Researchers using a new approach to identifying
genes associated with depression have found that
variants in a group of genes involved in
transmission of signals by the neurotransmitter
glutamate appear to increase the risk of depression.
The report published in the journal Translational
Psychiatry suggests that drugs targeting the
glutamate system may help improve the limited
success of treatment with current antidepressant
drugs.
"Instead of looking at DNA variations one at a time,
we looked at grouping of genes in the same
biological pathways and found that a set of genes
involved in glutamatergic transmisson was associated
with the risk of depression," says Jordan Smoller,
MD, ScD, director of the Psychiatric and
Neurodevelopmental Genetics Unit in the
Massachusetts General Hospital (MGH) Department of
Psychiatry, senior author of the study.
"Our findings are particularly interesting in light
of recent studies showing that drugs affecting
glutamate transmission can have rapid antidepressant
effects."
While the risk of depression clearly runs in
families, the genome-wide association studies
typically used to identify gene variants that
increase disease risk have been unable to find
strongly associated genes.
The research team – which includes investigators
from the Broad Institute of MIT and Harvard and
other research centers in the U.S., Australia and
the Netherlands – adopted a strategy called gene set
pathway analysis.
Starting with a set of genes that previous studies
had implicated in depression, they used an analysis
process called text mining to scan the medical
literature for information on the biological
function of these genes.
Based on those findings, they identified 178
biological pathways that included these genes. Only
one of those pathways – the one involved in
transmission of neural signals carried by glutamate
– was significantly associated with the risk for
depression.
"Glutamate is the excitatory transmitter most widely
used by the central nervous system, and several
studies in animals and humans have suggested that it
may play a role in depression," explains Smoller, an
associate professor of Psychiatry at Harvard Medical
School.
"Most intriguingly, recent studies have found that
ketamine – a drug known to block one glutamate
receptor – appears to have antidepressant effects
that are much faster than those of traditional
antidepressants, which can take several weeks to
become effective.
Now additional research needs to confirm these
findings and investigate exactly how variation in
glutamate function affects brain systems involved in
depression."
Phil Hyoun Lee, PhD, of the MGH Psychiatric and
Neurodevelopmental Genetics Unit (PNGU) is lead
author of the Translational Psychiatry report.
Additional co-authors are Roy Perlis, MD, Richie
Siburian, Stephen Haddad, MS, Catherine Mayerfeld,
and Shaun Purcell, PhD, MGH PNGU; Erroll Rueckert,
PhD, MGH Center for Human Genetic Research; Jae-Yoon
Jung, PhD, Harvard Medical School; Enda Byrne, PhD,
Naomi Wray, PhD, and Nicholas Martin, PhD,
Queensland Institute of Medical Research, Australia;
Andrew Heath, DPhil, Michele Pergadia, PhD, and
Pamela Madden, PhD, Washington University, St.
Louis; Dorret Boomsma, PhD, and B.W. Penninx, PhD,
VU University, Amsterdam, The Netherlands; and
Pamela Sklar, MD, PhD, Mount Sinai School of
Medicine, New York. Lee, Perlis, Rueckert, Purcell
and Smoller are also affiliated with the Broad
Institute. The study was supported by grants from
the National Institute of Mental Health.
See also
Depression: genetic switch involved (19/09/2012)
Link...
For more information
Multi-locus genome-wide association analysis
supports the role of glutamatergic synaptic
transmission in the etiology of major depressive
disorder
Link...
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