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DISC1 mRNA expression is not influenced by common Cis-acting regulatory polymorphisms or imprinting.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 147B:1065– 1069 (2008)
DISC1 mRNA Expression is Not Influenced by Common
Cis-Acting Regulatory Polymorphisms or Imprinting
J.B.G. Hayesmoore,1 N.J. Bray,1,2 M.J. Owen,1 and M.C. O’Donovan1*
1
Department of Psychological Medicine, School of Medicine, Cardiff University, Cardiff, UK
Centre for the Cellular Basis of Behaviour, Department of Neuroscience, Institute of Psychiatry, King’s College London,
London, UK
2
The hypothesis that genetic variation in Disrupted in Schizophrenia 1 (DISC1) influences risk
of schizophrenia and other major psychiatric
disorders is supported by a growing body of
genetic association data and plausible functional
biology. Risk of psychiatric disorder is not attributable to non-synonymous changes that alter
the protein coding sequence of DISC1, although
certain such variants possibly contribute to risk
haplotypes. Thus, it is widely hypothesized that
the risk variants at DISC1 influence its expression. As a complicating factor, it has also been
recently proposed that DISC1 is subject to
imprinting, a hypothesis that would profoundly
influence the interpretation of current genetic
studies. We have tested these two main hypotheses using allelic expression analysis. Of
148 human brain mRNA samples, 65 were informative for analysis. However, only a single
sample showed evidence for unequal expression
of paternal and maternal transcripts. Analysis of
the proximal promoter region in that subject
revealed the presence of a previously unknown
duplication of the 22 nucleotides 168 to 147
relative to the transcription start site. However,
the altered expression in that subject did not
appear to be explained by this insertion. Our data
robustly demonstrate that DISC1 is not imprinted
in the adult human brain, and strongly suggest
that reports of genetic association between DISC1
and psychiatric disorder are not explicable by
sequence changes that alter mRNA abundance.
ß 2008 Wiley-Liss, Inc.
KEY WORDS:
schizophrenia; bipolar disorder;
allelic expression; regulatory
polymorphism; imprinting
Please cite this article as follows: Hayesmoore JBG,
Bray NJ, Owen MJ, O’Donovan MC. 2008. DISC1 mRNA
Expression Is Not Influenced by Common cis-Acting
Regulatory Polymorphisms or Imprinting. Am J Med
Genet Part B 147B:1065–1069.
Grant sponsor: MRC (UK).
*Correspondence to: M.C. O’Donovan, Department of Psychological Medicine, School of Medicine, Cardiff University, Heath
Park, Cardiff, CF14 4XN, UK. E-mail: odonovanmc@cardiff.ac.uk
Received 5 October 2007; Accepted 14 December 2007
DOI 10.1002/ajmg.b.30715
Published online 12 February 2008 in Wiley InterScience
(www.interscience.wiley.com)
ß 2008 Wiley-Liss, Inc.
INTRODUCTION
St Clair et al. [1990] described a large Scottish family
in which a balanced translocation t(1;11)(q42.1;q14.3) cosegregated with schizophrenia, bipolar disorder and other
major mental illnesses. The translocation breakpoint on
chromosome 1 was subsequently found to directly interrupt two novel genes, which were named Disrupted
in Schizophrenia 1 and -2 (DISC1, DISC2) [Millar et al.,
2000a]. Human DISC1 spans 414 kb of chromosome 1q42,
includes 13 exons and encodes a full-length protein of 854
amino acids. The translocation interrupts the coding sequence,
potentially resulting in a truncated protein (mutDISC1) that
lacks the C-terminal 257 amino acids [Millar et al., 2000a;
Ozeki et al., 2003]. DISC2 appears to specify a non-coding RNA
that is transcribed from the antisense strand, and which may
regulate DISC1 expression [Millar et al., 2000a].
The results of genetic linkage and association studies that
have followed the Scottish family report suggest that DISC1
may operate more generally as a susceptibility gene for
psychiatric illness. Chromosome 1q42 has been reported to
show linkage to schizophrenia [Ekelund et al., 2001, 2004; Hwu
et al., 2003], schizoaffective disorder [Hamshere et al., 2005],
and bipolar disorder [Curtis et al., 2003; Macgregor et al.,
2004]. A frameshift variant within DISC1 has been identified
in a second family affected by schizophrenia [Sachs et al.,
2005]. Initially postulated to be a rare highly penetrant
mutation, this variant was subsequently reported in controls
[Green et al., 2006] making this hypothesis unlikely. Evidence
for genetic association between DISC1 SNPs and haplotypes
and schizophrenia, schizoaffective disorder, and bipolar
disorder has been reported in several independent populations
[Hennah et al., 2003; Hodgkinson et al., 2004; Callicott
et al., 2005; Cannon et al., 2005; Thomson et al., 2005;
Chen et al., 2007; Qu et al., 2007] as have negative findings
[Devon et al., 2001; Kockelkorn et al., 2004; Zhang et al., 2005],
the latter unsurprising even for true susceptibility genes given
the presumed genetic complexity of these disorders. It should
also be noted that, across the diverse populations, not all of the
associated haplotypes overlap, indeed when put together, they
span the entire gene [Hennah et al., 2006]. This may reflect
population differences in linkage disequilibrium structure, or
more likely given the distance across which the signals span,
the presence of multiple susceptibility variants.
If variation in DISC1 confers susceptibility to mental illness
in the general population, unless the mRNA influences cellular
function directly, DISC1 must contain sequence variation that
influences the structure and/or expression of DISC1 protein.
A common non-synonymous base substitution, encoding
Ser704Cys, has been reported to be associated with schizophrenia and to influence hippocampal structure and function
[Callicott et al., 2005]. Two other non-synonymous polymorphisms in DISC1, encoding Arg264Gln and Phe607Leu, form
part of haplotypes that have been reported to show altered
representation in schizophrenia [Hennah et al., 2003; Cannon
et al., 2005]. However, these and other associated haplotypes
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Hayesmoore et al.
include non-coding variants that do not appear to tag polymorphism with obvious effects on DISC1 protein structure,
raising the possibility that associations are mediated, at least
in part, by sequence variation affecting DISC1 expression.
The potential pathogenic importance of altered DISC1
expression is suggested by the observation that lymphoblastoid cell lines derived from family members carrying the t(1;11)
translocation show 50% lower DISC1 expression than cell
lines from family members without the translocation [Millar
et al., 2005]. No truncated protein was detected in that study
leading the authors to suggest that haploinsufficiency of
DISC1 underlies increased susceptibility to psychiatric illness
in the translocation cases. That DISC1 contains regulatory
variation operating in general populations is suggested by a
recent study in which a putative risk haplotype for bipolar
disorder was associated with reduced DISC1 expression in
lymphoblastoid cell lines [Maeda et al., 2006]. However, others
have found no correlation between SNPs that showed association with schizophrenia and DISC1 mRNA abundance in
human brain [Lipska et al., 2006]. Thus, the mechanism by
which variation in DISC1 influences the function of the
encoded protein and thereby susceptibility to mental disorders
remains open to dispute.
Assays based on measures of a gene’s absolute expression
level can be influenced by a host of trans-acting factors—both
genetic and environmental—that can impair their sensitivity
to detect cis-acting genetic influences on expression and also
have the potential to produce spurious results. An alternative
method for investigating cis-acting regulatory influences
involves comparing the relative level of each mRNA transcript
in individuals who are heterozygous for an expressed polymorphism [Yan et al., 2002; Bray et al., 2003]. In heterozygous
subjects, an expressed single nucleotide polymorphism (SNP)
enables discrimination between mRNA molecules transcribed
from each parental chromosome. In the absence of cis-acting
variation affecting expression of the assayed transcript, each
parental transcript will be equally expressed. In contrast,
where an individual is also heterozygous for a cis-acting
regulatory variant affecting expression of that transcript, the
two transcripts will be expressed at different levels. This will
occur regardless of where that cis-acting polymorphism is
located relative to the gene, or whether that polymorphism is in
linkage disequilibrium with the assayed SNP. By assaying a
series of individuals, it is thus possible to indirectly screen a
gene for the presence of cis-acting variation affecting expression of that gene in the selected tissue. Importantly, this
‘within-subjects’ approach allows detection of genuine cisacting effects, whilst controlling for the trans-acting factors
that can confound measures of total expression between
samples. This is because within an individual, factors that
affect mRNA quality or quantity such as tissue state, use of
medication, and population variation in trans-regulatory
proteins, are expected to equally influence the mRNA transcribed from each chromosome [Bray et al., 2003].
In the present study, we have applied this method to DISC1
expression using a large number of human brain samples. In
addition to looking for the influence of regulatory cis-acting
polymorphism, our data also allowed us to investigate whether
the gene is imprinted in humans, a possibility suggested by two
recent studies of the murine genome [Luedi et al., 2005; Zhao
et al., 2006]. This is important because if DISC1 is imprinted in
human brain, interpreting the extant association data would
have to be re-evaluated in the context of parent of origin effects.
MATERIALS AND METHODS
Samples
Post-mortem brain tissue derived from frontal, parietal or
temporal cortex of 148 unrelated individuals was obtain-
ed from three reputable tissue sources (The MRC London
Neurodegenerative Diseases Brain Bank, UK; The Stanley
Medical Research Institute Brain Bank, USA; The Karolinska
Institute, Sweden). Genomic DNA was extracted by standard
phenol–chloroform procedures. Total RNA was extracted
using the RNAwizTM isolation reagent (Ambion, Huntingdon,
UK) and then treated with DNase. Reverse transcription was
performed using random decamers and the RETROscriptTM
kit (Ambion).
Genotyping
All PCR reactions were carried out by standard procedures using ‘Hot Star’ Taq polymerase (Qiagen, Crawley,
UK). PCR primers were designed by use of the Primer3
program (sequences on request). Genotyping was performed by
primer extension using the SNaPshot Multiplex Kit (Applied
Biosystems, Warrington, UK).
Allelic Expression Assay
Genomic DNA from all subjects was initially genotyped to
identify heterozygotes for expressed SNP rs3738401. cDNA
samples from heterozygous subjects were then assayed twice,
each time as two separate RT reactions, alongside the
corresponding genomic DNA samples. Samples were PCRamplified using primers based on a single exonic sequence,
capable of amplifying either cDNA or genomic DNA. RNA
samples did not yield detectable levels of product in the absence
of an RT step. The same analytic conditions were used for
genomic DNA and cDNA so that we could use, for each assay,
the average of the ratios observed from genomic DNA
(representing a perfect 1:1 ratio of the two alleles) to correct
allelic ratios obtained from cDNA for any inequalities in allelic
representation specific to that assay [Hoogendoorn et al.,
2000]. Allelic representation was measured by primer extension using SNaPshot chemistry (Applied Biosystems), as
described previously [Bray et al., 2003]. Peak heights of allelespecific extended primers were determined using Genotyper
version 2.5 software (Applied Biosystems). The ratio of cDNA
peak heights, corrected using the average genomic ratio, was
used to calculate relative expression of the two alleles in each
individual sample. To confirm altered allelic expression,
individuals showing expression of one allele at a level 20% or
more than the other were assayed on four further occasions,
again as two separate RT reactions, alongside genomic DNA.
In line with previous studies [Yan et al., 2002; Bray et al.,
2003], an allelic expression difference >20% for any individual
sample was chosen as indicative of the influence of cis-acting
polymorphism since measurements surpassing this threshold
are generally reproducible and unlikely to reflect measurement error. Finally, where an average difference in allelic
expression of >20% was maintained over the subsequent
eight reactions, as an additional test, allelic expression was
assessed at a second expressed SNP, rs821616, using identical
methodology.
Sequencing
Genomic DNA from selected individuals was sequenced in
both directions using BigDye chemistry (Applied Biosystems)
according to manufacturer’s protocols. Prior to sequencing,
amplicons with and without the duplicated sequence were
isolated by agarose gel electrophoresis using standard
protocols.
RESULTS
One hundred forty-eight individuals were genotyped for the
expressed SNP rs3738401, which was used for the primary
analysis of DISC1 relative allelic expression. This SNP, located
Cis-Acting Influences on DISC1 Expression
1067
Fig. 1. The organization of the DISC1 gene and its four major mRNA transcripts, and the position of SNPs assayed in this study. L ¼ Long isoform,
Lv ¼ Long variant isoform, S ¼ Short isoform, Es ¼ Extremely short isoform. Transcripts are based on reference sequences NM_018662, NM_001012957,
NM_001012959, and NM_001012958, respectively. The Long variant transcript differs from the Long transcript in that it lacks the 30 terminal 66 bp of exon
11 as indicated by the white rectangle with black outline. Protein-coding portions of exons are represented by black rectangles, and 50 and 30 untranslated
regions are represented by gray rectangles. Asterisks indicate the position of SNPs rs3738401 in exon 2, and rs821616 in exon 11, which were used for relative
allelic expression analysis.
in exon 2, and encoding Arg264Gln, is present in all known
DISC1 transcripts (see Fig. 1). SNP rs3738401 is not predicted
to be transcribed as part of DISC2. However, exon 2 of DISC1
has been found to be contained in low abundance hybrid
transcripts formed through intergenic splicing of DISC1 and
the adjacent gene translin-associated factor X (TSNAX)
[Millar et al., 2000b]. Sixty-five individuals were heterozygous
for rs3738401, and therefore informative for allelic expression
analysis. Their mean age at death was 57 years (SD ¼ 19.69),
36 were male, and 29 were female.
Analyses of cDNA ratios showed good reproducibility, with
an average coefficient of variation (SD/mean) of 0.09. Only
one of the 65 assayed individuals met the relative allelic
expression threshold >20% at SNP rs3738401. The individual
was a 57-year-old anonymous male with no known history of
neurological or psychiatric disorder. For this individual, the
average A/G ratio over eight replicate cDNA reactions was 0.66
(95% CI ¼ 0.60–0.72). Thus, in this individual, expression
of the A-allele was reduced by 34% (using the G-allele as an
arbitrary reference point), or expression of the G-allele
increased by 51% (using the A-allele as an arbitrary reference
point). Observed cDNA ratios from this individual were
significantly different from ratios derived from genomic DNA
(P ¼ 1.89 1013).
We assessed relative allelic expression in this individual at
a second exonic SNP, rs821616, for which this individual was
also heterozygous. SNP rs821616 is located in exon 11 and is
predicted to be contained in the long (L) and long-variant (Lv)
DISC1 transcripts, but absent from the short (S) and extremely
short (Es) DISC1 transcripts (see Fig. 1). SNP rs821616 is not
predicted to be contained in the DISC2 transcript as defined by
NCBI sequence GI 61806647. When assayed at this SNP,
the average A/T ratio in cDNA from this individual was 0.63
(95% CI ¼ 0.52–0.73). This accords well with the ratio observed
at rs3738401, and indicates that the identified cis-effect
operates on the L and/or Lv DISC1 transcripts, although an
effect on the S and Es transcripts cannot be excluded.
To explore whether the large difference in allelic expression
observed in the one individual can potentially be accounted for
by changes in the proximal promoter region, we sequenced
approximately 1 kb immediately upstream of the transcription
start site for all major DISC1 transcripts in this individual and
an additional three individuals that did not show altered allelic
expression. A novel insertion polymorphism was identified, a
duplication of the 22 nucleotides that are 168 to 147 relative
to the DISC1 transcription start site (bases 675–696 in
reference sequence AF222982). The duplication was inserted
immediately 50 to and in tandem with the original sequence.
The individual that showed consistent allelic expression
imbalance was heterozygous for this duplication. However,
after screening a further eight samples, two additional individuals that did not show allelic imbalance (A/G ratio ¼ 1.06
and 1.03) were also found to be heterozygous for this
duplication, suggesting that it does not in itself alter DISC1
expression. The novel duplication includes a TG repeat that
has previously been reported to be polymorphic [Devon et al.,
2001]. In the present study, all chromosomes carrying the
duplicated sequence carried one (TG)8 repeat unit and one
(TG)10. In principle, it is possible that the altered allelic
expression reflects differences in repeat size between the
duplicated and non-duplicated chromosomes. However, this
does not seem likely since the individual that showed
consistent allelic imbalance carried a (TG)9 on the chromosome
without an insertion, a repeat which in size is close to both
those on the duplicated chromosome. Moreover, our data do not
suggest the repeat is per se functional, since some individuals
that showed no allelic expression imbalance were heterozygous
for two alleles that differed to a greater extent in size (e.g., 9
and 14 repeats). Thus, our data suggest neither the insertion
nor the TG repeat polymorphism influence DISC1 expression
in brain.
DISCUSSION
Alteration of DISC1 expression is a potential mechanism by
which DISC1 variants increase risk for psychiatric illness. The
present study sought to test this hypothesis by applying a
powerful assay of relative allelic expression to a large number
of human brain samples. At the same time our data allowed us
to seek evidence for the more recent hypothesis that DISC1 is
imprinted, a hypothesis that if correct, would have important
ramifications for interpreting the existing association findings.
Out of 65 informative heterozygous brain samples, only one
showed allelic expression differences, this being 50%, whilst
the remainder showed approximately equal expression of both
parental alleles. These data robustly demonstrate that DISC1
is not imprinted in the adult human brain, and that imprinting
is therefore unlikely to be of relevance to the association
findings to date. Our data also show that haplotypes that alter
DISC1 expression are rare in our population, with a frequency
of approximately 0.01. This frequency is much lower than that
of most of the haplotypes that have been reported to be
associated with psychiatric illness in Caucasian populations.
Thus, while our study supports the existence in rare cases of
cis-acting variation that influences DISC1 expression in adult
brain, our study does not support the hypothesis that the
relatively common haplotypes associated with schizophrenia
and bipolar disorder tag functional variation that acts through
this mechanism. It remains possible that our rare observation
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Hayesmoore et al.
of allelic expression is relevant to one of the many rare
haplotypes that have been reported to be associated with
illness [e.g., see Thomson et al., 2005], but this hypothesis is
difficult to test using inferred haplotypes from a single subject.
Finally, as for all quantitative assays, we cannot exclude the
possibility that more common variants exist but that their
effects are below the threshold for detection.
Most of what is currently known about the function of DISC1
relates to its role in brain development. DISC1 expression
peaks during periods of active neurogenesis [Schurov et al.,
2004], again at puberty [Schurov et al., 2004], and is expressed
in some regions of the developing brain that do not express
DISC1 in adulthood [Austin et al., 2004]. It remains possible
that risk alleles or haplotypes exert effects on expression
exclusively in a developmental context, but testing this
hypothesis is currently impractical as it would require large
numbers of fetal brain samples, each at different developmental time points. We should also stress that our study does
not address quantitative post-transcriptional effects, for
example in the abundance of the protein or its sub-cellular
distribution. The latter may be of importance, one recent study
reporting altered sub-cellular distribution of DISC1 in the
orbitofrontal cortex of patients with schizophrenia [Sawamura
et al., 2005].
These caveats aside, we conclude that most reports of genetic
association between DISC1 and psychiatric disorder are
neither explicable by sequence changes that alter protein
structure nor, as we have shown, changes that alter mRNA
abundance. These considerations suggest that researchers
seeking to elucidate the potential role of DISC1 in mental disorder will need to turn their attention to post-transcriptional
pathogenic mechanisms.
ACKNOWLEDGMENTS
JBGH is a Medical Research Council (MRC (UK)) student.
This work was additionally supported by an MRC Program
Grant to MOD and MJO and an MRC Co-operative Group
Grant.
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expressions, regulatory, polymorphism, common, acting, disco, imprinting, influence, mrna, cis
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