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Association study between the TNXB locus and schizophrenia in a Japanese population.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 144B:305 –309 (2007)
Association Study Between the TNXB Locus and
Schizophrenia in a Japanese Population
Mamoru Tochigi,1 Xuan Zhang,2,3 Jun Ohashi,2 Hiroyuki Hibino,1 Takeshi Otowa,1 Mark Rogers,1
Tadafumi Kato,4 Yuji Okazaki,5 Nobumasa Kato,1 Katsushi Tokunaga,2 and Tsukasa Sasaki1,6*
1
Department of Neuropsychiatry, Graduate School of Medicine, University of Tokyo, Bunkyo, Tokyo, Japan
Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Bunkyo, Tokyo, Japan
3
Jilin University Research Center for Genomic Medicine, National Center of Human Genome Research, Jilin, P.R. China
4
Laboratory for Molecular Dynamics of Mental Disorders, Brain Science Institute, RIKEN, Wako-City, Saitama, Japan
5
Department of Neuropsychiatry, Faculty of Medicine, Mie University, Edobashi, Tsu City, Mie, Japan
6
Health Service Center, University of Tokyo, Bunkyo, Tokyo, Japan
2
The chromosome 6p21–24 region, which contains
the human leukocyte antigen (HLA) region, has
been suggested as an important locus for a
susceptibility gene for schizophrenia. Recently,
a significant association between schizophrenia
and the TNXB locus, located immediately telomeric of the NOTCH4 locus in the HLA region, was
observed. Few studies have further investigated
the region in schizophrenia. In the present study,
we investigated the region in a Japanese population. Subjects included 241 patients with schizophrenia and 290 controls. Twenty-six single
nucleotide polymorphisms (SNPs) and the corresponding haplotypes were analyzed. As a result,
exactly the same SNPs in the TNXB locus
(rs1009382 and rs204887) as in the previous study
were associated with schizophrenia (P ¼ 0.034
and 0.034, respectively, uncorrected). A SNP
(rs2071287) in the NOTCH4 locus and haplotype
around it were also suggested to associate with
the disease, consistent with another previous
study (P ¼ 0.041 and permutation P ¼ 0.024, respectively, uncorrected). Although these associations
became insignificant after Bonferroni correction,
the findings might provide support for the association of the TNXB locus or its adjacent region
of the NOTCH4 locus with schizophrenia.
ß 2006 Wiley-Liss, Inc.
KEY WORDS:
tenascin X (TNXB); NOTCH4;
chromosome 6; schizophrenia;
association study
Please cite this article as follows: Tochigi M, Zhang X,
Ohashi J, Hibino H, Otowa T, Rogers M, Kato T, Okazaki
Y, Kato N, Tokunaga K, Sasaki T. 2007. Association
Study Between the TNXB Locus and Schizophrenia in
a Japanese Population. Am J Med Genet Part B
144B:305–309.
*Correspondence to: Dr. Tsukasa Sasaki, M.D., Ph.D., Associate Professor, Associate Director, Health Service Center, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan.
E-mail: psytokyo@yahoo.co.jp
Received 28 March 2006; Accepted 14 August 2006
DOI 10.1002/ajmg.b.30441
ß 2006 Wiley-Liss, Inc.
INTRODUCTION
Linkage studies have indicated that the chromosome 6p21–
24 region may contain a susceptibility locus of schizophrenia
[Schwab et al., 1995; Straub et al., 1995; Wang et al., 1995;
Schizophrenia Linkage Collaborative Group for Chromosomes
3, 6, and 8, 1996]. The human leukocyte antigen (HLA) region,
located at 6p21.3, has been suggested as a particularly
important locus for a candidate gene for schizophrenia
(reviewed by Wright et al. [2001]).
In a previous study, Wei and Hemmings [2000] observed that
the NOTCH4 locus, located at the centromeric end of the HLAclass III region, was strongly associated with schizophrenia by
using five markers. However, subsequent studies using mainly
the same markers failed to replicate the initial findings
[McGinnis et al., 2001; Sklar et al., 2001; Fan et al., 2002;
Tochigi et al., 2004]. Nor did a meta-analysis of the association
studies of these five markers find a significant association
[Glatt et al., 2005]. Zhang et al. [2004], however, observed an
association of rs520692; not one of the five original markers
employed by Wei and Hemmings [2000], in 141 Han Chinese
trios (P ¼ 0.017).
Recently, linkage disequilibrium (LD) mapping was conducted in the region immediately telomeric of the NOTCH4
locus [Wei and Hemmings, 2004]. As a result, an association
between two single nucleotide polymorphisms (SNPs) in the
tenascin X (TNXB) locus (rs1009382 and rs204887) and
schizophrenia was observed in 122 family trios recruited in
the UK (P ¼ 0.00047 and 0.007, respectively). The tenascins
are a family of large multimeric extracellular matrix proteins
[Bristow et al., 1993]. There have been at least three family
members identified in humans [Erickson, 1993], including
tenascin R (TNR) located in 1q24, tenascin C (TNC) in 9q33 and
tenascin X (TNXA and TNXB) in 6p21.3. The TNXB gene spans
approximately 68.2 kb of DNA and consists of 45 exons [Yang
et al., 1999]. The TNXA gene is a partially duplicated segment
corresponding to intron 32 to exon 45 of the TNXB gene. The
tenascins are known to be involved in the morphogenesis,
migration, and growth of many organs and tissues. TNR and C
are prominent in the nervous system and have an impact on
neurite outgrowth and synaptic functions [Fuss et al., 1993;
Gotz et al., 1996]. TNX, structure of which shows a striking
similarity to TNR and C, is important for the proper deposition
of collagen fibers in dermis. TNX deficiency causes an
autosomal recessive form of Ehlers-Danlos syndrome, which
is a connective tissue disorder characterized by hyperextensive
skin, hypermobile joints, and tissue fragility [Burch et al.,
1997; Schalkwijk et al., 2001]. TNX is also known to be
associated with growth of central and peripheral nerves
[Geffrotin et al., 1995; Tucker et al., 2001]. Thus, the TNXB
306
Tochigi et al.
locus has been suggested to be a candidate gene for schizophrenia. To our knowledge, the initial study [Wei and
Hemmings, 2004] has been followed by only one replication
study from the same group, which observed no association
between TNXB and schizophrenia in 136 Chinese family trios
[Liu et al., 2004]. Further investigation of additional sites
throughout the NOTCH4 and TNXB loci should be conducted.
In the present study, we investigated the 6p21.3 region,
mainly the TNXB locus and the adjacent region of the NOTCH4
locus, in Japanese patients with schizophrenia. A greater
number of SNPs were investigated than in the previous studies
[Liu et al., 2004; Wei and Hemmings, 2004; Zhang et al., 2004].
To our knowledge, this is the first study which investigated the
region in a Japanese population.
SUBJECTS AND METHODS
Japanese patients and control subjects were recruited in the
vicinity of Tokyo, Japan. Subjects were 241 unrelated patients
with schizophrenia diagnosed by the DSM-IV criteria
(137 males and 104 females; age, 46.2 14.8 years, mean SD)
and 290 sex-matched unrelated healthy volunteers (165 males
and 125 females; age, 41.6 11.6 years). The objective of the
present study was clearly explained and written informed
consent was obtained from all subjects. The study was
approved by the Ethical Committee of the Faculty of Medicine,
the University of Tokyo.
Genome-DNA was extracted from leukocytes by using the
standard phenol-chloroform method. We genotyped 26 SNPs
as detailed in Table I. SNPs 1–9, 11, 12, 14–20, and 22 were
analyzed by using the fluorescence correlation spectroscopysequence specific primer-PCR (FCS-SSP-PCR) protocols
[Bannai et al., 2004]. SNPs 10, 13, 21, and 23–26 were selected
form the list of the Assay-on-DemandTM Products for ABI
PRISM 7900HT and analyzed by using the ABI PRISM
7900HT Sequence Detection System (Applied Biosystems,
Foster City, CA). SNPs 9, 12, 14, 17, 19, 20, and 22 were in
common with Wei and Hemmings [2004] and we covered all the
SNPs which showed a significant association with schizophrenia in that study (SNPs 12, 17, and 19).
A chi-square test was used to compare the SNP frequencies
between the patients and the controls. Haplotypes of the SNPs
and their frequencies were estimated by the maximumlikelihood method with an expectation–maximization algorithm [Excoffier and Slatkin, 1995]. The pairwise LD was
measured by using r2. The results of pairwise r2 were
visualized by using the GOLD program [Abecasis and Cookson,
2000]. Permutation P values were calculated in comparison of
haplotype frequencies between patients and controls [Fallin
et al., 2001]. The SNPAlyze 3.0Pro software (DYNACOM,
Yokohama, Japan) was used to estimate haplotype frequencies, LD, and permutation P values.
RESULTS
Genotypic distributions and allelic frequencies of the
26 SNPs compared between patients and controls are shown
in Table II. In the patients, the distributions of SNPs 17 and
19 deviated significantly from Hardy–Weinberg equilibrium
(P ¼ 0.044 and 0.044, respectively, uncorrected), while the
distributions of the other 24 SNPs were within the values
expected from the Hardy–Weinberg equilibrium. In the
controls, the distribution of SNP 21 deviated significantly
(P ¼ 0.008, uncorrected), while the distributions of the other
25 SNPs were within the values expected. Allelic frequencies
of SNPs 8 and 10 were significantly different between the
TABLE I. Profile of SNPs Located at 6p21.3, Genotyped in the Present Study
SNP
ID
dbSNP ID
Alleles
(major/minor)
Amino acid
change
Locus
Size of interval
(add up) (bp)
1
2
3
4
5
6
7
8
9
10
11
12a
13
14
15
16
17a
18
19a
20
21
22
23
24
25
26
rs447459
rs915894
rs2071282
rs2071284
rs520688
rs520692
rs422951
rs2071287
rs8365
rs1061808
rs204999
rs8283
rs2071293
rs204900
rs185819
rs2269428
rs204887
rs2269429
rs1009382
rs6472
rs6474
rs641153
rs7887
rs644827
rs660594
rs480092
C/T
C/A
C/T
G/A
A/G
A/G
A/G
G/A
G/C
C/A
A/G
T/C
C/T
T/G
G/A
C/A
C/T
G/A
A/G
C/G
G/A
C/T
A/C
C/T
A/G
A/G
—
Gln/Lys
Pro/Leu
—
Pro/Pro
Asp/Gly
Ala/Thr
—
—
—
—
—
—
Ser/Ala
Arg/His
Pro/His
—
Gly/Ser
Glu/Gly
Ser/Thr
Arg/Lys
Arg/Gln
—
—
—
—
—
NOTCH4
NOTCH4
NOTCH4
NOTCH4
NOTCH4
NOTCH4
NOTCH4
AGER
AGPAT1
—
CREBL1
TNXB
TNXB
TNXB
TNXB
TNXB
TNXB
TNXB
CYP21A2
CYP21A2
BF
BAT8
C6orf29
C6orf29
LSM2
0 (0)
18,283 (18,283)
1,447 (19,730)
216 (19,946)
85 (20,031)
2 (20,033)
257 (20,290)
17,950 (38,240)
22,030 (60,270)
11,856 (72,126)
26,568 (98,694)
26,679 (125,373)
20,613 (145,986)
6,107 (152,093)
6,513 (158,606)
19,867 (178,473)
974 (179,447)
43 (179,490)
3,076 (182,566)
18,257 (200,823)
963 (201,786)
92,706 (294,492)
49,633 (344,125)
26,106 (370,231)
1,191 (371,422)
72,351 (443,773)
AGER, advanced glycosylation end product-specific receptor; AGPAT1, 1-acylglycerol-3-phosphate O-acyltransferase 1; CREBL1, cAMP responsive element binding protein-like 1; CYP21A2, cytochrome P450, family 21,
subfamily A, polypeptide 2; BF, B-factor, properdin; BAT8, HLA-B associated transcript 8; C6orf29, chromosome 6
open reading frame 29; LSM2, LSM2 homolog; U6 small nuclear RNA associated (S. cerevisiae).
a
Significant associations with schizophrenia were observed in Wei and Hemmings [2004].
TNXB and Schizophrenia in Japanese
307
TABLE II. Genotypic Distributions and Allelic Frequencies of 26 SNPs Genotyped in the Present Study
Genotypic distributiona
Schizophrenia
Controls
SNP
ID
AA
Aa
aa
AA
Aa
aa
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
136
62
202
202
123
149
149
113
206
51
214
154
117
200
91
202
105
202
105
202
109
209
118
106
106
131
87
121
36
36
90
80
80
103
35
114
25
75
100
39
107
38
97
37
97
37
99
31
101
104
104
95
18
58
3
3
28
12
12
25
0
76
2
12
24
2
43
1
39
2
39
2
33
1
22
31
31
15
172
79
241
241
137
172
172
116
246
82
254
166
137
236
117
244
126
236
126
237
140
250
137
119
118
156
105
151
48
48
121
101
101
129
44
137
35
106
123
54
136
46
135
54
135
53
107
40
123
128
129
113
13
60
1
1
32
17
17
45
0
70
1
18
30
0
36
0
29
0
29
0
41
0
28
41
41
18
a
b
Minor allele frequency
P-valueb
P-value for
recessive model
(aa vs. AA þ Aa)b
Schizophrenia
Controls
P-valueb
0.33
0.64
0.44
0.44
0.59
0.81
0.81
0.12
0.98
0.072
0.64
0.29
0.95
0.24
0.22
0.55
0.077
0.19
0.077
0.21
0.65
0.52
0.94
0.80
0.76
1.00
0.14
0.35
0.23
0.23
0.83
0.66
0.66
0.081
1.00
0.061
0.46
0.54
0.88
0.12
0.083
0.27
0.034
0.12
0.034
0.12
0.86
0.27
0.82
0.65
0.65
0.98
0.255
0.492
0.087
0.087
0.303
0.216
0.216
0.317
0.073
0.552
0.060
0.205
0.307
0.089
0.400
0.083
0.363
0.085
0.363
0.085
0.342
0.068
0.301
0.344
0.344
0.259
0.226
0.467
0.086
0.086
0.319
0.233
0.233
0.378
0.076
0.479
0.064
0.245
0.316
0.093
0.360
0.079
0.333
0.093
0.333
0.091
0.328
0.069
0.311
0.365
0.366
0.260
0.26
0.43
0.96
0.96
0.57
0.51
0.51
0.041
0.84
0.019
0.81
0.13
0.77
0.83
0.18
0.83
0.30
0.65
0.30
0.72
0.63
0.97
0.73
0.49
0.46
0.99
‘‘A’’ and ‘‘a’’ represent major and minor alleles at each SNP site, respectively.
Uncorrected values. Significant values are shown in italics.
controls and patients (P ¼ 0.041 and 0.019, respectively,
uncorrected). No significant difference was observed in the
allelic frequencies of the other SNPs between the two groups.
No significant difference was observed in the genotypic
distributions between patients and controls (2 3 comparison). However, when analyzed in the recessive model,
genotypic distributions of SNPs 17 and 19 differed significantly
between the controls and patients (P ¼ 0.034 and 0.034,
respectively, uncorrected). No significant difference was
observed in the recessive-model genotypic distributions of the
other SNPs between the two groups.
The pairwise r2 between the 17 SNPs with a high-frequency
(>20%) minor allele in the patients is shown in Figure 1. There
was no significant difference in r2 between the controls and
patients (data not shown). Figure 1 suggests the presence of
two blocks of strong LD, roughly coinciding with the NOTCH4
(SNPs 5–8) and TNXB (SNPs 13–21) genes, respectively. In
each LD block, haplotypes and their frequencies were
estimated. Table III shows estimated frequencies of the
haplotypes consisting of SNPs 5–8. A significant difference
was observed in the frequency of one of the haplotypes
(‘‘0-0-0-1’’) between the controls and patients (0.145 vs. 0.102,
permutation P ¼ 0.024, uncorrected). No significant difference
was observed in frequencies of other estimated haplotypes or in
distributions of all estimated haplotypes between the controls
and patients (global permutation P ¼ 0.10). With respect to the
haplotypes consisting of SNPs 13–21, no significant difference
was observed in the frequencies of any estimated haplotype or
in distributions of all estimated haplotypes between the
controls and patients (global permutation P ¼ 0.24). Further
haplotype estimation of the LD block including SNPs 13–21
was conducted by selecting five SNPs with a high-frequency
(>30%) minor allele (SNPs 13, 15, 17, 19, and 21). However, no
significant difference was observed (global permutation
P ¼ 0.22).
Fig. 1. Pattern of LD in the telomeric region of the NOTCH4 locus in the
patients. Pairwise LD between SNPs, as measured by r2, is represented.
Regions of high and low degrees of LD are shown in red and blue,
respectively. [Color figure can be viewed in the online issue, which is
available at www.interscience.wiley.com.]
308
Tochigi et al.
TABLE III. Estimated Frequencies of the Haplotypes Consisting
of SNPs 5–8
Haplotype
Frequency
SNP 5 6
7
8
0
1
0
1
0
1
0
0
0
1
1
0
0
1
0
0
Schizophrenia Control
0.595
0.216
0.102
0.087
0.536
0.233
0.145
0.087
w2
Permutation
P-value
3.75
0.44
4.48
0.0029
0.06
0.52
0.024
0.91
Haplotypes whose frequencies were estimated >3% were described. In
each SNP, 0 and 1 correspond to the major allele and the minor allele,
respectively.
DISCUSSION
In the present study, we investigated the association of
26 SNPs in the telomeric region of the NOTCH4 locus and
schizophrenia. LD analysis suggests the presence of two LD
blocks in the region, roughly coinciding with the NOTCH4
(SNPs 5–8) and TNXB (SNPs 13–21) genes, respectively. In
the block including SNPs 5–8, allelic frequency of SNP 8 was
significantly different between the controls and patients
(P ¼ 0.041, uncorrected). Analysis of haplotype consisting of
SNPs 5–8 also showed a significant difference in the frequency
of one of the estimated haplotypes between the two groups
(permutation P ¼ 0.024, uncorrected). In the block including
SNPs 13–21, significant differences were observed in recessive-model genotypic distributions of SNPs 17 and 19 between
the controls and patients (P ¼ 0.034 and 0.034, respectively,
uncorrected). In the region between the two LD blocks,
there was a significant difference in allelic frequency of SNP
10 between the two groups (P ¼ 0.019, uncorrected).
Since all these differences were insignificant after
Bonferroni correction, these results must be interpreted with
caution. The possibility of type I error could be considered.
However these non-significant trends do point to SNPs 17 and
19; the SNPs which showed a significant association in the
previous Caucasian study, with the same excessive alleles
observed in the present study (P ¼ 0.007 and 0.00047,
respectively, uncorrected; Wei and Hemmings, 2004). Both
the present and previous studies observed low frequencies of
heterozygotes in the patients, resulting in deviation from
Hardy–Weinberg equilibrium in SNP 19 in the present and
previous study (P ¼ 0.044 and 0.01, respectively, uncorrected)
and in SNP 17 in the present study (P ¼ 0.044, uncorrected).
SNP 19 is a missense mutation located in exon 24 of the TNXB
gene, changing glutamic acid into glycine. These results
suggest that SNP 19 might be a candidate of susceptible
variants of schizophrenia. SNP 19 or other variants at strong
LD with it might affect the function of the TNXB gene,
although no study has investigated the effect of SNP 19 to our
knowledge. SNP 17 is a synonymous SNP located about 3 kb
away from SNP 19. The association of SNP 17 may be due to
complete LD with SNP 19. Estimated frequencies of the
haplotype consisting of SNPs 13–21, however, showed no
significant difference between the controls and patients. It
would be interesting to examine whether the estimated
haplotype is associated with schizophrenia in a recessive
model by a permutation procedure, although the available
software does not allow us to conduct the calculation at present.
The deviation from Hardy–Weinberg equilibrium in SNP 21 in
the controls might be a chance observation, although other
possibility could not be totally ruled out.
The haplotype consisting of SNPs 5–8 showed a significant
association with schizophrenia. SNP 8, which also showed a
significant association, has not been investigated in previous
studies, to our knowledge. Zhang et al. [2004], using 141 Han
Chinese trios, observed the association of the haplotype
consisting of SNPs 6 and 7, a part of the haplotype consisting
of SNPs 5–8 in the present study (global P ¼ 0.018, uncorrected). SNP 6 was by itself associated with schizophrenia in
Zhang et al. [2004] (P ¼ 0.017, uncorrected) and the excessive
allele of the SNP in their patients was in LD with that of SNP 8
in the present study. The LD block containing SNPs 5–8 might
be worth further investigation.
In contrast, SNP 10 showed the association independently
with the two LD blocks. To our knowledge, SNP 10 has not
been investigated in the previous studies. SNP 10 is in the
gene encoding 1-acylglycerol-3-phosphate O-acyltransferase 1
(AGPAT1), an enzyme that converts lysophosphatidic acid
(LPA) into phosphatidic acid (PA) in the endoplasmic reticulum [Leung, 2001]. Replication studies with a larger sample set
may be needed to confirm the association.
In conclusion, we might provide support for an association
between the TNXB locus or its adjacent region of the NOTCH4
locus and schizophrenia in Japanese subjects. Two SNPs (SNP
17 and 19 or rs204887 and rs1009382) in the TNXB locus were
significantly associated with schizophrenia in agreement with
previous research [Wei and Hemmings, 2004]. An association
between schizophrenia and SNP 8 and haplotype analysis
around it (SNPs 5–8) was also suggested, consistent with
another previous study [Zhang et al., 2004]. Further research
with a larger sample set and variant screening of the LD block
might provide more definite conclusions.
ACKNOWLEDGMENTS
The authors thank Mr. Fumitaka Sakurai for technical help.
MR was supported by postdoctoral fellowship from the Japan
Society for the Promotion of Science (ID: P 05234).
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