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Same Genes Suspected in Both Depression and Bipolar Illness
DIR By: Bipolar Girl
Date: August 31, 2010, 4:19 pm
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Same Genes Suspected in Both Depression and Bipolar Illness
Increased Risk May Stem From Variation in Gene On/Off Switch
Researchers, for the first time, have pinpointed a genetic
hotspot that confers risk for both bipolar disorder and
depression. People with either of these mood disorders were
significantly more likely to have risk versions of genes at this
site than healthy controls. One of the genes, which codes for
part of a cell's machinery that tells genes when to turn on and
off, was also found to be over-expressed in the executive hub of
bipolar patients' brains, making it a prime suspect. The results
add to mounting evidence that major mental disorders overlap at
the molecular level.
"People who carry the risk versions may differ in some dimension
of brain development that may increase risk for mood disorders
later in life," explained Francis McMahon, M.D., of the NIMH
Mood and Anxiety Disorders Program, who led the study.
McMahon and an international team of investigators, supported,
in part by NIMH, report on the findings of their genome-wide
meta-analysis online January 17, 2010 in the journal Nature
Genetics.
Background
Major mood disorders affect 20 percent of the population and are
among the leading causes of disability worldwide. It's long been
known that bipolar disorder and unipolar depression often run
together in the same families, hinting at some shared lineage.
Yet, until now, no common genes or chromosomal locations had
been identified.
McMahon and colleagues analyzed data from five different
genome-wide association studies (GWAS) totaling more than 13,600
people, and confirmed their results in 3 additional independent
samples totaling 4,677 people.
Findings of This Study
Genetic variations on Chromosome 3 were significantly associated
with both mood disorders. The suspect gene, called PBRM1, codes
for a protein critical for chromatin remodeling, a key process
in regulating gene expression. A neighboring gene is involved in
the proliferation of brain stem cells.
The researchers pinpointed a "protective" version of the PBRM1
gene that is carried by 41 percent of healthy controls, but only
38 percent of people with bipolar and unipolar depression. The
risk version was found in 62 percent of mood disorder cases and
59 percent of controls. The researchers also showed that PBRM1
is expressed more in the prefrontal cortex of people with
bipolar disorder than in controls.
Significance
Since mood disorders likely involve altered gene expression
during brain development and in response to stress, PBRM1's
profile makes it a good potential candidate gene. This first
genetic evidence of unipolar/bipolar overlap is also the first
significant genome-wide association with any psychiatric illness
in the Chromosome 3p region.
However, the findings underscore limitations of the GWAS
approach, which looks for connections to gene versions that are
common in the population. Having one copy of this risk variant
increases vulnerability for developing a mood disorder by a
modest 15 percent. Why do some people with this variant — and
presumably other, yet to be discovered, shared risk genes —
develop bipolar disorder while others develop unipolar
depression or remain healthy? Environmental influences and
epigenetic factors may be involved, suggest the researchers, who
note that "genetic association findings so far seem to account
for little of the inherited risk for mood disorders."
"Our results support the growing view that there aren't common
genes with large effects that confer increased risk for mood
disorders," said McMahon. "If there were, in this largest sample
to date, we would have found them. The disorders likely involve
many genes with small effects — and different genes in different
families — complicating the search. Rarer genes with large
effects may also exist."
What's Next?
Ultimately, findings such as these may lead to identification of
common biological pathways that may play a role in both unipolar
and bipolar illness and suggest strategies for better treatment,
said McMahon. The results add to other evidence of overlap that
is spurring a new NIMH initiative to make sense of research
findings that don't fit neatly into current diagnostic
categories. See: Genes and Circuitry, Not Just Clinical
Observation, to Guide Classification for Research.
depression and bipolar disorder in same family
Bipolar disorder and unipolar depression often run in the same
families, as this pedigree diagram illustrates. The new study is
the first to trace both illnesses to a shared chromosomal
hotspot.
Source: NIMH Genetics Initiative Bipolar Disorder Consortium
Reference
Meta-analysis of genome-wide association data identifies a risk
locus for major mood disorders on 3p21.1.the Bipolar Disorder
Genome Study (BiGS) Consortium, McMahon FJ, Akula N, Schulze TG,
Muglia P, Tozzi F, Detera-Wadleigh SD, Steele CJ, Breuer R,
Strohmaier J, Wendland JR, Mattheisen M, Mühleisen TW, Maier W,
Nöthen MM, Cichon S, Farmer A, Vincent JB, Holsboer F, Preisig
M, Rietschel M. Nat Genet. 2010 Jan 17. [Epub ahead of
print]PMID: 20081856
Samples included in the meta-analysis:
dbGaP National Institute of Mental Health bipolar disorder
Genetic Association Information Network MDD
Wellcome Trust Case Control Consortium
German sample
Systematic Treatment Enhancement Program for Bipolar Disorder
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