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Association of DAO and G72(DAOA)G30 genes with bipolar affective disorder.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 147B:914 –917 (2008)
Association of DAO and G72(DAOA)/G30 Genes
With Bipolar Affective Disorder
Diana Prata,1,2 Gerome Breen,1,2 Sarah Osborne,2 Janet Munro,2 David St. Clair,3 and David Collier1,2*
Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, London, UK
Division of Psychological Medicine, Institute of Psychiatry, London, UK
Department of Mental Health, University of Aberdeen, Aberdeen, UK
There is growing evidence of partial aetiological
overlap between schizophrenia and bipolar disorder (BP) from linkage analysis, genetic epidemiology and molecular genetics studies. In the
present study we investigated whether individual polymorphisms or haplotypes of the DAO
and G72(DAOA)/G30 genes, which have been
previously implicated in schizophrenia, are also
associated with bipolar disorder. For each gene,
we genotyped 213 cases and 197 controls for
SNPs previously associated with schizophrenia:
rs2111902 (MDAAO-4), rs3918346 (MDAAO-5),
rs3741775 (MDAAO-6) and rs3918347 (MDAAO-7)
in DAO and rs746187 (M7), rs3916966 (M13),
rs2391191 (M15) and rs3916972 (M25) in G72.
Although none of the individual SNPs in these
genes reached statistical significance, we found
haplotype wise associations with bipolar disorder
for both genes. These included a two-SNP haplotype in DAO (rs2111902-A and rs3918346-T; global
P ¼ 0.003, individual P ¼ 0.002, Z ¼ 3.1) and a twoSNP haplotype for G72(DAOA)/G30 (rs746187-G and
rs3916972-G; global P ¼ 0.05; individual P ¼ 0.005,
Z ¼ 2.81). However, we found no evidence for an
epistatic interaction between the SNPs and/or
haplotypes of the two genes. In summary, our
findings provide some support for the individual
involvement of DAO and G72(DAOA)/G30 in the
etiology of bipolar disorder.
ß 2007 Wiley-Liss, Inc.
KEY WORDS: bipolar disorder; DAO; G72; SNPs;
Please cite this article as follows: Prata D, Breen G,
Osborne S, Munro J, St. Clair D, Collier D. 2008.
Association of DAO and G72(DAOA)/G30 Genes With
Bipolar Affective Disorder. Am J Med Genet Part
B 147B:914–917.
Twin studies indicate a substantial role for genetic factors
in bipolar affective disorder with heritability of 80–90%
[Craddock and Forty, 2006]. This is a similar level of
heritability to schizophrenia and schizoaffective disorder
*Correspondence to: David Collier, Section of Molecular
Genetics, Division of Psychological Medicine, Institute of Psychiatry, London SE5 8AF, UK. E-mail:
Received 21 June 2007; Accepted 30 October 2007
DOI 10.1002/ajmg.b.30682
ß 2007 Wiley-Liss, Inc.
[Cardno et al., 1999]. Over the last decade family-based
linkage analysis has provided evidence for a locus for
schizophrenia on chromosome 13q, over a broad region of
about 70 cM [Detera-Wadleigh and McMahon, 2006]. Suggestive linkage was first reported by Lin et al. [1997]. Since there
have been a series of both positive [e.g., Blouin et al., 1998;
Brzustowicz et al., 1999] and negative linkage studies, which
culminated in two important meta analyses, one positive,
using the multiple scan probability method [MSP; Badner and
Gershon, 2002], and another which was negative, using
genome scan meta-analysis (GSMA), a rank-order method
[Lewis et al., 2003]. Linkage evidence for chromosome 13q is
also suggestive in BP: one of three meta-analyses showed
significant association [Badner and Gershon, 2002]. Overall, it
seems probable but not certain that there is a locus for
schizophrenia and for bipolar affective disorder on chromosome 13q [Detera-Wadleigh and McMahon, 2006].
A number of candidate genes have been examined on
chromosome 13q, but only one systematic study has examined
the locus [Chumakov et al., 2002], which used homozygosity
mapping and case–control association in a French-Canadian
isolate to identify two distinct clusters in 13q32–33 of
schizophrenia-associated SNPs. These mapped to novel transcripts, G72 and G30, which are plausible candidate genes.
Most subsequent effort has focused on G72, a human-specific
gene expressed in the caudate and amygdala [Chumakov et al.,
2002] with excess expression in the dorso-lateral pre-frontal
cortex of schizophrenics [Korostishevsky et al., 2004]. Interactive cloning using yeast two-hybrid analysis, revealed that
G72’s protein product binds to and activates D-amino acid
oxidase (DAO), which is also expressed in the human brain
[Chumakov et al., 2002]. Hence, G72 has since been referred to
as D-amino-acid oxidase activator (DAOA). DAO maps to
12q24, a region with some evidence of linkage to schizophrenia
and bipolar disorder [Sklar, 2002].
Subsequently association between bipolar affective disorder
and the G72(DAOA)/G30 locus has also been reported with in
two North American family samples [Hattori et al., 2003] and a
further North American family sample [Chen et al., 2004],
a German case–control sample [Schumacher et al., 2004] and a
UK case–control sample [Williams et al., 2006]. In all studies,
evidence for association came from individual SNPs as well
as multilocus haplotypes, although there is no consensus
about the specific risk alleles or haplotypes across studies.
Further studies of schizophrenia have also shown association
with G72(DAOA)/G30 [Hall et al., 2004; Korostishevsky et al.,
2004; Wang et al., 2004]. Recently, a meta-analysis [DeteraWadleigh and McMahon, 2006] of 18 individual SNPs from
10 association studies found evidence for association of G72
(DAOA)/G30 with schizophrenia and, to a lesser extent with
bipolar disorder. A second meta-analysis by Li and He [2007]
of 16 polymorphisms in schizophrenia also found evidence
for association, albeit weak. The largest study to date was of
2831 individuals, of whom 709 had DSMIV schizophrenia,
706 had bipolar-I disorder, and 1416 were controls [Williams
et al., 2006]. This study suggested that G72(DAOA)/G30 does
Association of DAO and G72(DAOA)/G30 Genes
not contribute to the susceptibility to psychosis per se, but to
episodes of mood disorder across the bipolar and schizophrenia
DAO has been examined in one German case–control study
of bipolar disorder [Schumacher et al., 2004] which found no
association. However, Fallin et al. [2005] reported a significant
association of this gene with bipolar affective disorder in an
Ashkenazi Jewish case-parent trios design, although not with
schizophrenia. Given the evidence for the involvement of its
interacting partner, G G72(DAOA)/G3072, in psychosis and
mood disorders, DAO warrants further investigation in bipolar
disorder. Thus we set out to investigate its effect in a Scottish
sample of cases with bipolar I disorder and controls. We also
tried to detect a gene-by-gene interaction as suggested by
Chumakov et al. [2002].
Our sample consisted of 213 bipolar disorder I patients, and
197 healthy controls. Subjects were recruited through psychiatric hospitals in Scotland, met DSM-IV criteria for bipolar I
disorder, and had been receiving lithium therapy for at least
3 years. All subjects were Caucasian with at least three of their
four grandparents born in Scotland. Consensus diagnosis
was determined by trained psychologists and psychiatrists
based on case-note review and clinical interview using semistructured diagnostic questionnaires. The Operational Criteria Checklist for Psychotic Illness program was used to define
diagnoses. Patients with schizoaffective disorder were excluded. Final decisions on any diagnostic disagreements
([N ¼ 31] for reasons of missing data or discrepancies between
DSM-IV and International Classification of Diseases-10
diagnoses [N ¼ 31]) were made by one of the authors (D.St.C.)
and corroborated by another (R.S.). The sample has 97% power
to detect a heterozygote odds ratio of 2 at the 0.05 level for a risk
allele of frequency 0.19. Power analysis was performed using
the genetic power calculator (
We genotyped four SNPs in the DAO gene used in the
original study of Chumakov et al. [2002]: rs2111902 (alleles G
or T; alias MDAAO-4), rs3918346 (C/T; MDAAO-5), rs3741775
(G/T; MDAAO-6), rs3918347 (A/G; MDAAO-7). rs2111902
occurs in an untranslated mRNA region and the remaining
three SNPS in introns. In the G72(DAOA)/G30 gene, we
genotyped the four SNPs originally analyzed by Chumakov
et al. [2002]: rs746187 (C/T; alias M7), rs3916966 (A/C; M13),
rs2391191 (A/G; M15); and by Hall et al. [2004], rs3916972 (G/
T; M25). rs2391191 is in an untranslated mRNA region and the
remaining three in regions of uncertain function.
Genotyping was performed under contract by KBioscience
( using a competitive allele specific PCR system (CASP). Quality control criteria were that
genotypes form three distinct clusters, water controls were
negative, the number of callable genotypes was higher than
90% and minor allele frequency was greater than 0.02. In
addition interplate and intraplate duplicate testing of known
DNAs was performed. All genotyping was performed sequentially by the same method and blind to status.
For the genotype and allele-wise statistical analysis we used
both w2 and Fisher’s Exact Test to analyze the individual
polymorphisms. GENECOUNTING software (version 1.3,
March 2003; Zhao et al., 2002] was used to estimate the
haplotype frequencies from the genotype data (with 1000
permutations/simulations) and Cramer’s V and Absolute D0 to
assess linkage disequilibrium (LD) between the SNPs within
each gene. To test for interaction between the two genes, we
used GAIA (Genetic Association Interaction Analysis) software
[Macgregor and Khan, 2006] as well as WHAP version 2.06
[Purcell et al., 2007].
All SNPs were in Hardy–Weinberg equilibrium. Pairwise
LD analysis between the markers in each gene, with Cramer’s
V and Absolute D0 tests showed the SNPs within each gene
were in strong LD (Table I). Analysis of each SNP individually
showed no significant association (data not shown). However,
one SNP within the G72(DAOA)/G30 gene, rs746187, showed a
trend for a higher frequency of the G allele in the cases group
(P ¼ 0.07; OR ¼ 1.31).
Haplotype analysis revealed a two-SNP haplotype of
rs2111902 and rs3918346 of DAO to be globally significant at
P ¼ 0.003, the haplotypes A–T being the most probable risk
haplotype at an individual P ¼ 0.002 (Z-score 3.1). Adding
allele T of rs3741775 or the A allele of rs3918347 to this
haplotype still gave a significant association of global P ¼ 0.01
and P ¼ 0.02, respectively, and a specific P-value of 0.002 (both
Z-score 3.1) for each individual haplotype (Table II). For
G72(DAOA)/G30, we found borderline significance for a twoSNP haplotype composed of rs746187 and rs3916972 (global
P ¼ 0.05) but an individual P ¼ 0.005 (Z score 2.81) for the G–G
haplotype (Table II).
We then tested for interaction between DAO and
G72(DAOA)/G30. Using GAIA software, we investigated the
presence of additive and multiplicative interaction between
any of the SNPs of each gene. With WHAP, we attempted to
TABLE I. Pairwise LD Analysis (Cramer’s V and Absolute D0 ) Between the Markers in Each Gene
Absolute D0
1 rs2111902
2 rs3918346
3 rs3741775
4 rs3918347
Cramer’s V
1 rs746187
2 rs3916966
3 rs2391191
4 rs3916972
1 rs2111902
2 rs3918346
3 rs3741775
4 rs3918347
1 rs746187
2 rs3916966
3 rs2391191
4 rs3916972
Prata et al.
TABLE II. Haplotype Association Between DAO Bipolar Affective Disorder
Risk haplotypes
14.94, df ¼ 3
16.76, df ¼ 7
15.22, df ¼ 6
2–2: A–T
2–2–1: A–T–T
2–2–1: A–T–A
6.64, df ¼ 3
1–1: G–G
1, 2
1, 2, 3
1, 2, 4
1, 4
Cases/controls Z-score
Presented is the w statistic text and the correspondent global P-value as well as the frequency and P-values for the
specific risk haplotypes.
detect an interactive effect by analyzing the significant
haplotype of DAO while covarying for risk genotypes of
G72(DAOA)/G30, assuming an additive model. We found no
indication of epistatic effects.
Our results support a contribution of DAO to the development of bipolar disorder, which is in line with previous linkage
findings [Sklar, 2002]. We found significant association of twoand three-SNP risk haplotypes with the disorder in our case–
control design. The original study of Chumakov et al. [2002]
found schizophrenia to be associated with all the four SNPs
investigated here. So far, two published association studies
have investigated this gene in bipolar disorder [Schumacher
et al., 2004; Fallin et al., 2005]. Schumacher et al. used three of
the four SNPs (rs2111902, rs3918346, and rs3741775) analyzed in the present study. They found a significant association
for each of the individual SNPs and the three-SNP haplotype
with schizophrenia, but not with bipolar disorder. The family
trio study of Fallin et al. [2005] found this gene to be associated
with bipolar disorder in single-SNP and haplotype-based
transmission disequilibrium tests, using other SNPs as part
of two LD blocks spanning roughly half of the gene. We detected
a significant association for that three SNP haplotype (A–T–T)
and a stronger association for the two-SNP rs2111902–
rs3918346 haplotype (A–T) with bipolar disorder. We found
the rs2111902 risk allele (A), to be the same as the
schizophrenia risk allele in Schumacher et al. [2004], but not
the rs3918346 or rs3741775 alleles which were C and G
respectively in that study. The associated three-marker
haplotype in Chumakov et al. [2002] was C–T–T.
In contrast to DAO, a body of evidence provides compelling
evidence of association between G72(DAOA)/G30 with bipolar
disorder [Detera-Wadleigh and McMahon, 2006]. Although
there may be difficulties with the haplotypic association
approach, our association replicates previous positive findings
of association with G72(DAOA)/G30 in the form of a two-SNP
haplotype of rs746187-G and rs3916972-G. Across studies of
both bipolar disorder and schizophrenia, the specific associated
alleles of nearly every marker have varied, as shown in DeteraWadleigh and McMahon [2006], which could reflect the
possibility that multiple, possibly rare disease alleles exist
across different populations. From our set of four SNPs in
G72(DAOA)/G30, we did not find a significant individual SNP
association with bipolar disorder, even thought SNP
rs2391191 (M15) had shown strong significance of association
(P ¼ 0.0006) with schizophrenia in the meta-analysis of
Detera-Wadleigh and McMahon [2006]. In terms of haplotype
association, these four SNPs might mark a significantly undertransmitted (possibly protective) haplotype (M7–M12–M12–
M13–M14–M15–M23-–M25) in schizophrenia as found by
Hall et al. [2004] in South African and USA samples. Within it,
a core haplotype flanked by M12 and M15 has also been found
to be over-transmitted in schizophrenia with complimentary
alleles, in the French Canadian sample of Chumakov et al.
[2002]. In our Scottish bipolar sample, we found a significant
over-representation of M7–M25 haplotype, for the G–G allelic
version, which is under-transmitted in schizophrenic in the
USA schizophrenia sample of Hall et al. [2004]. It remains
unclear why different (although closely related) haplotypes
show association across populations, although in our case, this
may represent a difference in the genetic etiology of each
The fact that our sample did not show any gene by gene
interaction is possibly due to power limitations that did not
allow us to detect small rare allelic effects or to lack of strong
association with the putative risk polymorphisms in the gene.
Our study provides additional evidence for an involvement of
G72(DAOA)/G30 and DAO in the etiology of bipolar disorder,
but does not support epistatic interaction. Given that, to date,
more studies have investigated G72(DAOA)/G30 and DAO in
schizophrenia than in bipolar disorder, a larger pool of data,
sufficient for meta-analysis, will be required for the association
of these genes with bipolar disorder to be definitive.
We thank FCT—Fundacao para a Ciencia e Tecnologia
(Portugal) for sponsoring the genotyping, and the SIM
foundation, the University of Aberdeen (UK) and the patient
and control volunteers for the case–control sample.
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g30, g72, associations, affective, disorder, genes, bipolar, dao, daoa
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