Genes & Cells
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New studies link schizophrenia risk
to thousands of common variants
Specific chromosome regions may play role in the disease
By Laura Sanders
Large collections of common genetic
variants, rather than just the harmful
actions of a few key mutations, probably predispose people to schizophrenia,
three large genetic studies suggest.
The studies, all published online July 1
in Nature, sifted through genetic data
from patients with schizophrenia and
people without the disease looking for
spelling differences in the sequence of
DNA “letters” making up the genome.
The studies turned up specific chromosome regions that probably play a role in
the disease. Understanding genetic factors, estimated to account for 80 percent
of the risk of getting schizophrenia, may
ultimately lead to better treatments.
“This is a pretty major breakthrough
for us,” said Michael O’Donovan of Cardiff
University’s School of Medicine in Wales
at a July 1 press briefing. O’Donovan, who
coauthored one of the studies as part of
the International Schizophrenia Consortium, says a person with schizophrenia
probably has hundreds or thousands of
risk-increasing variants.
Using a method called genome-wide
association, each of the three studies
compared DNA samples from several
thousand people diagnosed with schizophrenia with samples from thousands of
others, some healthy and some with other
diseases. Association studies are designed
to find single letter differences, called
SNPs, at many points along the DNA.
Variants popping up more frequently
in the schizophrenia patients’ DNA are
presumed to be markers of regions of the
genome that contribute to the disease.
Many thousands of common DNA
variants (those found in about 5 percent
of the total population) turned up more
often in people with schizophrenia, the
studies found. “This is the first empirical DNA-based evidence” for many small
genetic effects adding up to schizophrenia, says Pamela Sklar of Massachusetts
General Hospital and Harvard University,
who coauthored the consortium study.
On their own, each variant identified in the new studies raises the risk
of schizophrenia just slightly —from
1 percent (the risk in the general population) to, in some cases, around 1. 2 percent. Collectively, common variants may
account for about a third of the genetic
risk, Sklar says. Other factors include
variations in the number of copies of
certain genes and rare but high-risk variants of specific DNA letters.
Researchers will need many more
DNA samples to identify all the genetic
variants that heighten risk, Sklar says.
Although few of the variants could be
identified conclusively by these studies,
some variants were found in stretches
of chromosomes previously linked to
schizophrenia. Such regions occurred
near genes involved in the formation of
brain cell connections and genes involved
in controlling the activity of other genes.
“The interesting thing about taking
these together is that we start to identify pathways involved in the disease,”
David Collier of King’s College London,
a coauthor of the second paper, said in
the briefing. Such pathways could point
to potential therapeutic interventions.
DNA variations in a region of chromosome 6 called the major histocompat-ibility complex were also found in the
schizophrenia patients’ DNA in all three
studies. This region contains genes that
make proteins important for immune
system function. Earlier studies have
suggested a link between disruptions in
the immune system and a heightened
risk of schizophrenia.
“It’s extremely provocative to have an
association there,” says Pablo Gejman,
a psychiatric geneticist at NorthShore
University HealthSystem Research
Institute in Evanston, Ill., and coauthor
of the third study. “This is the start. This
is not the last chapter.”
Limb doesn’t regrow from scratch
Given a chance to regrow a limb, salamanders don’t change a thing, a study
in the July 2 Nature finds. Scientists had
thought that in axolotls, a type of salamander, some stem cells at amputation
sites became pluripotent, giving rise to
all new tissues in a generated limb. Now
Elly Tanaka of the Dresden University of
Technology in Germany and colleagues
show that cells at the wound site retain
their identity and replicate into the same
cell types in the new limb. Scientists used green fluorescent protein to track the origins of the new growth in a regenerated axolotl leg (shown). Schwann cells in the new
limb arose from Schwann cells in the original tissue. “Definitely it’s putting the conventional wisdom upside-down,” says Alejandro Sánchez Alvarado, a Howard Hughes Medical Institute investigator at the University of Utah School of Medicine in Salt Lake City.
This gives scientists hope that human cells remaining at an amputation site could
someday be coaxed into generating a new limb, Tanaka says. — Tina Hesman Saey
DUNJA KNApp, E. TANAKA
10 | SCIENCE NEWS | August 1, 2009
