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Association of PIP5K2A with schizophrenia A study in an indonesian family sample.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 147B:1310 –1313 (2008)
Brief Research Communication
Association of PIP5K2A With Schizophrenia: A Study in an
Indonesian Family Sample
L. Saggers-Gray,1,2 H. Heriani,3 H.Y. Handoko,4 I. Irmansyah,3 A.A.A.A. Kusumawardhani,3 I. Widyawati,3
N. Amir,3 M.W.S. Nasrun,3 S.G. Schwab,1,2,5* and D.B. Wildenauer2,6
1
Western Australian Institute for Medical Research, Centre for Medical Research, University of Western Australia, Perth,
Western Australia, Australia
2
School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, Western Australia, Australia
3
Department of Psychiatry, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
4
Queensland Institute for Medical Research, Brisbane, Australia
5
School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia
6
Centre for Clinical Research in Neuropsychiatry, Graylands Hospital, Mt Claremont, Western Australia, Australia
PIP5K2A variants have been shown to be associated with schizophrenia in Caucasian populations. This study tested 12 PIP5K2A SNPs for
association with schizophrenia in a sample of 152
sib-pair families of Indonesian descent. All SNPs
had previously been tested for association with
schizophrenia in a German family sample by
Schwab et al. [2006; Mol Psychiatry] and seven
SNPs were nominally associated with schizophrenia in this previous study. The purpose of the
study was to examine whether previously implicated PIP5K2A variants influence susceptibility
to schizophrenia in populations of non-European
descent. No single markers showed nominal association with schizophrenia in this Indonesian
family sample, however multi-marker haplotypes
including a previously associated exonic SNP
marker revealed nominally significant association (P ¼ 0.03). Power to detect association was
greater than 80% for all previously implicated
variants except for rs11013052, where power
was greatly reduced due to the low minor allele
frequency of this marker in the Indonesian
sample. An explorative study combining the
results of this study with those of our previous
study indicated that rs11013052 was significantly
associated with schizophrenia in the combined
sample (P ¼ 0.002). The results of this study suggest that any contribution of previously implicated DNA variants within the PIP5K2A gene
to schizophrenia susceptibility in the Indonesian
population is only minor.
ß 2008 Wiley-Liss, Inc.
KEY WORDS: schizophrenia; PIP5K2A; association; Indonesia; genetic heterogeneity
Please cite this article as follows: Saggers-Gray L,
Heriani H, Handoko HY, Irmansyah I, Kusumaward-
Grant sponsor: NHMRC; Grant number: 404012.
*Correspondence to: Dr. S.G. Schwab, SCGH QEII, B-Block
Ground Floor, Hospital Avenue, 6009, Western Australia, WA
6009, Australia. E-mail: sschwab@cyllene.uwa.edu.au
Received 28 October 2007; Accepted 23 January 2008
DOI 10.1002/ajmg.b.30736
Published online 3 March 2008 in Wiley InterScience
(www.interscience.wiley.com)
ß 2008 Wiley-Liss, Inc.
hani AAAA, Widyawati I, Amir N, Nasrun MWS, Schwab
SG, Wildenauer DB. 2008. Association of PIP5K2A With
Schizophrenia: A Study in an Indonesian Family
Sample. Am J Med Genet Part B 147B:1310–1313.
The phosphatidylinositol-4-phosphate-5-kinase type IIa
(PIP5K2A) gene has been proposed as a putative susceptibility
gene for schizophrenia and bipolar disorder on both positional
and functional grounds. The gene maps to chromosome 10p
(10p12), a replicated linkage region for both disorders [Rice
et al., 1997; Faraone et al., 1998; Schwab et al., 1998; Straub
et al., 1998; Foroud et al., 2000; Levinson et al., 2000; DeLisi
et al., 2002; Holliday et al., 2005]. The PIP5K2A enzyme
catalyses the phosphorylation of phosphatidylinositol-5-phosphate on the D-4 position of the inositol ring to form
phosphatidylinositol-4,5-bisphosphate, an important phosphoinositide signaling molecule [Rameh et al., 1997]. Attenuation of phosphoinositide signaling has been proposed as a
mode of action for the mood stabilizing drugs lithium, valproic
acid, and carbamazepine, therefore the PIP5K2A gene has
been implicated as a functional candidate for both disorders
[Hallcher and Sherman, 1980; Wolfson et al., 2000; Shaltiel
et al., 2004].
DNA sequence variants within the PIP5K2A gene have
previously been shown to be associated with schizophrenia in
two samples of Caucasian origin. Schwab et al. examined
54 variants in the vicinity of the PIP5K2A gene in a sample of
65 families. Four variants were significantly associated with
schizophrenia at an experiment wide level including a coding
SNP (rs10828317), located in exon 7 of the gene. This SNP
causes a non-synonymous amino-acid exchange (N ! S) in the
PIP5K2A protein [Schwab et al., 2006]. This association
between rs10828317 and schizophrenia has been replicated
by Bakker et al. [2006] in a Dutch sample [Bakker et al., 2006].
While association of the SNP rs10828317 with schizophrenia
has been replicated in independent samples, the evidence for
association is not as strong for other SNPs within the PIP5K2A
gene [Bakker et al., 2006; Schwab et al., 2006]. Studies by Abou
Jamra et al. [2006] and Stopkova et al. [2003, 2005] were
unable to detect a significant association between PIP5K2A
polymorphisms and schizophrenia or bipolar disorder [Stopkova et al., 2003, 2005; Abou Jamra et al., 2006].
All of the studies investigating the association of PIP5K2A
variants with schizophrenia have been conducted in populations of European descent. Genetic heterogeneity may play a
role in the non-replication of linkage and association findings
in psychiatric disorders. As such, it is unclear whether the
association between PIP5K2A variants and schizophrenia in
European populations will also be detected in populations of
Association of PIP5K2A With Schizophrenia
different ethnicity. This report describes a family based
association study that was conducted in a sample of 152
Indonesian sib-pair families. The purpose of this study was
to investigate whether variation at the PIP5K2A locus is
associated with schizophrenia in a population of non-European
descent.
The Indonesian sib-pair family sample comprised 687
individuals from 152 families. The sample size was reduced
to 612 individuals from 126 families following the exclusion of
75 individuals. These DNA samples were excluded primarily
on the basis of preliminary results from a genome-wide scan
using the same family sample, which indicated Mendelian
errors in some families, or DNA of insufficient quantity or
quality for the genotyping procedure. All individuals were
interviewed using Psychosis Screen (PS), Diagnostic Interview
for Psychosis (DIP) [Jablensky et al., 2000], Psychiatric and
Personal History Schedule (PPHS) [WHO, 1996], and Family
Interview for Genetic Studies (FIGS) [Maxwell, 1992]. Consensus diagnosis of schizophrenia was established by independent psychiatrists based on DSM-IV and ICD-10 criteria.
Written informed consent was obtained from all participants.
This research was approved by the local Human Research
Ethics Committees.
Twelve SNPs from within the PIP5K2A gene and the
surrounding regions were selected for examination of association with schizophrenia. All SNPs had previously been
studied for association with schizophrenia in a sample of 65
families by Schwab et al. [2006]. Seven of these SNPs were
associated with schizophrenia in our previous study
(rs1417374, rs11013052, rs943190, rs10828317, rs10430590,
rs746203, and rs8341).
Individuals were genotyped for the 12 markers using either
the Amplifluor1 SNPs Genotyping System or a TaqMan1
Validated SNP Genotyping Assay (Applied Biosystems, Foster
City, CA), as described by us previously [Morar et al., 2007].
Departure from Hardy–Weinberg equilibrium in the parental
generation was assessed using a w2 test (1 d.f.). P-values for
association of single markers and two- and three-marker
haplotypes with schizophrenia were calculated using FAMHAP 15 with the ‘‘zhao’’ option. Under this option the program
performs a haplotypes TDT-like test for association which is
valid for families containing multiple offspring, even in the
presence of linkage. Monte Carlo simulations are used to
produce an overall corrected P-value for the global null
1311
hypothesis of no association in the presence of linkage [Zhao
et al., 2000; Knapp and Becker, 2003; Becker and Knapp,
2004a,b].
Genotyping completeness was >98% for all markers except
rs943194 (97.4%) and rs8341 (95.1%). Genotyping completeness was lowest for the one marker genotyped using the
TaqMan1 method. No deviation from Hardy–Weinberg
equilibrium was detected for any of the markers in the parental
generation. Single markers were not associated with schizophrenia (P < 0.05). Transmitted/non-transmitted ratios and
P-values for association with schizophrenia for all markers are
shown in Table I. rs1171506 and rs11013052 had high
transmitted/non-transmitted ratios (13/6 and 10/3, respectively), but low minor allele frequencies (<4.5%), which
resulted in reduced power to detect association.
All possible two- and three-marker haplotype combinations
were calculated and tested for association with schizophrenia.
Seven haplotypes produced nominally significant P-values
(0.047–0.022), however under the global null hypothesis of no
association in the presence of linkage, none of these P-values
remained significant. The three haplotypes with the lowest
nominal P-values contained either rs1171506 or rs11013052.
Transmitted/non-transmitted ratios and P-values for association with schizophrenia for all nominally associated multimarker haplotypes are shown in Table II.
Power to detect association was calculated using the Genetic
Power Calculator [Purcell et al., 2003] and genotypic relative
risks as reported by Schwab et al. [2006], assuming a multiplicative model. Power to detect association at the a ¼ 0.05 level
was greater than 80% for all previously associated markers
except rs11013052, for which power was only 19%. Allele
frequencies had a major impact on power, as power was less
than 30% for the two markers where the over-transmitted
allele had a frequency greater than 0.96 (rs11013052 and
rs1171506).
In order to increase power for rs11013052 and rs1171506, we
combined the data from the current study with the data
previously reported by Schwab et al. [2006]. rs11013052 was
significantly associated with schizophrenia (P ¼ 0.002) in this
exploratory study. The P-value of 0.002 for association of
rs11013052 with schizophrenia in the combined sample was
slightly lower than the P-value of 0.005 in the German sample
alone, indicating that the Indonesian sample contributed to the
observed association.
TABLE I. Characteristics and P-Values for All SNPs Tested for Association With Schizophrenia in the Present Study
Variant
dbSNP IDa
Distance to
next locus
(kb)b
M1
M2
M3
M4
M5
M6
M7
M8
M9
M10
M11
M12
rs1417374
rs946961
rs1891898
rs1132816
rs1171506
rs943194
rs11013052
rs943190
rs10828317
rs10430590
rs746203
rs8341
33.6
77.3
14.4
51.4
42.0
47.4
20.1
2.7
6.6
2.5
5.4
—
a
Frequencyd
Location
Polymorphismc
Intergenic
Intergenic
Intergenic
PIP5K2A, exon 1
PIP5K2A, intron 1
PIP5K2A, intron 1
PIP5K2A, intron 4
PIP5K2A, intron 6
PIP5K2A, exon 7
PIP5K2A, intron 7
PIP5K2A, intron 8
Intergenic
C/T
G/C
T/C
T/C
G/A
T/G
C/A
A/G
A/G
T/A
A/G
C/T
Affected
0.820459
0.47247
0.860174
0.886159
0.963629
0.905369
0.973025
0.609114
0.579898
0.563777
0.557479
0.622669
Unaffected
T/NTe
PTDT
0.80897
0.483088
0.851056
0.879718
0.960636
0.877327
0.953869
0.558567
0.556701
0.563509
0.537547
0.588886
46/45
76/73
36/25
34/26
13/6
31/22
10/3
71/72
69/75
67/78
74/85
67/71
1.000
0.885
0.1453
0.300
0.215
0.224
0.125
1.000
0.685
0.399
0.423
0.816
Variant ID as listed on the NCBI dbSNP database.
Calculated from the locations given in the UCSC Human Genome Browser Gateway March 2006 Assembly.
Major/minor allele. Note that alleles are described in relation to the þ strand.
d
Frequency estimates for ‘‘affected’’ are based on the frequency in a single affected offspring per family, frequency for ‘‘unaffected’’ is calculated from the nontransmitted alleles to a single affected offspring per family. Frequencies are given for the major allele as determined by Schwab et al. [2006]. These alleles
correspond to the major alleles in the Indonesian population for all markers except rs946961.
e
Transmitted/non-transmitted alleles, corresponding to major alleles.
b
c
1312
Saggers-Gray et al.
TABLE II. Transmission of Two and Three-Locus Haplotypes to Affected Offspring
a
Loci
M3-M5
M3-M5-M7
M5-M7
M4-M10
M4-M9-M10
M4-M7-M10
M3-M4-M10
Risk haplotypeb
T/NTc
PTDT
1-1
1-1-1
1-1
1-2
1-2-2
1-1-2
1-1-2
38/21
38/21
14/3
66.04/42.04
61.04/41.04
66.04/42.04
66.04/42.04
0.02198
0.0274
0.03128
0.03288
0.03288
0.0415
0.04716
P(Global) >0.05.
a
Loci are labeled as per Table I.
b
1; major allele, 2; minor allele.
c
Transmitted/non-transmitted from heterozygous parents.
From our data it appears that any role that the PIP5K2A
gene plays in the etiology of schizophrenia in the Indonesian
population may be minor. While rs11013052 showed a statistically significant association with schizophrenia in the combined Indonesian and German sample and was more strongly
associated than in the German sample alone, this ad hoc
analysis was of an exploratory nature and does not provide
sufficient evidence to conclude that the variant influences
susceptibility to schizophrenia in the Indonesian population.
The three haplotypes that showed the strongest nominal
evidence for association all contained one or both of rs1171506
and 11013052, the two markers that displayed high T/NT
ratios and very low minor allele frequencies. As such, we
cannot exclude the possibility that the low minor allele
frequencies of these markers are driving the observed nominal
association.
The study had over 80% power to detect association for all
previously implicated PIP5K2A variants except rs11013052,
using the genotypic relative risks calculated by Schwab et al.
[2006]. While these estimates for relative risk are the best
available, it is known that estimates of relative risk arising
from the first positive association report for a given gene are
frequently overestimates [Lohmueller et al., 2003]. If these
estimates of relative risk are substantially higher than the true
values, the power calculations may have overestimated the
power of this study to detect association between these
variants and schizophrenia. The power of this study was
further undermined by the differences in allele frequencies
observed between the Indonesian and Caucasian populations.
As such, it is possible that this study failed to detect a true
association due to insufficient power.
Genetic heterogeneity has been proposed as a major factor in
the non-replication of linkage studies in schizophrenia [Risch,
1990]. Linkage and association studies of schizophrenia have
not only implicated different genes (inter-locus heterogeneity),
but also different variants within the same gene (intra-locus
heterogeneity). The Neuregulin 1 (NRG1) gene provides an
example of this phenomenon. Different NRG1 haplotypes have
been shown to be associated with schizophrenia in European
and East Asian populations, as summarized by Munafo et al.
[2006]. Differences in allele and haplotype frequencies
between populations are likely to play a major role in this
intra-locus heterogeneity. Allele frequencies are known to vary
substantially between populations of East Asian and Caucasian descent and this phenomenon has also been demonstrated
for NRG1 [Risch et al., 2002; Gardner et al., 2006].
The LD patterns seen in the Indonesian sample were very
similar to those seen in the HapMap Data for both the JPTCHB
and CEPH populations, with haplotype blocks formed between
markers rs1891878 and rs1132816, and between rs943190 and
rs8341 (data not shown). A notable difference between the
JPTCHB and CEPH samples is that the size of these two
haplotypes blocks is larger in the CEPH sample (53 and 47 kb
in the CEPH sample, as opposed to 28 and 44 kb in the JPTCHB
sample) [Barrett et al., 2005]. One possible explanation for the
differences in association seen between the Indonesian and
Caucasian samples is that associated markers within these
blocks are tagging additional markers in the Caucasian
samples.
In conclusion, from the current study, support for the
involvement of previously implicated PIP5K2A variants in
the etiology of schizophrenia in the Indonesian population is
only weak. Due to relying on results from Caucasian
populations for our SNP selection we cannot exclude the
possibility that there are PIP5K2A variants associated with
schizophrenia in the Indonesian population which are not
covered in our study.
ACKNOWLEDGMENTS
We are extremely grateful for the support of all patients and
their families, without which this work would not have been
possible.
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