Two Studies Clarify the Genetic
Disruptions in Schizophrenia
by Jeremy Cherfas
Biology
Top Ten Papers
Rank
Papers
Cites
Mar-Apr 09
Rank
Jan-Feb 09
1
K. Takahashi, et al.,
"Induction of pluripotent
stem cells from adult human
fibroblasts by defined factors,"
Cell, 131(5): 861-72, 30
November 2007. [Kyoto U., Japan; CREST,
Kawaguchi, Japan; Gladstone Inst.
Cardio. Dis., San Francisco, CA] *243MG
88
2
2
Intl. HapMap Consortium (K.A. Frazer,
et al.), "A second generation
human haplotype map of over 3.1 million
SNPs," Nature, 449(7164):
854-61, 18 October 2007. [72
institutions worldwide] *221LY
62
1
3
The ENCODE Project Consortium (E.
Birney, et al.),
"Identification and analysis of
functional elements in 1% of the human
genome by the ENCODE pilot project,"
Nature, 447(7146): 799-816, 14
June 2007. [80 institutions worldwide]
*178FV
55
†
4
A. Barski, et al.,
"High-resolution profiling of histone
methylations in the human genome,"
Cell, 129(4): 823-37, 18 May
2007. [NHLBI, NIH, Bethesda, MD; U.
Calif., Los Angeles] *172FA
54
4
5
V. Cherezov, et al.,
"High-resolution crystal structure of
an engineered human
beta2-adrenergic G
protein-coupled receptor,"
Science, 318(5854): 1258-65,
23 November 2007. [Scripps Res. Inst.,
La Jolla, CA; Stanford U., CA] *233JG
40
5
6
E. Zeggini, et al.,
"Meta-analysis of genome-wide
association data and large-scale
replication identifies additional
susceptibility loci for type 2
diabetes," Nature
Genetics, 40(5): 638-45, May 2008.
[5 U.S. and U.K. institutions] *293WS
39
†
7
T. Walsh, et al., "Rare
structural variants disrupt multiple
genes in neurodevelopmental pathways in
schizophrenia," Science,
320(5875): 539-43, 25 April 2008. [9
U.S. institutions] *292EM
39
†
8
D.F. Easton, et al.,
"Genome-wide association study
identifies novel
breast cancer
susceptibility loci,"
Nature, 447(7148):
1087-93, 28 June 2007. [87
institutions worldwide] *183HT
38
4
9
M. Wernig, et al., "In
vitro reprogramming of fibroblasts
into a pluripotent ES-cell-like state,"
Nature, 448(7151): 318-24, 19
July 2007. [5 U.S. institutions] *191GC
37
6
10
J.A. Todd, et al., "Robust
associations of four new chromosome
regions from genome-wide analyses of
type 1 diabetes," Nature
Genetics, 39(7): 857-64, July
2007. [7 institutions worldwide] *184CX
Schizophrenia typically afflicts around 1% of
the general population, and although it runs in families, the
inheritance pattern, like the illness itself, is complex. Early
claims to have identified a schizophrenia gene were fraught with
difficulties of interpretation and replicability. Now, two recent
papers shed light on why a schizophrenia gene has proved so elusive
and, more importantly, on the true genetic basis of the disease.
Large teams, one led by Jon McClellan at the University of Washington
in Seattle (paper #7) and the other by David St Clair of the University
of Aberdeen in Scotland and Kari Stefansson of deCODE genetics in
Iceland (H. Stefansson, et al., Nature, 455[7210]:
232-7, 2008; currently ranked at #14, with 32 citations this period and
58 total), have shown that copy number variants (CNVs)—relatively
large deletions and duplications that may disrupt the functioning of
several genes—are common in patients with schizophrenia but not
in their unaffected relatives or non-sufferers. McClellan’s group
started by comparing schizophrenics with controls, while the others
looked for new mutations and then asked whether they were more
prevalent in schizophrenics.
Image by Paul Thompson,
Christine Vidal, Judy Rapoport, and
Arthur Toga.
The Washington group scanned the DNA of 418 people—150 of whom
had been diagnosed with schizophrenia or similar psychiatric
illnesses—using the increasingly powerful and widespread tool of
microarray analysis to look for variant DNA patterns associated with
disease. (See also, for example, the discussion of autism and other
conditions in the previous Biology Top Ten commentary,
July-August 2009).
Among the variants were 53 mutations that were by definition rare; they
had not previously been reported in the literature. Not all of these
variants changed the functioning of genes, of course, but of those that
did, cases with schizophrenia were three times more likely to have one
than unaffected controls. And cases that showed symptoms early, at less
than 18 years of age, were four times more likely than controls to have
a rare variant. Rare mutations that did not affect function were
equally common in cases and controls.
The group went on to look for the rare variants in an independent group
of severely affected cases with childhood onset schizophrenia,
comparing their DNA with that of their parents. The same pattern
emerged.
St Clair and Stefansson’s team reasoned that the reduced
fecundity associated with severe mental illness is continually
selecting against the underlying mutations, which is why the variants
are rare. So they screened almost 10,000 trios (two parents and a
child) and parent-child pairs, looking for CNVs present in children but
not their parents. This picked up 66 novel variants, which were then
sought in 1,433 schizophrenia cases and 33,250 unrelated controls.
Eight of the 66 were found in at least one schizophrenia patient, and
three were statistically associated with the disease. Six other sets of
patients and controls showed essentially similar results. The three
mutations are between 2.5 and 10 times more common in cases than
controls.
What of the genes that these mutations disrupt? The Washington group
asked whether particular functional classes of genes were
over-represented in the sample. The affected genes in schizophrenia
cases did indeed over-represent pathways that are clearly important for
brain development, including systems that regulate the growth of nerve
axons and others related to specific neurotransmitters. By contrast,
genes disrupted in the controls were not from any particular functional
pathways.
The St Clair and deCODE group also examined the specific genes in the
CNVs that they identified, and came up with very similar results. One
deletion contains a gene associated with outgrowths that connect nerves
and is also important in the maintenance of neuronal structures.
Another deletion contains a gene associated with working memory.
One of the fascinating aspects of the studies is that the symptoms
associated with the rare CNVs are not limited to those associated with
schizophrenia, even though that was the target illness. For example, in
the deCODE study one of the controls who carried a deletion was
autistic but not schizophrenic, and others showed dyslexia.
This opens the prospect of a much more nuanced approach to mental
disorders with a genomic component. As the University of Washington
group reported, "Our design does not prove the involvement with the
illness of any specific variant or even the involvement of any specific
gene." It does, however, dispel any simplistic notion of a gene "for"
schizophrenia or any other complex mental illness. The CNVs identified
in both studies, exciting though they are, do not account for a very
large fraction of the genetic risk of schizophrenia. There must be many
other factors involved.
Both studies also, in a roundabout way, illustrate the robustness of
the development of the brain. Disruptions are indeed associated with
illness. But many individuals harbor these variants and yet show no
signs of abnormal function. There’s obviously a lot we still have
to learn.
Dr. Jeremy Cherfas is Science Writer at Bioversity
International in Rome, Italy.
KEYWORDS: SCHIZOPHRENIA, SCHIZOPHRENIA GENE, JON MCCLELLAN, DAVID ST
CLAIR, COPY NUMBER VARIANTS, CNVS, DECODE, KARI STEFANSSON, MICROARRAY
ANALYSIS.