Secondary Schizophrenia (117 page)

All STR and SNP marker positions are based on the NCBI Build 36 assembly of the human genome (November 2005).

Organic Syndromes of Schizophrenia – Section 3

genotypes include reduced hippocampal volume
[206,

DISC1 function
[232].
A recent network analysis of
211]
, reduced prefrontal grey-matter density
[206],

these studies implicates DISC1 in cell-cycle/division,
reduced cingulate grey-matter volume
[212],
and
cytoskeletal organization, and intracellular transport,
altered engagement of the hippocampus during cog-

incorporating 127 proteins and 158 interactions in a
nitive tasks assayed with functional MRI
[211].

“DISC1 interactome,” providing evidence that DISC1

may be an essential synaptic protein
[233].
More-Functional studies
over, DISC1 and DTNBP1 appear to share interac-

tions thus suggesting functional convergence of SZ

Expression studies: mRNA

candidate genes. Millar and colleagues
[234]
recently
As with many putative candidate genes, DISC1 is

reported a balanced translocation in two affected
transcriptionally complex with evident multiple alter-family members that disrupted the gene encod-

nate splicing events, antisense transcription, and intering phosphodiesterase 4B (PDE4B), which inacti-

genic splicing
[193].
DISC1 has eight coding tran-vates adenosine 3’,5’-monophosphate (cAMP), a sec-scripts, the longest containing 13 exons, a transcript
ond messenger implicated in learning, memory, and
length of 7,059 bp, and 854 amino acid (AA) residues
mood. It is proposed that DISC1 interacts with

(Figure 23.2)
[193,
219].
The translocation breakpoint
the UCR2 domain of PDE4B in a cAMP feedback
is located between exons 8 and 9 and may produce a
loop.

truncated protein via loss of 257 amino acids at the C-Thus, DISC1 illustrates a number of issues charac-terminus. SNP rs821616 is a major alternative splice
terizing most current candidate genes for SZ: (i) link-site and is responsible for an AA change from serine
age and association evidence is present for several psy-to leucine at codon 704 (Ser704Cys), with a deletion of
chiatric disorders including SZ, BP, and SA; (ii) multi-22 AAs from exon 11. This results in two of the eight
ple populations with variable ancestry have been stud-isoforms, DISC1ser and DISC1cys, which are widely
ied, with most but not all reporting positive findings;
expressed in the brain and other tissues. In the brain,
and (iii) the precise polymorphism(s) conferring risk
the dentate gyrus of the hippocampus has the highest
and their functional implications remain unknown;
DISC1 mRNA expression levels in adult mouse
[220]

most replication studies have been inconsistent with
and primate brains
[221].
DISC1 is conserved across
respect to the associated alleles, haplotypes, and con-primates, rodents, and fish, but it appears to have no
ferred risks. This may reflect the low a priori probabil-insect or worm homologue
[193,
222].

ity of directly genotyping a causal variant, combined
with population variation in LD patterns, such that dif-

Expression studies: protein

ferent alleles show association in different populations
Expression at the protein level is similarly complex,
[82].

with antibodies against several portions of DISC1

detecting a variety of protein products
[223, 224, 225,

226, 227, 228].
DISC1 expression occurs preferentially

in the forebrain (hippocampus, cerebral cortex, olfac-It is likely that most SZ susceptibility genes will be
tory bulbs) throughout life and is regulated devel-found to individually exert small to modest effect on
opmentally, with the highest expression in rat cor-overall disease risk (with the possible exception of the
tex occurring during late embryonic and postnatal
t(1:11), with an effect size the equivalent of MZ inher-stages
[223, 225],
suggesting DISC1 has a crucial role
itance). Thus, for any individual locus, its importance
in neurodevelopment and maturation
[229].
Subcellu-will lie not in its population-attributable risk (i.e. the
lar studies have revealed four major distribution sites:
proportion of disease that would be cured in the pop-

(i) microtubule-associated cytoskeletons and the cen-ulation if the allele were absent), but in contributing to
trosome
[225, 226, 228, 230];
(ii) mitochondria in pri-understanding the molecular mechanisms and path-

mary neurons
[225, 226, 227, 228];
(iii) post-synaptic
ways involved in disease
[235].
However, in combina-density of adult brains
[231]
; and (iv) the nucleus
tion with the discovery of other susceptibility loci and
[231].

environmental exposures, impending clinical implica-Protein interactors: Many yeast-2-hybrid screen-

tions could include molecular diagnosis and personal-ing studies have been conducted to further investigate
ized treatment.

Chapter 23 – The status of genetic investigations of schizophrenia

Molecular diagnosis

populations. In addition, recruiting smaller-sized samples from population isolates could make a valuable
The presence of risk alleles in an unaffected individ-contribution through reduced phenotypic variability,
ual may motivate the detailed study of environmental
increased environmental homogeneity
[82,
238],
fewer
risk factors and perhaps the application of preventa-distinct risk variants (decreasing genetic heterogene-tive therapeutics
[235]
. However, the discovery of sus-ity), and more extensive LD, improving the power to
ceptibility alleles alone may not be sufficient to carve
detect disease-associated variants
[239, 240, 241, 242].

the complicated nature of psychiatric nosology “at its
joints”
[236].

Laboratory

Molecular treatment

Systematic large-scale association studies, including
LD mapping of candidate regions (including genes)
With the availability of the reference human genome
and GWA approaches are needed. LD mapping of

sequence and the International HapMap, pharmaco-

a disease-associated region will entail (i) exhaustive
genetics (single-gene focus) and pharmacogenomics
genotyping, including screening for submicroscopic
(multiple-gene focus) are set to yield valuable out-structural variants such as CNVs, insertion/deletion
comes for psychiatric disorders
[237].
Combinations
variants, and inversions
[73];
(ii) thorough resequenc-of susceptibility alleles could help subclassify patients
ing in order to identify all known variation (both com-for inclusion in drug response trials
[235].
For exam-mon and rare)
[243];
and (iii) screening for sequence
ple, based on association between familial P50 audi-conservation across the entire region and the iden-tory evoked potential suppression deficits and alpha7

tification of highly conserved noncoding elements
nicotinic acetylcholine receptor gene (CHRNA7) vari-

(CNEs)
[244],
which may be involved in gene regu-ants
[47],
SZ patients who are poor P50 suppres-lation. The identified disease-associated variants will
sors may be candidates for adjunctive therapy using
then require interrogation with functional studies in
CHRNA7 agonists.

molecular, cellular, and animal models.

Functional studies could include (i) DNA microar-

ray studies in postmortem brain tissue to discover
genes whose altered expression contributes to dis-Clinical
ease
[245];
(ii) cellular and molecular studies to iden-Further refinement of the SZ phenotype is warranted
tify mutations altering the expression of candidate
and could involve: (i) supplementing a comprehen-

gene mRNA and/or protein; (iii) epigenomic studies
sive diagnostic approach (standardized individual and
to investigate factors that alter gene expression in the
family diagnostic interviews, medical records collec-absence of DNA mutation
[246, 247];
(iv) microRNA
tion) with psychopathological dimensions, to high-studies to identify additional levels of regulation and to
light clinical variability within categories and simi-explore the downstream effects of altered gene expres-larities across categories; (ii) addressing sources of
sion
[248]
; and (v) the development of animal models,
clinical variability such as geographical origin (vari-including knock-out and transgenic mice, to elucidate
able environmental exposures, sociocultural factors)
gene function.

and ascertainment methods (variable clinical set-

tings producing different clinical profiles)
[21];
and
Analytic

(iii) wherever feasible, incorporating neuroimaging,
Given the large-scale datasets generated in GWA stud-neurophysiological, and neuropsychological endophe-ies and expression studies, it is important that more
notypes. This should help reduce phenotypic hetero-robust methods are developed to deal with multi-

geneity and thereby facilitate our investigations of
ple comparisons
[249]
. New methods are also needed
genotype/phenotype relationships.

to reduce confounding by locus and allelic heterogeneity, and to detect gene-environment interactions.

Population characteristics

Population-specific HapMaps would be a welcome

It is important to undertake studies of sufficiently
development given variability in LD block structure
large, ethnically homogeneous samples across diverse
among populations, notwithstanding the conservation

Organic Syndromes of Schizophrenia – Section 3

(and hence transferability) of tagSNP patterns across
also on associations with chromosomal abnormalities,
populations
[250].

a number of candidate genes are now implicated in
SZ predisposition. Each has attracted support from
Replication

multiple studies across a range of populations. These
developments have been founded on improved con-

Replication is the gold standard of both linkage and
sistency of phenotyping, molecular genetic advances
association studies. The field must attempt to consis-such as completion of the human genome sequence,
tently replicate new and current findings across dif-and the availability of the human HapMap and SNP

ferent studies and populations. The National Cancer
databases, together with the evolution of statistical
Institute–National Human Genome Research Insti-

genetics theory and practice. For each gene, however,
tute (NCI-NHGRI) Working Group on Replication

unequivocal evidence of association is lacking, and no
in Association has recently published criteria for
allele/haplotype has been conclusively implicated. Rig-establishing replication in an effort to help separate
orous phenotyping of large ethnically homogeneous
“true associations from the blizzard of false positives”

samples and comprehensive LD mapping should facil-expected with the transition of the field to GWA stud-itate identification and replication of risk variants for
ies
[104].
Thus, replication studies should be of suffi-SZ. Functional studies of these variants should then
cient sample size to convincingly distinguish the pro-help clarify underlying molecular mechanisms that
posed effect from no effect, conducted in independent
may in turn lead to the development of targeted molec-data sets, analyzing the same phenotype with the same
ular treatments. The future certainly holds promise.

genetic model, and demonstrating a similar magnitude
of effect and significance with the same SNP, or a SNP

in perfect or very high LD with the prior SNP
[104].

The author thanks Elizabeth Holliday, PhD, for her
helpful comments. This work was supported in part by

the Australian National Health and Medical Research
Great advances have been made in the last 5 years.

Council grant 339454 and the US National Institute of
Based primarily on consensus linkage findings but
Mental Health grant R01 MH59588.

Chapter 23 – The status of genetic investigations of schizophrenia