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#Post#: 25--------------------------------------------------
Schizophrenia and Bipolar Disorder Share Genetic Roots
DIR By: Bipolar Girl
Date: August 31, 2010, 4:29 pm
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Schizophrenia and Bipolar Disorder Share Genetic Roots
Chromosomal Hotspot of Immunity/Gene Expression Regulation
Implicated
A trio of genome-wide studies collectively the largest to date
has pinpointed a vast array of genetic variation that
cumulatively may account for at least one third of the genetic
risk for schizophrenia. One of the studies traced schizophrenia
and bipolar disorder, in part, to the same chromosomal
neighborhoods.
"These new results recommend a fresh look at our diagnostic
categories," said Thomas R. Insel, M.D., director of the
National Institute of Mental Health (NIMH), part of the National
Institutes of Health. "If some of the same genetic risks
underlie schizophrenia and bipolar disorder, perhaps these
disorders originate from some common vulnerability in brain
development."
Three schizophrenia genetics research consortia, each funded in
part by NIMH, report separately on their genome-wide association
studies online July 1, 2009, in the journal Nature. However, the
SGENE, International Schizophrenia (ISC) and Molecular Genetics
of Schizophrenia (MGS) consortia shared their results - making
possible meta-analyses of a combined sample totaling 8,014 cases
and 19,090 controls.
All three studies implicate an area of Chromosome 6 (6p22.1),
which is known to harbor genes involved in immunity and
controlling how and when genes turn on and off. This hotspot of
association might help to explain how environmental factors
affect risk for schizophrenia. For example, there are hints of
autoimmune involvement in schizophrenia, such as evidence that
offspring of mothers with influenza while pregnant have a higher
risk of developing the illness.
"Our study was unique in employing a new way of detecting the
molecular signatures of genetic variations with very small
effects on potential schizophrenia risk," explained Pamela
Sklar, M.D., Ph.D., of Harvard University and the Stanley Center
for Psychiatric Research, who co-led the ISC team with Harvard's
Shaun Purcell, Ph.D.
"Individually, these common variants' effects do not all rise to
statistical significance, but cumulatively they play a major
role, accounting for at least one third and probably much more
of disease risk," said Purcell.
Among sites showing the strongest associations with
schizophrenia was a suspect area on Chromosome 22 and more than
450 variations in the suspect area on Chromosome 6. Statistical
simulations confirmed that the findings could not have been
accounted for by a handful of common gene variants with large
effect or just rare variants. This involvement of many common
gene variants suggests that schizophrenia in different people
might ultimately be traceable to distinct disease processes, say
the researchers.
"There was substantial overlap in the genetic risk for
schizophrenia and bipolar disorder that was specific to mental
disorders," added Sklar. "We saw no association between the
suspect gene variants and half a dozen common non-psychiatric
disorders."
Still, most of the genetic contribution to schizophrenia, which
is estimated to be at least 70 percent heritable, remains
unknown.
"Until this discovery, we could explain just a few percent of
this contribution; now we have more than 30 percent accounted
for," said Thomas Lehner, Ph.D., MPH, chief of NIMH's Genomics
Research Branch. "The new findings tell us that many of these
secrets have been hidden in complex neural networks, providing
hints about where to look for the still elusive and
substantial remaining genetic contribution."
The MGS consortium pinpointed an association between
schizophrenia and genes in the Chromosome 6 region that code for
cellular components that control when genes turn on and off. For
example, one of the strongest associations was seen in the
vicinity of genes for proteins called histones that slap a
molecular clamp on a gene's turning on in response to the
environment. Genetically rooted variation in the functioning of
such regulatory mechanisms could help to explain the
environmental component repeatedly implicated in schizophrenia
risk.
The MGS study also found an association between schizophrenia
and a genetic variation on Chromosome 1 (1p22.1) which has been
implicated in multiple sclerosis, an autoimmune disorder.
"Our study results spotlight the importance not only of genes,
but also the little-known DNA sequences between genes that
control their expression," said Pablo Gejman, M.D., of the
NorthShore University HealthSystem Research Institute, of
Evanston, ILL, who led the MGS consortium team. "Advances in
biotechnology, statistics, population genetics, and psychiatry,
in combination with the ability to recruit large samples, made
the new findings possible."
The SGENE consortium study pinpointed a site of variation in the
suspect Chromosome 6 region that could implicate processes
related to immunity and infection. It also found significant
evidence of association with variation on Chromosomes 11 and 18
that could help account for the thinking and memory deficits of
schizophrenia.
The new findings could eventually lead to multi-gene signatures
or biomarkers for severe mental disorders. As more is learned
about the implicated gene pathways, it may be possible to sort
out what's shared by, or unique to, schizophrenia and bipolar
disorder, the researchers say.
Schizophrenia/bipolar disorder genetic overlap
Schizophrenia and bipolar disorder share genetic roots that
appear to be specific to serious mental disorders, and are not
shared by non-psychiatric illnesses. Bars representing different
study samples show that the same genetic variations that account
for risk in both mental disorders account for virtually none of
the risk for coronary artery disease (CAD), Crohn's disease
(CD), hypertension (HT), rheumatoid arthritis (RA), or Type 1
(T1D) or Type 2 (T2D) diabetes.
Source: Psychiatric and Neurodevelopmental Genetics Unit, Center
for Human Genetic Research, Harvard University.
References
Jianxin S, et al. Common variants on chromosome 6p22.1 are
associated with schizophrenia. July 1, 2009, Nature
Stefansson H, et al. Common variants conferring risk of
schizophrenia. July 1, 2009, Nature
Purcell SM, et al. Common polygenic variation contributes to
risk of schizophrenia that overlaps with bipolar disorder. July
1, 2009, Nature
###
The mission of the NIMH is to transform the understanding and
treatment of mental illnesses through basic and clinical
research, paving the way for prevention, recovery and cure. For
more information, visit the NIMH website.
The National Institutes of Health (NIH) The Nations 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 the NIH website.
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