A NOS-III haplotype that includes functional polymorphisms is associated with bipolar disorder
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International Journal of Neuropsychopharmacology (2006), 9, 13–20. Copyright f 2005 CINP
A R T IC L E
doi:10.1017/S1461145705005560
A NOS-III haplotype that includes
functional polymorphisms is associated
with bipolar disorder
Andreas Reif1, Alexander Strobel2, Christian P. Jacob1, Sabine Herterich3,
Christine M. Freitag4, Theresia Töpner1, Rainald Mössner1, Sabrina Fritzen1,
Angelika Schmitt1 and Klaus-Peter Lesch1
1
Clinical and Molecular Psychobiology, Department of Psychiatry and Psychotherapy, University of Würzburg,
Würzburg, Germany
2
Institute of Psychology II, Dresden University of Technology, Dresden, Germany
3
Department of Clinical Biochemistry and Pathobiochemistry, University of Würzburg, Würzburg, Germany
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4
Department of Child and Adolescent Psychiatry, University Hospital Saarland, Homburg, Germany
Abstract
The pleiotropic messenger molecule nitric oxide (NO) has been implicated in a variety of higher CNS
functions, including learning, memory, and emotionality. In the human brain, NO is predominantly
formed by neuronal NO synthase (NOS-I), while the so-called ‘ endothelial’ isoform NOS-III also con-
tributes to NO generation. We recently reported that NOS-III knockout mice display decreased adult
neurogenesis and reduced responsiveness in a learned helplessness paradigm. To examine whether
NOS-III plays a role in affective disorders as well, we tested a NOS-III gene haplotype, consisting
of three functional polymorphisms, for an association with bipolar disorder and major depression.
A significant global haplotype association with bipolar disorder (n=284 controls ; n=91 patients ;
pglobal=0.021 ; pt-a-g14 A. Reif et al.
helplessness paradigm which has been suggested as a cis-acting enhancer element in an epistatic
to represent an animal-based model of depression manner depending on T-786C genotype (Wang et al.,
(Vollmayr and Henn, 2001). We thus hypothesized 2002). The haplotype which can be constructed from
that the NOS-III genotype may contribute to the those three polymorphisms displays marked inter-
genetic basis of depressive disorders as well, or – on ethnic variation (Tanus-Santos et al., 2001), which has
the contrary – that a certain genotype could protect to be taken into account when comparing different
against affective disorders. studies.
Nitric oxide (NO) is a pleiotropic messenger Since we found that NOS-III knockout mice display
molecule generated by a family of three NO synthases diminished adult neurogenesis but reduced respon-
(NOS), termed NOS-I, NOS-II and the so-called siveness in a learned helplessness paradigm (Reif et
‘endothelial ’ NOS-III. In the human brain, more al., 2004), and no study has as yet addressed the role of
than 1 % of all neurons express NOS-I, and it has been the NOS-III in affective disorders, we have tested this
estimated that almost every neuron receives input NOS3 haplotype for association with MD or BD re-
from a nitrinergic cell (Snyder and Ferris, 2000). While spectively.
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NOS-I is expressed in neurons, neuronal expression
of NOS-III, which can be found abundantly in endo-
thelium where it produces NO to regulate vascular Materials and methods
tone, remains to be demonstrated unambiguously.
Subjects
Although highly controversial, it has been suggested
that NOS-III is present in hippocampal CA1 pyra- A total of 136 patients from the Lower Franconia area
midal cells (Dinerman et al., 1994 ; Doyle and Slater, in Germany were enrolled in the study, the patients
1997 ; O’Dell et al., 1994). Likewise, it is unclear were ascertained from the Department of Psychiatry
whether NOS-III is expressed in astrocytes (Gabbott and Psychotherapy. Ninety-one patients (27 males)
and Bacon, 1996 ; Luth et al., 2002 ; Wiencken and suffered from bipolar affective disorder (BD) accord-
Casagrande, 1999) or not (Burette et al., 2002). These ing to DSM-IV criteria, and only patients with at least
contradictory findings may be explained by regional one manic and one depressive episode were classified
specificity or differences across species. However, due as BD (i.e. strict bipolar I criteria). A further 45 patients
to the strong expression in CNS endothelium, NOS-III with unipolar depression (MD, 16 males) were in-
has the physical and biochemical potential to exert cluded in the study, however, only when no signs
influences on neural cells, thus facilitating for a cross- of bipolarity were present throughout the whole
talk between vasculature and excitable tissue. course of the disease ; those patients fulfilled the
The human gene for NOS-III, NOS3, is located on DSM-IV criteria of recurring depressive disorder, and
chromosome 7q35.1 and comprises 26 exons, spanning had at least two depressive episodes. All patients
21 kb (Marsden et al., 1993). Of several known NOS3 were in-patients at the Department of Psychiatry at
polymorphisms, three have been extensively studied least once. Diagnoses were made by an extensive,
in cardiovascular disease. Although results were semi-structured interview analogous to the AMDP
inconsistent, probably due to ethnic stratification interview (Arbeitsgemeinschaft für Methodik und
and single-SNP association designs, the association of Dokumentation in der Psychiatrie, 2000) performed by
NOS-III genotype and ischaemic heart disease was an experienced psychiatrist (A.R., C.P.J. or K.P.L.),
confirmed in a recent meta-analysis incorporating along with chart reviews. If possible, further infor-
>20 000 subjects (Casas et al., 2004). Since these three mation was retrieved from family informants and case
polymorphisms are functional with evidence for records from other hospitals to ensure consistent
epistasis, they have been selected in the present study : diagnoses. Chart reviews of every patient were done
(1), a promoter single nucleotide polymorphism (SNP) by A.R. None of the subjects showed significant
(T-786C), (2), an intronic 27-bp variable number of neurological comorbidity, epilepsy, mental retard-
tandem repeats polymorphism (VNTR) in intron 4, and ation, or a history of substance addiction, or other
(3) a coding SNP (G894T) which causes an amino-acid organic disorders suggesting organic affective dis-
change from Glu to Asp in exon 7. G894T has been order. The average age was 50¡3 yr for the BD group
suggested to alter the enzyme’s susceptibility to and 59¡14 yr for the MD group respectively. While
proteolytic cleavage (Tesauro et al., 2000), T-786C has 67 BD subjects had a positive family history for BD
been found to influence the NOS3 promoter activity as or depression in first- or second-degree relatives,
assessed by the luciferase reporter assay (Nakayama only 12 MD patients had a positive family history
et al., 1999), and intron 4 VNTR is thought to function ( x2=27.27, d.f.=1), in almost all cases for depression.NOS-III and affective disorders 15
Table 1. Sequences of nucleotide primer pairs used for NOS3 genotyping
Primer name Sequence
T-786C forward 5k-TGG AGA GTG CTG GTG TAC CCC A-3k
T-786C reverse 5k-GCC TCC ACC CCC ACC CTG TC-3k
Intron 4 VNTR forward 5k-AGG CCC TAT GGT AGT GCC TTT-3k
Intron 4 VNTR reverse 5k-TCT CTT AGT GCT GTG GTC AC-3k
G894T forward 5k-GCA TTC AGC ACG GCT GGA-3k
G894T reverse 5k-GCT CCA GGG GCA CCT CAA-3k
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DNA samples were collected from of 284 control Statistical analysis
subjects (158 males) consisting of healthy blood
Deviation of genotype frequencies from Hardy–
donors from the same area as the patient group ; the
Weinberg equilibrium was determined separately
sample was not screened for a history of psychiatric
for the two patient populations and the controls
disorders. All control subjects however were free of
by calculating x2 statistics with d.f.=1 for T-786C and
any regular medication, and the study was explained
G894T and with d.f.=3 for the intron 4 polymorphism
to them, so that the chance that severe psychiatric
using an online calculator software (http://kursus.
disorders were present in the control sample was low.
kvl.dk/shares/vetgen/_Popgen/genetik/applets/
Mean age of controls was 35¡13 yr. Both patients and
kitest.htm). Single association tests were performed
controls were of Caucasian origin. Only patients and
by means of x2 tests using SPSS for Windows version
volunteers who gave written informed consent after
9.0 (SPSS Inc., Chicago, IL, USA). Pairwise linkage
oral as well as written explanation about aim and
disequilibrium between the three polymorphisms
scope of the investigation were enrolled in the study.
was assessed using 2 LD (Zhao, 2004). Haplotype
The study was approved by the Ethics Committee of
analyses and tests for significance of differences in
the University of Würzburg.
estimated haplotype frequencies between controls
and patients were performed using the GENECOUNTING/
Genotyping
PERMUTE utility of the GENECOUNTING software (Zhao,
Following DNA extraction, the three NOS-III 2004). Both programs are available from the Institute
polymorphisms were determined using standard of Psychiatry, King’s College, London (IOP, 2005).
protocols (Tanus-Santos et al., 2001) : the promoter GENECOUNTING implements an EM algorithm which
polymorphism T-786C SNP, an intronic 27-bp VNTR can handle missing genotypes and ambiguously
in intron 4, and the coding SNP G894T. Briefly, PCR phased data to estimate haplotype frequencies in un-
reactions were performed in a reaction volume of related subjects (Dempster et al., 1977). GENECOUNTING/
25 ml, including y50 ng of template genomic DNA, PERMUTE performs permutation tests for global associ-
7 pmol of each primer (Table 1), 2.5 mM of each dNTP, ation by randomly reassigning case and control labels
1 mM MgCl2 (0.75 mM MgCl2 for G894T), 50 mM KCl, in the actual data. The resulting p values reflect
10 mM Tris–HCl (pH 8.3 at 25 xC), 0.025 mg/ml BSA, the proportion of replicates that produce values of
0.025 % Tween-20, and 1 U of Taq DNA polymerase. statistics at least as large as those observed. In the
Annealing temperature was 58 xC for intron 4 VNTR current study, 10000 permutations were performed.
(35 cycles) and G894T (40 cycles), and 64 xC for T-786C The significance of specific haplotypes was assessed
(35 cycles). For the determination of T-786C, PCR by a proportion test also.
products were digested with MspI (overnight at
37 xC ; fragment sizes : wild type, 140 and 40 bp ; SNP,
Results
90, 50 and 40 bp). G894T PCR amplicons were
digested with MboI (overnight at 37 xC ; fragments : Ninety-one patients with BD, 45 patients with MD,
wild type, 129 bp ; SNP, 71 and 58 bp). Fragments, or and 284 controls were genotyped for three poly-
PCR products in the case of the intron 4 VNTR (4a, morphisms of NOS3 : T-786C, intron 4ab, and G894T.
393 bp ; 4b, 420 bp ; 4c, 447 bp), were subsequently Genotype frequencies at all loci were in Hardy–
visualized on a 4 % agarose gel. Weinberg equilibrium for cases and controls (all16 A. Reif et al.
Table 2. Genotypes and genotype frequencies of NOS3 polymorphisms
Controls (n=284) BD (n=91) MD (n=45)
Observed Percentage Observed Percentage Observed Percentage
T-786C
C/C 49 (17.2) 14 (15.4) 11 (24.4)
C/T 130 (45.8) 37 (40.6) 19 (42.2)
T/T 105 (37.0) 40 (44.0) 15 (33.3)
x2 ( p)=1.42a p=0.49 x2 ( p)=1.35a p=0.51
Intron 4
aa 9 (3.2) 3 (3.3) 1 (2.2)
ab 71 (25.0) 22 (24.2) 10 (22.2)
bb 202 (71.1) 66 (72.5) 34 (75.6)
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bc 2 (0.7) 0 (0.0) 0 (0.0)
x2 ( p)= 0.68a p=0.88 x2 ( p)= 0.66a p=0.88
G894T
G/G 128 (45.1) 45 (49.5) 18 (40.0)
G/T 127 (44.7) 41 (45.1) 22 (48.9)
T/T 29 (10.2) 5 (5.5) 5 (11.1)
x2 ( p)= 1.98a p=0.37 x2 ( p)= 0.41a p=0.82
BD, Bipolar disorder ; MD, major depression.
a 2
x tests vs. controls with d.f.=2 except for analyses with regard to the intron 4 VNTR (d.f.=3).
p>0.20). All three polymorphisms were in significant the global association with BD remained significant.
linkage disequilibrium with each other (T-786C/in- Table 3 shows the haplotype frequency estimates
tron 4 VNTR : D’=0.83, S.D.=0.05 ; T-786C/G894T : for BD patients and controls for the eight non-zero
D ’=0.56, S.D.=0.04 ; intron 4 VNR/G894T : D ’=0.96, haplotypes observed in our sample as well as the
S.D.=0.03 ; all pNOS-III and affective disorders 17 Table 3. Estimated NOS3 haplotype frequencies for MD patients, BD patients, and controls NOS3 haplotype (T-786C – Intron 4 VNTR – G894T) Controlsa BD pb MD pb c-a-g 0.130 (0.14) 0.150 0.515 0.133 0.949 c-a-t 0.000 (0.00) 0.003 0.212 0.001 0.484 c-b-g 0.040 (0.04) 0.006 0.022 0.073 0.182 c-b-t 0.228 (0.24) 0.197 0.408 0.249 0.696 c-c-t 0.004 (0.00) 0.000 0.523 0.000 0.291 t-a-g 0.027 (0.02) 0.000
18 A. Reif et al.
In a series of studies in NOS-III knockout mice, we 5-HT uptake (Kilic et al., 2003). A recently reported
found that animals lacking NOS-III exhibit reduced coding region variant of 5-HTT, segregating with a
responsiveness in a learned helplessness paradigm complex phenotype related to obsessive–compulsive
compared to wild-type controls (Reif et al., 2004). and affective disorders (Ozaki et al., 2003), results in
Since the learned helplessness paradigm has been continuously elevated 5-HT uptake and concomitant
suggested to represent an animal model of behav- loss of 5-HTT regulation by NO (Kilic et al., 2003).
ioural despair and depression (Vollmayr and Henn, These findings strongly point further towards an
2001), NOS-III knockout mice display an anti- interaction of both the nitrinergic and serotonergic
depressant-like phenotype. The notion that NOS-III systems in humans (Kiss and Vizi, 2001), and that
impacts on behavioural control is further sub- dysregulation of this interplay may be involved in
stantiated by several recent studies investigating the the pathogenesis of affective disorders.
behavioural phenotype of NOS-III knockout mice. In the recent years, there has been an increasing
Taken together, the main findings of these investi- interest in a hypothetical disease entity designated
gations are that animals lacking NOS-III are (a) less ‘ vascular depression’ (Alexopoulos et al., 1997)
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helpless, (b) better learners (Frisch et al., 2000), and thought to delineate a subgroup of depressive
(c) not as aggressive (male mice ; Demas et al., 1999). disorders, in which vascular dysfunction is proposed
Thus, several key syndromal dimensions of affective to underlie psychiatric symptoms especially in the
disorders including emotionality, impulsivity, ag- elderly (Baldwin and O’Brien, 2002 ; Camus et al.,
gression, and cognition are altered in NOS-III knock- 2004) suffering from cerebrovascular disease. The
out mice. finding that NOS3 haplotypes are associated with
Pharmacological studies provide further evidence the risk to develop cerebral small vessel disease
for an involvement of NOS in affective illness. (Hassan et al., 2004) suggests that NOS-III may
Although not isoform-specific and thus, not dis- contribute to the risk towards vascular depression.
criminatory between NOS-I and NOS-III, inhibitors While the connection between cerebrovascular
of NOS were shown to have antidepressive prop- disorder and depression might still be explained by
erties in the elevated plus maze (Volke et al., 1995) vascular lesions in critical brain regions and not by
and the forced swim test (Harkin et al., 1999 ; Volke a common pathophysiology, it remains an unresolved
et al., 2003), which seems to be mediated by the question why depression – with prognostic value –
serotonergic system. Serotonin (5-HT) depletion re- also occurs more frequently in cardiovascular disease.
sulted in a complete loss of the antidepressant NOS-III could be a possible link between cardio-
actions of NOS inhibitors (Harkin et al., 2003), vascular risk and affective disorder on a genetic basis,
whereas their effect was further augmented by 5-HT which makes it an apparent candidate gene in coron-
reuptake inhibitors (Harkin et al., 2004). This corre- ary disease with depression.
sponds well with neurochemical studies in which In conclusion, there is a small but significant
NOS-III knockout mice were found to display in- contribution of NOS3 to the genetic risk towards BD
creased 5-HT turnover in the cortex and the striatum which does not explain the evidence for possible
(Frisch et al., 2000). major gene effects found in informative pedigrees. As
As there are no animal models of BD, the investi- the protective haplotypes are relatively rare in the
gation of behavioural traits related to affective dis- general population, other genetic influences are
orders – e.g. helplessness and cognitive deficits related likely to play an important role in the pathogenesis of
to depression ; aggression and hyperactivity occurring affective disorders, with the NOS-III variation prob-
in mania – without regarding them as specific for ably modulating this genetic risk only in only a few
a given diagnostic entity (BD, MD, etc.) is the only subjects. NOS-III is, therefore, likely to represent a
way to obtain candidate genes from animal studies. disease modifier gene influencing the penetrance of
Nevertheless, this approach obviously has drawbacks. other genes. Given a prevalence of y1 % (Waraich
Apart from the limitations of the present study et al., 2004) of BD in the general population, a
mentioned above, which have to be borne in mind, protective factor of modest impact, however, can
there is, however, converging evidence from NOS-III also become important on a population-based level.
knockouts and human genetic findings pointing in Whether NOS3 influences the genetic risk towards
the same direction, that is, a distinct role for NOS-III affective disorders should be further tested in family-
in affective disorders. based studies, which would be a worthwhile future
Interestingly, the 5-HT transporter (5-HTT) can be task as NO synthases represent a novel and inno-
modulated by NO in that binding of NO increases vative drug target.NOS-III and affective disorders 19
Acknowledgements for synaptic plasticity. Proceedings of the National Academy
of Sciences USA 91, 4214–4218.
This study was supported by the Deutsche Forschung- Doyle CA, Slater P (1997). Localization of neuronal and
sgemeinschaft (Grant RE1632/1-1 to A.R., KFO 125/ endothelial nitric oxide synthase isoforms in human
1-1 to A.R. and K.P.L. and SFB581 to K.P.L.) and hippocampus. Neuroscience 76, 387–395.
the European Commission (NEWMOOD LSHM-CT- Frisch C, Dere E, Silva MA, Godecke A, Schrader J,
2003-503474). Huston JP (2000). Superior water maze performance and
increase in fear-related behavior in the endothelial nitric
oxide synthase-deficient mouse together with monoamine
Statement of Interest changes in cerebellum and ventral striatum. Journal of
Neuroscience 20, 6694–6700.
None. Gabbott PL, Bacon SJ (1996). Localisation of NADPH
diaphorase activity and NOS immunoreactivity in
astroglia in normal adult rat brain. Brain Research 714,
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