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Candidate gene analysis of 21q22 Support for S100B as a susceptibility gene for bipolar affective disorder with psychosis.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 144B:1094 –1096 (2007)
Brief Research Communication
Candidate Gene Analysis of 21q22: Support for S100B as a
Susceptibility Gene for Bipolar Affective Disorder
With Psychosis
S. Roche,1* F. Cassidy,1 C. Zhao,2 J. Badger,2 E. Claffey,3 L. Mooney,3 C. Delaney,3 S. Dobrin,5 and P. McKeon3,4
1
Smurfit Institute of Genetics, Trinity College, Dublin, Ireland
The Marshfield Clinic Center for Human Genetics, Marshfield, Wisconsin
3
St. Patrick’s Hospital, James’s Street, Dublin, Ireland
4
Department of Psychiatry, Trinity College, Dublin, Ireland
5
Monsanto Company, 3302 SE Convenience Blvd, Ankeny, Iowa
2
A genome-wide scan in 60 bipolar affective disorder (BPAD) affected sib-pairs (ASPs) identified
linkage on chromosome 21 at 21q22 (D21S1446,
NPL ¼ 1.42, P ¼ 0.08), a BPAD susceptibility locus
supported by multiple studies. Although this
linkage only approaches significance, the peak
marker is located 12 Kb upstream of S100B, a
neurotrophic factor implicated in the pathology
of psychiatric disorders, including BPAD and
schizophrenia. We hypothesized that the linkage
signal at 21q22 may result from pathogenic disease variants within S100B and performed an
association analysis of this gene in a collection of
125 BPAD type I trios. S100B single nucleotide
polymorphisms (SNPs) rs2839350 (P ¼ 0.022) and
rs3788266 (P ¼ 0.031) were significantly associated
with BPAD. Since variants within S100B have also
been associated with schizophrenia susceptibility, we reanalyzed the data in trios with a history
of psychosis, a phenotype in common between the
two disorders. SNPs rs2339350 (P ¼ 0.016) and
rs3788266 (P ¼ 0.009) were more significantly associated in the psychotic subset. Increased significance was also obtained at the haplotype level.
Interestingly, SNP rs3788266 is located within a
consensus-binding site for Six-family transcription factors suggesting that this variant may
directly affect S100B gene expression. Fine-mapping analyses of 21q22 have previously identified
transient receptor potential gene melastatin
2 (TRPM2), which is 2 Mb upstream of S100B, as a
possible BPAD susceptibility gene at 21q22. We
also performed a family-based association analysis of TRPM2 which did not reveal any evidence
for association of this gene with BPAD. Overall,
our findings suggest that variants within the
S100B gene predispose to a psychotic subtype of
BPAD, possibly via alteration of gene expression.
ß 2007 Wiley-Liss, Inc.
Grant sponsor: AWARE; Grant sponsor: National Heart Lung
and Blood Institute (NHLBI).
*Correspondence to: S. Roche, Smurfit Institute of Genetics,
Trinity College, Dublin 2, Ireland. E-mail: siobhan.roche@tcd.ie
Received 24 October 2006; Accepted 2 April 2007
DOI 10.1002/ajmg.b.30556
ß 2007 Wiley-Liss, Inc.
KEY WORDS:
schizophrenia; association; single
nucleotide polymorphisms (SNPs);
haplotype; TRPM2; linkage; disease
variant
Please cite this article as follows: Roche S, Cassidy F,
Zhao C, Badger J, Claffey E, Mooney L, Delaney C,
Dobrin S, McKeon P. 2007. Candidate Gene Analysis of
21q22: Support for S100B as a Susceptibility Gene for
Bipolar Affective Disorder with Psychosis. Am J Med
Genet Part B 144B:1094–1096.
Whole genome linkage scans of bipolar affective disorder
(BPAD) have identified numerous potential susceptibility loci,
including region 21q22. Linkage of BPAD to 21q22 is highly
replicated with positive findings extending from 35 to 45 Mb
[McQuillin et al., 2006]. Fine-mapping and candidate gene
analyses of this region have identified the transient receptor
potential gene melastatin 2 (TRPM2) as a candidate susceptibility gene at 21q22 [McQuillin et al., 2006; Xu et al., 2006].
The TRPM2 gene is implicated in regulating calcium homeostasis, a disturbance of which has been identified in bipolar
patients.
We recently performed a whole genome scan for linkage to
BPAD in a collection of 60 Irish BPAD affected sib-pairs (ASPs)
and also obtained evidence for linkage at 21q22 at a slightly
more distal region (D21S1446/47 Mb, multipoint NPL ¼ 1.42,
P ¼ 0.078, bipolar I disease model) [Cassidy et al., 2007].
Interestingly, marker D21S1446 is located 12 Kb upstream of
the S100B gene which encodes a glial cell-derived neurotrophic
factor that has been implicated in both neurological and
psychiatric diseases [Rothermundt et al., 2003]. Increased
levels of the S100B protein have been detected in the serum of
patients with BPAD and major depression [Machado-Vieira
et al., 2002; Schroeter et al., 2002; Arolt et al., 2003] and both
CSF and serum of schizophrenic patients [Rothermundt et al.,
2001, 2004] and may predict course of illness and treatment
outcome. Furthermore, variants within the S100B gene are
associated with schizophrenia [Liu et al., 2005]. It is currently
unknown whether the same is true for BPAD. As this gene had
previously been implicated in the pathology of BPAD, we
hypothesized that linkage at 21q22 could result from pathogenic variants within the S100B gene instead of or in addition
to TRPM2. Here, we report the novel finding that variants
within S100B are associated with BPAD.
Single nucleotide polymorphisms (SNPs) spanning the
S100B and TRPM2 genes were genotyped in a collection of
125 bipolar type I trios of Irish ethnicity. Participants were
diagnosed according to DSM-IV criteria and information
S100B and Bipolar Affective Disorder
obtained from the Schedule for Affective Disorders and
Schizophrenia (Lifetime version: SADS-LB) or Structured
Clinical Interview for DSM-IV-TR Axis I Disorders (SCID).
Genotyping was performed at KBiosciences, Hoddesdon, UK
using competitive allele-specific PCR (proprietary KASPar and
Applied Biosystems TaqmanTM technologies, Warrington,
UK). Single- and multi-marker association tests were performed using the transmission disequilibrium test (TDT)
implemented in Haploview and Transmit, respectively. All
SNPs were in Hardy–Weinberg equilibrium.
There was modest evidence for association of S100B SNPs
M2, M3, and M9 with BPAD (M2: P ¼ 0.022; M3: P ¼ 0.052; M9:
P ¼ 0.031; Table I). Markers M2 and M3 are in strong linkage
disequilibrium (LD) and are included within a single haplotype
block that extends from M1 to M5 but not to M9 (data not
shown). A sliding window haplotype analysis also revealed
borderline evidence for association of haplotypes comprised of
alleles from M3 and M4 with BPAD (Table I: global P ¼ 0.047).
As S100B variants may also increase susceptibility to schizophrenia, we restricted the association analysis to trios with a
proband that had experienced at least one psychotic episode of
mania or depression (86 trios). Psychotic features reported by
probands included grandiose delusions (56%), persecutory
delusions (12%), both grandiose and persecutory delusions
(24%), and other forms of delusions (8%). Both delusions and
hallucinations occurred in 23% of probands. Despite the
decreased power due to the reduced sample size, markers M2
and M9 were more significantly associated (M2: P ¼ 0.0159;
M9: P ¼ 0.009; Table I: BPI þ psychosis). Furthermore, the
global P-value for M3_M4 haplotypes was reduced from 0.047
(Table I: BPI) to 0.016 (Table I: BPI þ psychosis) and
haplotypes comprised of alleles from M8 and M9 were now
significantly associated (BPI: P ¼ 0.075; BPI þ psychosis:
P ¼ 0.025; Table I). It should be noted that protective haplotypes were the most significantly associated individual haplotypes in the BPI analysis. However, the most significantly
associated individual M8_9 haplotype (GG) in the BPI þ
psychosis analysis confers risk consistent with the single allele
TDT result for M9. Overall, the data suggest that variants
within S100B predispose to a psychotic subtype of BPAD.
Fourteen SNPs spanning the TRPM2 gene were also tested
for association. There was no evidence for association in either
1095
the single- or multi-marker association analyses (Table II).
Markers M5, a nonsynonymous SNP in exon 11 of TRMP2, and
M8 were previously associated with BPAD [McQuillin et al.,
2006; Xu et al., 2006].
The discovery that S100B variants are associated with
BPAD is interesting given the elevation of the protein in serum
from patients with manic and depressive episodes and the
influence of anti-depressive treatments [Schroeter et al., 2002],
such as fluoxetine [Manev et al., 2001], on these levels. S100B
protein levels are also increased in the ouabain-induced rat
model of mania [Machado-Vieira et al., 2004]. Transgenic mice
overexpressing S100B are hyperactive and exhibit possible
memory defects [Gerlai and Roder 1995], both phenotypes of
relevance to BPAD, and mutant mice lacking S100B exhibit
enhanced synaptic plasticity, learning, and memory
[Nishiyama et al., 2002]. Finally, S100B is primarily secreted
by glial cells which are implicated in the pathology of both
schizophrenia and BPAD. It is unclear whether the altered
levels of S100B in psychiatric patients are due to increased
secretion of S100B from glial cells, glial-cell abnormalities, or
possibly pathogenic disease variants in the S100B gene.
Our findings suggest that S100B is a susceptibility gene for a
psychotic subtype of BPAD. S100B is also a susceptibility factor
for schizophrenia which may be more genetically related to
psychotic than nonpsychotic forms of the BPAD. Illness
susceptibility may occur via altered gene expression. The
location of the associated variants within the promoter (M9)
and 30 UTR (M2-3) regions of the gene suggests that they may
affect gene expression. The lack of LD extending between these
regions may indicate the existence of more than one disease
variant within S100B. Bioinformatics analysis revealed that
the disease-associated G allele of M9 disrupts a Trex/MEF3
consensus recognition site, which is bound by Six-family
proteins [Himeda et al., 2004], suggesting that it could directly
affect S100B expression and may represent a functional
variant. Six-family proteins are expressed in the brain and
regulate brain development and possibly differentiation/
maturation of neuronal cells [Ohto et al., 1998; Kawakami
et al., 2000].
Although variants within TRPM2 have been associated with
BPAD in both Canadian and British case–control analyses,
this first family-based analysis of TRPM2 does not support
TABLE I. Results of Association Analysis of S100B SNPs
BPI þ psychosis
BPI
Marker
M1: rs3804040
M2: rs2839350
M3: rs2839351
M4: rs9722
M5: rs881827
M6: rs2839355
M7: rs2839359
M8: rs2839363
M9: rs3788266
M1_2
M2_3
M3_4
M4_5
M5_6
M6_7
M7_8
M8_9
Allele
T/NT
w2df
G
G
T
T
T
C
T
G
G
40:29
36:19
52:34
14:10
54:45
37:24
34:29
57:48
63:41
1.754
5.255
3.767
0.667
0.818
2.770
0.397
0.771
4.654
0.185
0.022
0.052
0.414
0.366
0.096
0.529
0.380
0.031
4.6802
4.7012
7.9533
3.4343
3.3193
1.8343
0.7953
6.9063
0.096
0.095
0.047
0.329
0.345
0.608
0.850
0.075
CA
AC
CC
TC
CT
TT
TA
GA
P-value
T/NT
w2df
P-value
29:23
30:14
39:24
13:06
39:30
29:20
22:21
43:30
47:25
0.692
5.818
3.571
2.579
1.174
1.653
0.023
2.315
6.722
0.405
0.016
0.059
0.108
0.279
0.198
0.879
0.128
0.009
5.1002
5.0352
10.3823
5.5962
0.9252
0.6712
2.1233
9.3293
0.078
0.081
0.016
0.061
0.630
0.715
0.547
0.025
a
CC
TC
a
a
GG
T, transmitted; NT, not transmitted; df, degrees of freedom. P-values </¼0.05 are indicated in bold. Global P-values for haplotypes with frequencies >5% are
shown.
a
Most significant individual haplotype in BPI þ psychosis analysis which differs from that in the BPI analysis (listed in allele column).
1096
Roche et al.
TABLE II. Results of Association Analysis of TRPM2 SNPs
Marker
M1: rs734336
M2: rs2096860
M3: rs9984977
M4: rs4818917
M5: rs1556314
M6: rs9974831
M7: rs1785454
M8: rs933151
M9: rs8129542
M10: rs2238724
M11: rs2238725
M12: rs2010779
M13: rs6518189
M14: rs4818922
Allele
T/NT
w2
P-value
Haplotype
w2df
P-value
C
T
C
C
T
T
C
C
A
G
A
A
C
A
38:26
36:30
45:44
46:39
40:36
45:39
42:40
46:41
28:23
35:23
47:43
43:43
39:29
31:26
2.250
0.545
0.011
0.576
0.211
0.429
0.049
0.287
0.490
2.483
0.178
0.000
1.471
0.439
0.134
0.460
0.916
0.448
0.646
0.513
0.825
0.592
0.484
0.115
0.673
1.000
0.225
0.508
M1_2
M2_3
M3_4
M4_5
M5_6
M6_7
M7_8
M8_9
M9_10
M10_11
M11_12
M12_13
M13_14
1.7062
1.1522
4.0512
4.2962
1.1343
2.8473
1.4762
1.3523
2.7622
3.8672
1.3583
2.7793
0.9922
0.426
0.562
0.132
0.117
0.769
0.416
0.478
0.717
0.251
0.145
0.715
0.427
0.609
T, transmitted; NT, not transmitted; df, degrees of freedom; Global P-values for haplotypes with frequencies >5% are shown.
association of TRPM2 variants with BPAD in Irish families. It
is possible that there is more than one susceptibility gene at
21q22 for BPAD which may explain the variance is linkage
findings in this region and the identification of more than
one candidate susceptibility gene. Although the resolution of
the fine-mapping analysis of 21q22 performed by McQuillin
et al. [2006] was very high across a 500 Kb region containing
the TRPM2 gene, the resolution outside of this region was
very low for LD mapping and could have missed additional
candidate genes, such as S100B.
In summary, we have shown that variants within the S100B
gene are associated with a psychotic subtype of BPAD. These
data suggest that pathogenic disease variants within S100B
may contribute to the altered protein levels observed in
psychiatric disorders.
ACKNOWLEDGMENTS
We thank all of the families who kindly participated in these
studies. This research was funded by the voluntary organisation, AWARE, and the National Heart Lung and Blood
Institute (contract NO1-HV-48141).
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