent genome-wide association studies (GWAS) have identified few susceptibility variants or genes that are robustly associated with MDD. Standard single-SNP (single nucleotide polymorphism)-based GWAS analysis typically has limited power to deal with the extensive heterogeneity and substantial polygenic contribution of individually weak genetic effects underlying the pathogenesis of MDD. Here, we report an alternative, gene-set-based association analysis of MDD in an effort to identify groups of biologically related genetic variants that are involved in the same molecular function or cellular processes and exhibit a significant level of aggregated association with MDD. In particular, we used a text-mining-based data analysis to prioritize candidate gene sets implicated in MDD and conducted a multi-locus association analysis to look for enriched signals of nominally associated MDD susceptibility loci within each of the gene sets. Our primary analysis is based on the meta-analysis of three large MDD GWAS data sets (total N=4346 cases and 4430 controls). After correction for multiple testing, we found that genes involved in glutamatergic synaptic neurotransmission were significantly associated with MDD (set-based association P=6.9 Ã? 10(-4)). This result is consistent with previous studies that support a role of the glutamatergic system in synaptic plasticity and MDD and support the potential utility of targeting glutamatergic neurotransmission in the treatment of MDD.
DATE PUBLISHED
2012
HISTORY
PUBSTATUS PUBSTATUSDATE
entrez 2012/11/15 06:00
pubmed 2012/11/15 06:00
medline 2013/05/02 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Lee PH Lee P H PH Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
Perlis RH Perlis R H RH
Jung JY Jung J-Y JY
Byrne EM Byrne E M EM
Rueckert E Rueckert E E
Siburian R Siburian R R
Haddad S Haddad S S
Mayerfeld CE Mayerfeld C E CE
Heath AC Heath A C AC
Pergadia ML Pergadia M L ML
Madden PA Madden P A F PA
Boomsma DI Boomsma D I DI
Penninx BW Penninx B W BW
Sklar P Sklar P P
Martin NG Martin N G NG
Wray NR Wray N R NR
Purcell SM Purcell S M SM
Smoller JW Smoller J W JW
INVESTIGATORS
JOURNAL
VOLUME: 2
ISSUE:
TITLE: Translational psychiatry
ISOABBREVIATION: Transl Psychiatry
YEAR: 2012
MONTH:
DAY:
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
Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GRANTID AGENCY COUNTRY
AA07535 NIAAA NIH HHS United States
AA10248 NIAAA NIH HHS United States
AA13320 NIAAA NIH HHS United States
AA13321 NIAAA NIH HHS United States
AA13326 NIAAA NIH HHS United States
AA14041 NIAAA NIH HHS United States
K05 AA017688 NIAAA NIH HHS United States
K24 MH094614 NIMH NIH HHS United States
MH-079799 NIMH NIH HHS United States
MH-094614 NIMH NIH HHS United States
MH66206 NIMH NIH HHS United States
N01 MH-90003 NIMH NIH HHS United States
NIMH MH086026 PHS HHS United States
R01 MH-072802 NIMH NIH HHS United States
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Depressive Disorder, Major genetics
Genetic Predisposition to Disease genetics
Genome-Wide Association Study genetics
Glutamic Acid metabolism
Humans metabolism
Synaptic Transmission physiology
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
3KX376GY7L Glutamic Acid
OTHER ID's
OTHERID SOURCE
PMC3565768 NLM
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