Largest Study of Its Kind Implicates
Gene Abnormalities in Bipolar Disorder
Links Sodium, Calcium Imbalances to Manic Depressive
The largest genetic analysis of its kind to date for bipolar
has implicated machinery involved in the balance of sodium and
calcium in brain cells. Researchers supported in part by the
National Institute of Mental Health, part of the National Institutes
of Health, found an association between the disorder and variation
in two genes that make components of channels that manage the
flow of the elements into and out of cells, including neurons.
"A neuron’s excitability — whether it will fire — hinges
on this delicate equilibrium,"explained Pamela Sklar, M.D.,
Ph.D., of Massachusetts General Hospital (MGH) and the Stanley
Center for Psychiatric Research at the Broad Institute of MIT and
Harvard, who led the research. "Finding statistically robust
associations linked to two proteins that may be involved in regulating
such ion channels — and that are also thought to be targets
of drugs used to clinically to treat bipolar disorder — is
Although it’s not yet known if or how the suspect genetic variation
might affect the balance machinery, the results point to the possibility
that bipolar disorder might stem, at least in part, from malfunction
of ion channels.
Sklar, Shaun Purcell, Ph.D., also of MGH and the Stanley Center,
and Nick Craddock, M.D., Ph.D., of Cardiff University and the Wellcome
Trust Case Control Consortiuum in the United Kingdom and a large
group of international collaborators report on their findings online
Aug. 17 , 2008 in Nature Genetics.
"Faced with little agreement among previous studies searching
for the genomic hot spots in bipolar disorder, these researchers
pooled their data for maximal statistical power and unearthed surprising
results," said NIMH Director Thomas R. Insel, M.D. "Improved
understanding of these abnormalities could lead to new hope for
the millions of Americans affected by bipolar disorder."
In the first (http://www.nimh.nih.gov/science-news/2007/genetic-roots-of-bipolar-disorder-revealed-by-first-genome-wide-study-of-illness.shtml)
such genome-wide association
for bipolar disorder, NIMH researchers last fall reported the strongest
signal associated with the illness in a gene that makes an enzyme
involved the action of the anti-manic medication lithium. However,
other chromosomal locations were most strongly associated with
the disorder in two subsequent studies.
Since bipolar disorder is thought to involve many different gene
variants, each exerting relatively small effects, researchers need
large samples to detect relatively weak signals of illness association.
To boost their odds, Sklar and colleagues pooled data from the
latter two previously published and one new study of their own.
They also added additional samples from the STEP-BD (http://www.nimh.nih.gov/health/trials/practical/step-bd/index.shtml)
study and Scottish and Irish families, and controls from the NIMH
Genetics Repository (http://nimhgenetics.org/).
After examining about 1.8 million sites of genetic variation in
10,596 people — including 4,387 with bipolar disorder — the
researchers found the two genes showing the strongest association
among 14 disorder-associated chromosomal regions.
Variation in a gene called Ankyrin 3 (ANK3) showed the strongest
association with bipolar disorder. The ANK3 protein is strategically
located in the first part of neuronal extensions called axons and
is part of the cellular machinery that decides whether a neuron
will fire. Co-authors of the paper had shown last year in mouse
brain that lithium, the most common medication for preventing bipolar
disorder episodes, reduces expression of ANK3.
Variation in a calcium channel gene found in the brain showed
the second strongest association with bipolar disorder. This CACNA1C
protein similarly regulates the influx and outflow of calcium and
is the site of interaction for a hypertension medication that has
also been used in the treatment of bipolar disorder.
In addition to NIMH, the research was also funded by NARSAD (National
Alliance for Research on Schizophrenia and Depression), the Wellcome
Trust, Johnson & Johnson Pharmaceutical Research & Development,
the Johnson & Johnson Foundation, the Sylvan C. Herman Foundation,
the Stanley Medical Research Institute, the Dauten Family, the
Merck Genome Research Institute, and the National Health and Medical
Research Council of Australia.
The Genetics of Schizophrenia and Bipolar
Pamela Sklar, M.D., Ph.D., Massachusetts General Hospital (MGH)
and the Stanley Center for Psychiatric Research at the Broad Institute.
NIH Neuroscience Seminar Series
Dr. Sklar discusses her recent findings on the genetics of schizophrenia
and bipolar disorder.
Monday, March 17, 2008, 12:00:00 PM
Requires RealPlayer http://www.real.com/freeplayer/?rppr=fed
How to download a Videocast: http://videocast.nih.gov/launch.asp?14362
The National Institute of Mental Health (NIMH) mission is to reduce
the burden of mental and behavioral disorders through research
on mind, brain, and behavior. More information is available at
the NIMH website, http://www.nimh.nih.gov.
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Medical Research Agency — includes 27 Institutes and Centers
and is a component of the U.S. Department of Health and Human Services.
It is the primary federal agency for conducting and supporting basic,
clinical and translational medical research, and it investigates
the causes, treatments, and cures for both common and rare diseases.
For more information about NIH and its programs, visit www.nih.gov.
Reference: Ferreira MAR ,
association analysis of 10,596 individuals supports a role for Ankyrin-G
(ANK) and the alpha-C subunit of the L-type voltage-gated calcium
channel (CACNAC) in bipolar disorder. Nat Genet. 2008 Aug
17. [Epub ahead of print]