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Autosomal linkage analysis of a Japanese single multiplex schizophrenia pedigree reveals two candidate loci on chromosomes 4q and 3q.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 144B:735 –742 (2007)
Autosomal Linkage Analysis of a Japanese Single
Multiplex Schizophrenia Pedigree Reveals Two
Candidate Loci on Chromosomes 4q and 3q
Naoshi Kaneko,1 Tatsuyuki Muratake,1,2* Hideki Kuwabara,1 Takanori Kurosaki,3
Mitsuru Takei,4 Tsuyuka Ohtsuki,2,5 Tadao Arinami,2,5 Shoji Tsuji,6 and Toshiyuki Someya1
1
Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
CREST, Japan Science and Technology Agency, Kawaguchi-shi, Saitama, Japan
3
Honda Hospital, Uonuma, Niigata, Japan
4
Gunma Prefectural Psychiatric Medical Center, Isesaki, Gunma, Japan
5
Department of Medical Genetics, Graduate School of Comprehensive Human Sciences, University of Tsukuba,
Tsukuba, Ibaraki, Japan
6
Department of Neurology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
2
We analyzed a large multiplex schizophrenia
pedigree collected in mid-eastern Japan using
322 microsatellite markers distributed throughout the whole autosome. Under an autosomaldominant inheritance model, the highest pairwise
LOD score (LOD ¼ 1.69) was found at 4q (D4S2431:
theta ¼ 0.0), and LOD scores at two other loci 3q
(ATA34G06) and 8q (D8S1128) were 1.62 and 1.46,
respectively. In multipoint analysis, LOD scores of
the regions on 4q and 3q remained at a similar
level; however, the LOD score of the region on 8q
apparently decreased. Additional dense map analysis revealed haplotypes on 4q and 3q regions
shared by affected individuals. On chromosome
4q, the haplotype spanning about 8 centiMorgans
(cM) was shared by four of six genotyped individuals with schizophrenia and one affected individual whose haplotype was estimated. On 3q, the
haplotype spanning about 20 cM was shared by
five genotyped individuals with schizophrenia.
We obtained two candidate regions of major
susceptibility loci for schizophrenia on chromosomes 3q and 4q.
ß 2007 Wiley-Liss, Inc.
KEY WORDS:
genome scan; linkage analysis;
multiply affected family; schizophrenia; microsatellite marker
Please cite this article as follows: Kaneko N, Muratake
T, Kuwabara H, Kurosaki T, Takei M, Ohtsuki T,
Arinami T, Tsuji S, Someya T. 2007. Autosomal Linkage
Analysis of a Japanese Single Multiplex Schizophrenia
Pedigree Reveals Two Candidate Loci on Chromosomes
4q and 3q. Am J Med Genet Part B 144B:735–742.
*Correspondence to: Dr. Tatsuyuki Muratake, Department of
Psychiatry, Niigata University Graduate School of Medical and
Dental Sciences, 1-757 Asahimachi, Niigata 951-8510, Japan.
E-mail: mura@med.niigata-u.ac.jp
Received 27 August 2005; Accepted 21 November 2006
DOI 10.1002/ajmg.b.30488
ß 2007 Wiley-Liss, Inc.
INTRODUCTION
Genetic epidemiological studies, such as family, twin, and
adoption studies, have shown that genetic factors play an
important role in the pathogenesis of schizophrenia (MIM
181500) [Lichtermann et al., 2000; Tsuang et al., 2001];
however, its genetic factors are complex, and conclusive results
have not yet been determined. Like other complex diseases, it is
difficult to map the disease loci for several reasons, including
its non-Mendelian inheritance, diagnostic or phenotypic
definition, and disease and allelic heterogeneity. To overcome
those difficulties in the detection of susceptibility loci, several
approaches are possible. One method is to include more case
samples, such as a large number of affected pedigrees or pairs
of affected siblings, or more data for linkage disequilibrium
mapping with an extreme dense marker set. Over 20 genomewide linkage studies for schizophrenia have been reported and
two meta-analyses were performed. Badner and Gershon
[2002] applied the multiple scan probability method to
published genome scan data, and found evidence of schizophrenia susceptibility loci on chromosomes 8p, 13q, and 22q.
Lewis et al. [2003] applied the Rank-based genome scan metaanalysis method to published and unpublished data. They
reported that most significant evidence of schizophrenia was
found on chromosome 2q and evidence was also found in nine
other regions (5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p). Most
genome-wide linkage studies for schizophrenia analyzed a
relatively large number of pedigrees consisting of few members. Though a large number of pedigrees can increase the
power, it may cause pedigree-to-pedigree genetic heterogeneity. Another method is to analyze multiply affected pedigrees
with the same etiological background. Although the majority of
cases conceivably result from the interaction of several genes
and environment factors, it was proposed that the causes of
schizophrenia were diverse and that single rare genes or the
most common specific genes caused schizophrenia in a
minority of cases [Gottesman, 1991]. Compared with the nonparametric approach with a large number of pedigrees with
relatively few members such as affected sib-pair families, a
gene or genes with a major effect may be segregated in large
multiplex families. Small sets of large multiplex pedigrees are
powerful tools to study complex diseases as in the case of earlyonset Alzheimer’s disease [Schellenberg et al., 1992]. Therefore, we performed a genome scan on a multiply affected family
in mid-eastern Japan to identify the gene with the major effect
in schizophrenia. Here, we report linkage analysis with 322
736
Kaneko et al.
microsatellite markers distributed throughout the whole
autosome to identify an autosomal susceptibility locus.
MATERIALS AND METHODS
Pedigree Sample
A moderately large multiplex schizophrenia pedigree collected in mid-eastern Japan was analyzed (Fig. 1). All
individuals had Japanese ethnicity. The subjects participating
in this study gave written consent after receiving an explanation of the study procedures and their implications. This
study was approved by the ethics committee on genetics of the
Niigata University School of Medicine. We obtained peripheral
blood from 15 family members including 6 affected cases
(1 male and 5 females). Diagnoses were made using criteria of
the Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition (DSM-IV) on the basis of structured
interviews, review of clinical records, and information from
reliable relatives and mental health professionals who had
treated at least one of the pedigree members. Direct interviews
were conducted using the Structured Clinical Interview for
DSM-IV Axis I Disorders (SCID-I) and Axis II Disorders
(SCID-II). Final diagnoses were made by the consensus of two
trained psychiatrists (T.M. and H.K.) based on structured
interview records, medical charts, and other information. All
affected cases were diagnosed with schizophrenia according to
DSM-IV criteria. Eight family members were confirmed as
having no disorders on the Axis I Diagnosis of DSM-IV or any
personality disorders including schizotypal, schizoid, and
paranoid personality disorders that are regarded as being
within the schizophrenia spectrum [Kendler et al., 1995;
Tienari et al., 2003]. Those eight members were defined as
‘‘unaffected’’ in statistical analyses. One member had severe
mental retardation and was defined as ‘‘unknown.’’ Four
deceased individuals were defined as ‘‘affected’’ according to
the medical records and interviews with mental health
professionals. Other deceased members were defined as
‘‘unknown.’’
penetrance of the disease gene homozygote and heterozygote ¼ 0.8. Other estimated model parameters were as
follows: disease gene frequency ¼ 0.01, penetrance of the
normal gene homozygote ¼ 0.001. Age-dependant penetrance
was not used because the youngest unaffected man was
28 years old and woman was over 50, which exceeded the peak
age-at-onset of schizophrenia for each gender in the Japanese
population [Nakane et al., 1992].
Marker allele frequencies in the Japanese population
were obtained from the JSSLG web site (http://www.md.
tsukuba.ac.jp/public/basic-med/m-genetics/JSSLGhp/1stScr/
WeberJSSLGAlleleFreq.htm). For marker allele frequencies
not available on this site, we used frequencies in 25 newly
genotyped Japanese healthy individuals. After pairwise
linkage analysis, we obtained three promising regions at
chromosomes 3, 4, and 8. Multipoint LOD score linkage
analyses of these chromosomes were performed with the
LINKMAP program in the FASTLINK program. Marker order
and genetic distances between each marker were obtained
from the Marshfield Medical Clinic website [Broman et al.,
1998] (http://research.marshfieldclinic.org/genetics/).
Simulation analysis was also carried out with the same data
set. We used the same pedigree structure and the markers used
in the actual analysis to generate 1,000 unlinked replicates
with the SIMULATE program (ftp://linkage.cpmc.columbia.
edu/software/simulate) and then conducted analyses with the
MLINK used in the actual analysis. We obtained the LOD score
of 1 random occurrence per genome scan and 1 occurrence per
20 genome scans.
We also performed non-parametric linkage analysis using
the same data set by SIMWALK2, version 2.91 [Sobel and
Lange, 1996]. Non-parametric linkage analysis was performed
based on identity by descent measurements at the marker loci
and reports of empirical P-values for five non-parametric
statistics, BLOCKS, MAX-TREE, ENTROPY, NPL_PAIR, and
NPL_ALL. BLOCKS tended to be the most powerful for a
recessive trait and MAX-TREE for a dominant trait. The
remaining statistics were designed to be the most powerful for
additive traits. The level of significance was 0.05 in this
analysis.
Genotyping
Genomic DNA was extracted from peripheral blood by the
standard phenol/chloroform method. Microsatellite markers
were used (MapPairs human screening set ver. 9; Research
Genetics, Inc., Huntsville, AL), which are distributed throughout the genome with an average interval about 10 cM.
Polymerase chain reaction (PCR) was set up with 5 ng
genomic DNA, and PCR cycling consisted of denaturation
at 958C for 12 min, followed by 10 cycles at 948C for 15 sec, at
53–598C for 15 sec and at 728C for 30 sec, 20 cycles at 898C for
15 sec, at 53–598C for 15 sec and 728C for 30 sec, and concluded
with final extension at 728C for 10 min. All subjects were
genotyped using an ABI 377 genetic analyzer (Applied
Biosystems, Foster City, CA) with GeneScan program ver.2.1
(Applied Biosystems). Genotyping was performed under a
blind-to-diagnosis condition. Discrepancy from Mendelian
inheritance was checked using Checkfam software (http://
www.genstat.net/checkfam/). When a non-Mendelian pattern
of inheritance was observed, genotyping was repeated.
Additional Data
Two promising regions on chromosomes 4 and 3 were
obtained by pairwise and multipoint analyses, so we genotyped
24 and 34 SNPs spread over these regions, respectively
(Figs. 1, 2). These SNP markers were typed using the Illumina
BeadStation 500G (Illumina, San Diego, CA) according to the
manufacturer’s standard recommendation. We re-analyzed
the multipoint LOD score by LINKMAP program using SNPs
and microsatellite markers on these regions. Allele frequencies
of SNPs in Asian populations were obtained from the
Illumina website (http://www.illumina.com/General/support/
excel/11186808_Linkage_IV_B_Genetic_Map_v2_RevD.xls).
For dense analyses, marker order and genetic distances
between SNPs and microsatellite markers were based on the
deCODE map [Kong et al., 2002]. Haplotypes of these regions
were estimated using the MERLIN program [Abecasis et al.,
2002]. We employed a haplotype estimation mode which
provides haplotypes corresponding to the most likely pattern
of gene flow.
Statistical Analyses
Pairwise LOD score linkage analyses were performed with
the MLINK program in the FASTLINK package version 4.1
[Cottingham et al., 1993]. Based on the observation of disease
distribution in the pedigree, an autosomal-dominant inheritance model was employed. Consequently, we estimated the
RESULTS
Affected individuals were aggregated into two branches in
the pedigree. We found an affected married-in individual (II-2)
in the pedigree and surveyed these relatives as possible;
however, we could not identify more affected individuals.
Linkage Study of Single Multiplex Pedigree for Schizophrenia
737
Fig. 1. Structure of the pedigree with individual IDs and a shared haplotype on chromosome 4 are shown. Black rectangles represent affected cases.
Unenclosed IDs represent unaffected individuals. White rectangles are defined as unknown. Genotyped individuals are identified by (*) symbols. Deceased
individuals are identified by (þ) symbols. To protect personal information, gender, age, and order of siblings have been disguised. On the left of the figure,
genotyped markers are listed with genetic distances of microsatellite markers according to the Marshfield Medical Clinic website. A common haplotype was
shared by four genotyped cases (III-2, 8, 9, and IV-1), one estimated case (III-4), and one genotyped individual whose affected status is unknown (IV-4).
There were two pairs of transmission from a possible-carrier
father to an affected son in the pedigree; therefore, the mode of
inheritance was presumed to be not X-linked.
A total of 322 microsatellite markers were used in this
analysis (average interval 10.8 cM, range ¼ 0.6–26.4 cM). In
1,000 simulation analyses, we obtained on average one highest
LOD score, 1.30 per genome scan, in the absence of linkage. The
highest LOD score of 1.66 appeared only once in every
20 genome scans in the absence of linkage (Fig. 3).
The result of pairwise LOD score analysis is shown in
Figure 4 and the Table I. D4S2431 generated the highest
pairwise LOD score (LOD score ¼ 1.69: theta ¼ 0.0). This score
exceeded the one random occurrence per 20 genome scans in
simulation analysis. ATA34G06 and D8S1128 generated LOD
738
Kaneko et al.
Fig. 2. Haplotype on chromosome 3. A common haplotype was shared by five genotyped cases (III-1, 2, 3, 8, and 9). SNP markers unrelated to haplotype or
not informative were omitted.
Linkage Study of Single Multiplex Pedigree for Schizophrenia
Fig. 3. The distribution of the highest lod scores from the permutations.
Frequencies of the highest lod scores from the permutations were shown.
The frequencies were evaluated at intervals of a LOD score of 0.1.
739
analyses were conducted on these three chromosomes using
LINKMAP program. For chromosome 4, the highest LOD score
of 1.69 was obtained at 174.8 cM from p-ter (nearest marker:
D4S2431). The highest LOD score for chromosome 3 was 1.66
at 139.5 cM (nearest marker: ATA34G06). For chromosome 8,
the highest LOD score decreased to 1.04 at 138.3 cM.
Additional analysis using a dense SNP map was carried out
on promising regions on chromosomes 4 and 3 as they
maintained a relatively high multipoint LOD score. The
results of multipoint LOD score analysis using SNP and
microsatellite data are shown in Figure 5. On chromosome 4,
the multipoint LOD score was still high, and the estimated
haplotype from rs1824347 to rs2044868 (spanning about 8 cM)
was shared by five affected individuals (four genotyped and one
estimated) and one unknown individual (Fig. 1). Also on
chromosome 3, the multipoint LOD score was high over 20 cM,
and a haplotype from rs326361 to rs1355782 was shared by five
affected individuals (all genotyped) and not shared by all
unaffected and unknown individuals (Fig. 2).
DISCUSSION
scores of 1.62 (theta ¼ 0.0) and 1.46 (theta ¼ 0.0), respectively,
exceeding the score of one occurrence per genome scan; other
markers did not exceed this LOD score. On the other hand, by
non-parametric linkage analysis, significant linkage was
observed at GAAT1A4 on chromosome 8 (P-value for NPL_ALL
statistic ¼ 0.0428), D9S1118 on chromosome 9 (P-value for
ENTROPY statistic ¼ 0.0336 and P-value for NPL_PAIR
statistic ¼ 0.0394), and D10S212 on chromosome 10 (P-value
for ENTROPY ¼ 0.0368, P-value for NPL-PAIR ¼ 0.0474, and
P-value for NPL_ALL ¼ 0.0403); however, these values were
nominal and quite modest under the conditions of genome wide
analysis. Consequently, additional analyses were not carried
out on these regions.
As three promising regions on chromosomes 3, 4, and 8 were
found on pairwise parametric linkage analysis, multipoint
This study attempted to identify linkage to schizophrenia
susceptibility loci by analyzing a moderately large multiplex
schizophrenia pedigree in the Japanese population. The
pedigree is highly multiplex with schizophrenia and would be
useful for identifying a ‘‘pedigree-specific’’ Mendelian gene, if it
exists. It is considered that multiple genes and environments
are associated with developing schizophrenia in most cases;
however, it is helpful to identify rare single or major genes
associated with schizophrenia to realize the molecular pathogenesis of schizophrenia, as in other common diseases
(e.g., Alzheimer’s disease, diabetes, or hyperlipidemia) [Peltonen et al., 2006]. To avoid Type II error due to limited
information from the moderate extent of the pedigree, we
undertook simulation analysis to obtain the score of linkage
support.
Fig. 4. Pairwise LOD score throughout the whole autosome (theta ¼ 0.0). Chromosomes are arranged by number from p-ter to q-ter with genetic
distances on a linear scale. Horizontal broken lines are LOD scores 1.66 and 1.30, respectively.
b
124.2
134.6
138
152.6
161.0
158.0
167.6
176.2
181.9
195.1
125.3
135.1
139.5
148.1
164.5
110.2
58.3
170.9
cM
0.1
0.278750
0.722962
1.205113
0.682373
0.159391
0.305645
0.186203
1.217937
0.339390
0.054438
0.336288
0.704249
1.065193
0.096582
0.534285
0.667207
0.017026
0.208246
Theta ¼ 0.0
0.515631
0.923861
1.621723a
1.685463
0.100501
0.576538
0.229854
1.692203b
0.619805
0.371202
1.498008
0.883282
1.461049a
0.640357
2.372965
0.842408
0.467966
0.398779
0.4
0.042886
0.106277
0.134704
0.033017
0.048992
0.038391
0.044953
0.098516
0.041830
0.035219
0.040123
0.051849
0.094896
0.008530
0.017932
0.078233
0.055912
0.022703
0.3
0.091987
0.278214
0.405821
0.137655
0.106145
0.128451
0.091258
0.351513
0.142952
0.073772
0.086083
0.224380
0.327973
0.001397
0.070606
0.248104
0.046218
0.001753
0.2
0.160810
0.496608
0.784987
0.334330
0.151595
0.253256
0.139004
0.750962
0.272287
0.098514
0.161746
0.465290
0.672140
0.011664
0.196872
0.460766
0.000892
0.077187
The LOD scores 1.62 and 1.46 of ATA34G06 and D8S1128 exceed the highest score of random occurrence of a genome scan.
The LOD score 1.69 of D4S2431 exceeds the highest score of random occurrence of 20 genome scans.
3
3
3
3
3
4
4
4
4
4
8
8
8
8
8
8
9
10
D3S3045
D3S2460
ATA34G06
D3S1764
D3S1744
D4S1629
D4S2368
D4S2431
D4S2417
D4S408
D8S592
D8S1179
D8S1128
D8S256
D8S373
GAAT1A4
D9S1118
D10S212
a
Chr
Marker
Pairwise LOD score obtained by parametric linkage analysis
0.9382
0.6601
0.6566
0.4182
0.2437
0.6313
0.7743
0.6573
0.6548
0.9350
0.9463
0.6590
0.2109
0.3837
1.0000
0.3065
0.2145
0.1931
BLOCKS
0.5849
0.4847
0.4853
0.9476
0.4760
0.7892
0.6961
0.4843
0.9534
0.9578
0.9557
0.4839
0.4866
0.7899
0.9498
0.1560
0.1154
0.1641
MAX-TREE
0.7673
0.2636
0.2601
0.3741
0.1601
0.5174
0.5345
0.3643
0.4627
0.8991
0.8858
0.2191
0.0811
0.3487
0.9923
0.0827
0.0336
0.0368
ENTROPY
0.6894
0.2177
0.2101
0.5246
0.2561
0.5808
0.5175
0.3072
0.5455
0.9209
0.8925
0.1787
0.1396
0.4661
0.9923
0.0603
0.0394
0.0474
NPL_PAIR
P-value obtained by non-parametric analysis
TABLE I. The parametric and non-parametric pairwise LOD score of the promising markers and adjacent markers
0.6431
0.1601
0.1523
0.5485
0.2335
0.5644
0.4370
0.1543
0.5198
0.8928
0.8071
0.1364
0.1362
0.4416
0.9720
0.0428
0.0634
0.0403
NPL_ALL
740
Kaneko et al.
Fig. 5. The results of multipoint linkage analysis of SNPs and
microsatellite markers on chromosomes 4 and 3. a: Chromosome 4,
(b) Chromosome 3. Marker order and genetic distances between markers
are based on the deCODE map in those analyses.
As mentioned above, pairwise LOD score analysis provided
three promising loci with linkage to schizophrenia at marker
D4S2431 on chromosome 4q31, marker ATA34G06 on 3q13,
and marker D8S1128 on 8q24. In multipoint analysis, LOD
scores on two loci on 4q31 and 3q13 remained at a similar
level, whereas the LOD score of the locus on 8q24 apparently
decreased. These signals were very weak compared with
the thresholds for significant linkage and suggestive linkage
by Lander and Kruglyak [1995]. The thresholds of Lander
and Kruglyak were derived from the assumption of densemarker genotyping and complete extraction of inheritance
information; therefore, these thresholds were strict and
there was a risk of failure to detect significant linkage.
Wiltshire et al. [2002] conducted simulation analyses with
complete autosomal genomes for sets of sib-pair families under
the null hypothesis of no linkage and suggested that an
independent region showing evidence of linkage with a LOD
score of 1.51–1.55 is expected to occur once by chance per
autosomal genome scan under experimental and data conditions encountered during a typical primary autosomal genome
scan (a 10 cM marker map and 15% missing genotypes). Our
results of two-point linkage analysis on markers D4S2431 and
ATA34G06 exceeded this score.
Non-parametric linkage analysis did not show sufficient
results in this study. This might be due to our pedigree
structure and/or the number of genotyped individuals not
having adequate information to determine allele sharing or
identical descent between affected pedigree members.
Linkage Study of Single Multiplex Pedigree for Schizophrenia
Subsequent dense map analyses on chromosomes 4q and 3q
revealed two haplotypes shared by pedigree members with
schizophrenia. One haplotype spanned about an 8 cM around
marker D4S2431 on chromosome 4q. Straub et al. [2002]
reported linkage support at 4q24-32 including the D4S2431
locus in 270 Irish multiplex schizophrenia families. Both
Japanese linkage analysis with schizophrenia using sib pair
families [Japanese Schizophrenia Sib-Pair Linkage Group
(JSSLG), 2003] and using two multiply affected families in
Japan [Rees et al., 1999] did not provide linkage support at this
region. Another haplotype spanned about 20 cM including
markers D3S2460 and ATA34G06 on 3q. Paunio et al. [2001]
reported Zmax ¼ 2.17 for marker D3S2460 that was located
134.6 cM from p-ter of chromosome 3 using 53 pedigrees that
were internally isolated in Finnish schizophrenia pedigrees.
They subsequently failed to maintain a high LOD score using
238 Finnish pedigrees on this locus. Initial sib-pair analysis in
Japanese pedigrees reported nominal significance with MLS
1.11 at 40 cM distal from the region [Japanese Schizophrenia
Sib-Pair Linkage Group (JSSLG), 2003]. Chromosome 8p is one
of the most promising regions linked to schizophrenia [Badner
and Gershon, 2002; Berry et al., 2003; Owen et al., 2004],
whereas there are few reports of linkage support at chromosome 8q, especially around D8S1128. Since our multipoint
linkage analysis on 8q24 showed that the LOD score decreased
from the value of pairwise linkage analysis, this region may not
have a major role in the pedigree.
There have been several parametric linkage analyses for
schizophrenia in relatively large multiplex pedigrees. Coon
et al. [1998] reported the results of genome-wide parametric
linkage analysis using a large multiplex pedigree from the
Micronesian nation of Palau. Nine strictly defined cases of
schizophrenia and 17 unaffected relatives were genotyped and
the highest LOD score of 2.17 was found on 2p13-14. Rees et al.
[1999] analyzed 13 families, 11 UK families and 2 Japanese
families multiply affected with schizophrenia and related
disorders. Bailer et al. [2002] conducted genome-wide linkage
scan and the highest parametric LOD score of 1.33 was
observed for marker D3S1279 with five schizophrenia families.
We found two promising haplotypes on chromosomes 4q and
3q shared by most of the individuals with schizophrenia but
detailed examination is required to determine the schizophrenia susceptibility gene. Among several hundreds of genes
located in the two regions, the Dopamine receptor D3 gene
(DRD3) is located on 3q13. Association between the DRD3 gene
and schizophrenia was investigated in many populations as
well as in the Japanese population [Tanaka et al., 1996;
Ishiguro et al., 2000]; nevertheless, the results were conflicting. Recently, meta-analysis of association studies reported
that the DRD3 gene was genetically associated with schizophrenia [Lohmueller et al., 2003].
This study has some limitations, including an affected
married-in spouse (II-2), with four of six affected individuals
genotyped in this study being her offspring. Although we could
not find any affected individuals in her relatives, it is possible
that the spouse introduced susceptibility genes into the family.
This may produce a false assumption of the inheritance model
or reduce genetic homogeneity in the pedigree. Contrary to this
possibility, affected individuals in the left branch of the
pedigree (III-1, 2, 3, and IV-1) and those in the middle branch
(III-8 and 9) shared haplotypes on chromosomes 3q and 4q.
We, therefore, consider that the affected individuals of both
branches have a common genetic background. Separate
analysis of the left branch might reveal new candidate loci if
each branch of the pedigree has distinct genetic factors. This
analysis, however, could introduce type II error due to the
reduced observable number of meiosis.
In this study, we carried out an autosomal genome scan to
identify the major susceptibility locus for schizophrenia and we
741
located two candidate regions on chromosomes 3q and 4q.
Further linkage mapping of isolated populations might narrow
the candidate regions, or linkage disequilibrium tests of
familial schizophrenia on these regions might reveal the
susceptibility gene for schizophrenia.
ACKNOWLEDGMENTS
We express our deep gratitude to all the subjects who took
part in the study. We are grateful to Dr. Chizuko Kishi at Kishi
Hospital, Mr. Mamoru Fukushima at Ohiradai Gakuen, and
many other mental health professionals for their help in
recruiting the subjects. We thank Dr. Kenju Hara, Dr. Takeshi
Ikeuchi, Dr. Hisashi Kobayashi, and Dr. Takashi Suzuki at
Department of Neurology, Brain Research Institute, Niigata
University for their helpful advice. Hiroshi Kusano, Miki
Inomata, Hiromi Tanabe, and Tomoko Yamada provided
excellent technical assistance.
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