Molecular Psychiatry (2006) 11, 547–556
& 2006 Nature Publishing Group All rights reserved 1359-4184/06 $30.00
www.nature.com/mp
FEATURE REVIEW
The role of phospholipases A2 in schizophrenia
MH Law1, RGH Cotton1 and GE Berger1,2
1
Genomic Disorders Research Centre, Melbourne, VI, Australia and 2ORYGEN Research Centre, Melbourne, VI, Australia
A range of neurotransmitter systems have been implicated in the pathogenesis of
schizophrenia based on the antidopaminergic activities of antipsychotic medications, and
chemicals that can induce psychotic-like symptoms, such as ketamine or PCP. Such
neurotransmitter systems often mediate their cellular response via G-protein-coupled release
of arachidonic acid (AA) via the activation of phospholipases A2 (PLA2s). The interaction of
three PLA2s are important for the regulation of the release of AA – phospholipase A2 Group 2
A, phospholipase A2 Group 4A and phospholipase A2 Group 6A. Gene variations of these
three key enzymes have been associated with schizophrenia with conflicting results.
Preclinical data suggest that the activity of these three enzymes are associated with
monoaminergic neurotransmission, and may contribute to the differential efficacy of
antipsychotic medications, as well as other biological changes thought to underlie
schizophrenia, such as altered neurodevelopment and synaptic remodelling. We review the
evidence and discuss the potential roles of these three key enzymes for schizophrenia with
particular emphasis on published association studies.
Molecular Psychiatry (2006) 11, 547–556. doi:10.1038/sj.mp.4001819; published online 4 April 2006
Keywords: review; schizophrenia/genetics; PLA2/genetics; arachidonic acid; common diseases;
PLA2/schizophrenia
Introduction
Neurotransmitters, such as dopamine, serotonin and
glutamate often mediate their cellular response via
G-protein-coupled activation of second messengers.
One such common second messenger is arachidonic
acid (AA) that is released from membrane phospholipids via the G-protein-coupled activation of phospholipase A2 (PLA2).1 Phospholipase A2 activity and
AA-based signalling is also important for normal
brain development and synaptic functioning.2–5 This
review outlines how PLA2s, in particular PLA2G2A,
PLA2G4A and PLA2G6A, may be relevant for the
understanding of schizophrenia pathogenesis and its
treatments.6
Method
Medline and Google Scholar (www.scholar.google.com) were used to identify articles from 1970 to 2005
using the following key words: schizophrenia, essential fatty acids (EFA), polyunsaturated fatty acid
(PUFA), AA, PLA2, phospholipase A2 Group 4A
(PLA2GIVA, PLA2G4A), phospholipase A2 Group 2A
(PLA2GIIA, PLA2G2A), phospholipase A2 Group 6A
Correspondence: Dr G Berger, ORYGEN Research Centre/ORYGEN
Youth Health, 35 Poplar rd, Parkville, Victoria 3052, Australia.
E-mail: [email protected]
Received 14 December 2005; accepted 30 January 2006; published
online 4 April 2006
(PLA2GVIA, PLA2G6A), dopamine, serotonin, Gprotein-coupled receptor, eicosanoids and phospholipids. Crosschecking of references was used to
identify further papers of interest.
PLA2s – naming conventions
When analysing PLA2 studies it is essential to
properly define which enzymes are being examined.
Phospholipases A2 are a large family of enzymes that
specifically deacylate fatty acids from the sterospecifically numbered second carbon atom (sn2, thus
PLA2) of the triglyceride backbone of membrane
phospholipids, producing a free fatty acid and a
lyso-phospholipid (Figure 1).7 Historically, PLA2s
were named by activity location, that is pancreatic,
cytosolic or secretory. Later naming systems also
included calcium requirements, although this can be
misleading. Some calcium-dependent PLA2s require
calcium for catalytic activity, whereas others are
constitutively active and calcium promotes binding
to phospholipid membranes. The more structured
classification system based on genetic relationships
will be used in this review.7 In this system each PLA2
is assigned to one of (currently) 11 groups; each group
may contain multiple homologues further assigned a
letter. For example, phospholipase A2 Group 4A
(PLA2G4A) and phospholipase A2 Group 4B
(PLA2G4B) are evolutionarily related homologues (A
and B) within Group 4 (G4).
PLA2s and schizophrenia
MH Law et al
548
Figure 1 De-acylation of arachidonic acid (AA) from a
phospholipid by the activity of a PLA2 enzyme.
PLA2s and AA
PLA2s regulate both the availability of free lysophospholipids for AA membrane incorporation, and the
cleavage of AA from membranes for signalling
(Figures 1 and 2).8,9 The polyunsaturated fatty acid
(PUFA) AA itself is a potent signalling molecule, and
also the precursor for a range of messengers (eicosanoids) necessary for normal neuronal function.10,11 To
limit aberrant signalling AA is usually bound to cell
membranes phospholipids. In addition to creating a
reservoir for later release of AA in response to
appropriate signals, the ratio of saturated to unsaturated fatty acids (such as AA) also defines membrane
fluidity, which alters the activity of membrane bound
proteins including neurotransmitter receptors.12,13
PLA2G4A has a 50-fold preference for phospholipids containing AA over any other PUFA, whereas
PLA2G6A and PLA2G2A show no fatty acid preference.14 PLA2G4A initiates AA release and eicosanoid production, whereas PLA2G2A enhances the
production of AA (Figure 2).15–18 Mice with the genes
for PLA2G4A and PLA2G2A nullified (knocked out)
do not produce eicosanoids, have reduced incorporation rates of free AA into cell membranes, yet normal
AA levels.19,20
PLA2G6A cleavage of phospholipids is primarily
for the purpose of cellular membrane remodelling, by
altering phospholipids/fatty acid ratios and modifying membrane fluidity.21,22 Loss of PLA2G6A function
leads to significant reductions in the amount of AA
incorporated into the cell membrane.23
PLA2 in neurobiology
The neurodevelopmental hypothesis and the neurotransmitter theories of schizophrenia propose that
abnormal genetic and environmental processes interfere with normal brain maturation and result in
dysfunctional monoaminergic neurotransmission associated with the phenotype of schizophrenia.24,25
The following evidence outlines the roles of PLA2Molecular Psychiatry
Figure 2 Arachidonic acid release in response to receptor
activation. (a) Initial or early stage AA release requires
recruitment of PLA2G4A. (b) To promote and maintain AA
release PLA2GA recruits PLA2G2A.
G2A, PLA2G4A and PLA2G6A in both brain maturational processes and neurotransmission.
Neurotransmission
The receptors for neurotransmitter systems implicated in schizophrenia activate downstream responses via a family of guanosine triphosphate
binding proteins (G-proteins), which in turn
activates PLA2G4A-mediated release of AA 26,27
and recruit PLA2G2A to further enhance signalling
(Figure 2).5,11,17,28 The colocalisation of monoaminergic receptors with PLA2G4A, PLA2G2A and eicosanoid-synthesising enzymes further emphasise their
importance for monoaminergic neurotransmission.15,29–31 The proper functioning and availability
of these PLA2s are therefore crucial for G-proteincoupled neurotransmission.
Memory formation (long-term potentiation)
Long-term potentiation (LTP), the proposed mechanism for memory formation, is associated with
G-protein-coupled glutamate receptor (AMPAR) activation and release of AA.32–35 PLA2 inhibitors block
AMPAR-associated LTP, while increasing PLA2 activity enhances LTP.34 PLA2 enhancement of LTP is
halted by sequestering free AA, but not by removing
calcium or blocking eicosanoid production.34,36 General inhibition of brain PLA2 activity, and particularly
specific inhibition of PLA2G6A activity decreased
memory formation in rats and reduced membrane
fluidity, revealing the requirement of PLA2G6A in
memory formation.37
Brain maturation, cortical development and synaptic
remodelling
Brain maturation, cortical development and synaptic
remodelling involves removal of excess brain cells or
parts of cells such as dendrites or axons. Key regulator
PLA2s and schizophrenia
MH Law et al
proteins involved in these processes are the caspases,
in particular caspase 3. Caspases manage apoptotic
cellular metabolism via the cleavage of certain
proteins such as PLA2G4A and PLA2G6A into
alternative forms, altering their behaviour.22 Cleaved
PLA2G4A proteins have a dominant-negative function, halting cellular PLA2G4A activity. Truncation of
PLA2G6A upregulates its activity, allowing rapid
remodelling of the cellular membrane and generation
of free AA required for apoptosis.38 The remodelled
membranes generates phagocytic attraction signals to
allow correct disposal of the cell remnants created
resulting from the apoptotic process.22,39–41
While not required within apoptotic neurons,
complete loss of PLA2G4A and PLA2G2A abolishes
inflammation following central nervous system (CNS)
injury, and reduces neuronal apoptosis.19 Studies
have shown how PLA2G4A is expressed in adjacent
glial cells postinjury, but not within apoptotic
neurons.42,43 Together this indicates a primary role
for PLA2G6A activity in neuronal remodelling by
apoptosis, while PLA2G4A and PLA2G2A act peripherally to manage inflammation.44,45
PLA2s in schizophrenia
Horrobin46,47 suggested that schizophrenia might be a
prostaglandin deficiency disease and consequently
formulated the Membrane Phospholipid Hypothesis
of schizophrenia. This hypothesis can be examined in
the light of the combined functions of these three
PLA2s.
PLA2s and reduced PUFAs in schizophrenia
Red blood cell (RBC) and CNS cell membranes of
medicated and drug naı̈ve patients with schizophrenia have significantly lower levels of PUFAs, in
particular AA 48–52 suggesting that this is not only
a drug effect. The change in AA levels correlates
to decreased membrane fluidity and to psychosis
severity12,13,49,51,53 with some conflicting results.54 AA
reductions could not solely be explained by environmental factors such as smoking, diet or medication.55–57
As loss of PLA2G6A function results in reduced cell
membrane AA levels, variations in this gene may be
responsible for these results.23
PLA2s and in vivo phospholipid metabolism
31-Phosphorus magnetic resonance imaging (31P
MRS) allows measurement of membrane phospholipid dynamics in the living brain.45 31P MRS of drugnaı̈ve first episode schizophrenia patients reveals
significantly increased breakdown and reduced creation of cellular membranes in never treated patients
with schizophrenia.58,59 Interestingly, a significant
relationship between reduced peripheral RBC AA
levels and in vivo brain membrane breakdown
products has been demonstrated in patients with
schizophrenia.48 Changes in the activity of these
PLA2s, which are important for apoptosis and
membrane maintenance would explain the correla-
tion between peripheral AA levels and brain phospholipid metabolism.
549
Niacin insensitivity – a marker for an abnormal AA
metabolism
The vitamin nicotinic acid (niacin) induces the
release of inflammatory eicosanoids such as prostaglandin D2, which are produced from AA metabolism.60 Depending on the method/definitions used,
40–80% of patients with psychotic disorders and
10% of controls show an impaired sensitivity to
niacin.61–64 Niacin sensitivity is also impaired in
healthy first degree relatives of probands, suggesting
it is a marker for underlying genetic risk.65 Niacin
insensitivity remains associated with schizophrenia
after exclusion of environmental factors modifying
inflammation.66–69 Niacin insensitive patients have
significantly lower AA levels when compared to
niacin sensitive patients.70 Prospective monitoring
revealed conversion from niacin insensitive to sensitive was associated with restoration of AA levels and
improvement in symptomatology.70,71 Interestingly,
the abolishment of AA release and resultant eicosanoid production reported previously in mice with the
genes for PLA2G4A and PLA2G2A knocked out is
applicable to niacin insensitivity.8,20 Niacin sensitivity could serve as a readily measurable biological
marker of altered AA metabolism indicative of altered
PLA2 activity.
Direct evidence of altered PLA2 activity in
schizophrenia
To evaluate the Membrane Hypothesis of Schizophrenia a number of studies have measured PLA2 activity
in patients with schizophrenia. Most studies measuring PLA2 activity in psychotic disorders have
used either a radiometric or a fluorometric method
(Table 1). The fluorometric method measures all
calcium-independent PLA2s, including PLA2G6A,
whereas the radiometric method detects the activity
of calcium-dependent PLA2s, encompassing PLA2G4A and PLA2G2A.72 Additionally, a recent study has
reported on a direct measure of the PLA2G4A protein,
and found increased levels of PLA2G4A in schizophrenia.73 The method used by Noponen et al.74 to
detect increased PLA2 activity was novel, with the
target PLA2s unconfirmed, and thus will be excluded
from further discussion. Owing to the limitations in
methodology activity studies will be examined in
terms of PLA2 calcium requirements.
Calcium-independent PLA2 activity
Increased calcium-independent PLA2 activity in
patients with schizophrenia has been replicated both
peripherally and in post-mortem human brain tissue.62,72,75–78 Higher calcium-independent PLA2 activity has been correlated to greater severity of
psychopathology72 though other positive studies
have not seen this association.62,75 Katila et al.79
reported normal calcium-independent PLA2 activity
Molecular Psychiatry
PLA2s and schizophrenia
MH Law et al
550
Table 1
Biochemical analysis of phospholipase activity
Article
Diagnosis and
numbersa
Medicationb
Gattaz et al.75
Gattaz et al.76
Albers et al.81
Gattaz et al.80
Hudson et al.91
SZ 20, 6 Psych
SZ 14, Psych, 8
SZ/SZF 10, Psych 25
SZ 31, Psych 31
SZ 23
8 DN, AF
6 DN, AF
All DN
Y, AF
Y, AF
21
20
10
31
30
Katila et al.79
Ross et al.72
SZ 34, Psych, 28
SZ 24
11 DN, AF
Y
62
33
Ross et al.78
Tavares et al.62
SZ 10, Bipolar 8
SZ 38
Y, AF
19 DN, AF
12
28
Lasch et al.77
Macdonald et al.73
SZ/SZF 26
SZ 29
11 DN, AF
Y, AF
26
27
Controls
Analysis
Source
Resultc
Flourometric
Flourometric
Radiometric
Radiometric
Niacin sensitivity,
Radiometric
Flourometric
Flourometric,
Radiometric
Flourometric
Niacin sensitivity,
Flourometric
Flourometric
Protein measurement
Serum
Serum
Serum
Platelet
Serum
m CI
m CI
= CD
m CD
k CD
Plasma
Serum
= CI
m CI, = CD
Brain
Serum
m CI, k CD
m CI
Serum
RBC
m CI
m PLA2G4A
a
SZ, schizophrenia, SZF, schizophreniform, Psych., psychiatric Illnesses other than schizophrenia.
Y, yes, DN, drug naı̈ve, AF, medication state accounted for during statistical analysis.
c
CI, calcium-independent PLA2 activity; CD, calcium-dependent PLA2 activity.
b
in schizophrenia, though Lasch et al.77 suggest this
may have been a methodological problem.
Calcium-dependent PLA2
An initial report of increased peripheral calciumdependent PLA2 activity in schizophrenia has not
been replicated.64,72,80,81 Analysis of post-mortem
brain tissue found calcium-dependent PLA2 activity
was decreased, rather than increased.78
Could response to antipsychotic medication be due to
interactions with PLA2s?
Eight weeks of antipsychotic medication reduced the
high calcium-independent PLA2 activity of patients
with schizophrenia, replicating a result seen in
the original study of calcium-independent PLA2
activity.62,75 Three positive studies, and one negative
study measuring calcium-independent activity
utilised a portion of drug naı̈ve patients.62,75,76,79
Statistical analysis has found no correlation between
medication state and calcium-dependent PLA2 activity.64,72,80 A small population of drug naı̈ve patients
had normal calcium-dependent PLA2 activity.81
Niacin insensitivity and PLA2 activity
The increased calcium-independent PLA2 activity
associated with schizophrenia is greater still in the
niacin insensitive sub group.62 As reported, 8 weeks
of medication reduced the abnormally high calciumindependent PLA2 activity. Those patients who
converted to niacin sensitive showed further normalisation of calcium-independent PLA2 activity.62
Although Hudson et al.64 initially found no differences in calcium-dependent PLA2 activity, niacin
sensitive (normal) patients had significantly lower
calcium-dependent PLA2 activity compared to controls and insensitive patients. Calcium-dependent
Molecular Psychiatry
PLA2 activity of niacin insensitive patients did not
differ from controls.64
Genetic profiles of PLA2G2A, PLA2G4A and
PLA2G6A
As we are reviewing the possible involvement of
genetic variation in PLA2G2A, PLA2G4A and PLA2G6A, it is worthwhile briefly summarising their gene
structure in Table 2. Regions implicated in schizophrenia in genomewide linkage studies (GWL) are
recorded here, divided by the maximum 10 cM range
suggested as evidence of gene–signal relationship.82–
84
A published variant is defined as having minimum
verification when it has either been reported separately at least twice, or has been genotyped in a large
enough population to ensure it is truly polymorphic.85 Untranslated regions are exons that are
transcribed to the messenger RNA (mRNA) and not
translated into the protein while coding variants are
in exons translated into amino acids. A synonymous
coding variant does not change the amino acid coded
for, while non-synonymous variants alter the resulting protein structure.
Association analysis of PLA2s and schizophrenia
Interest in the Membrane Phospholipid Hypothesis
has fuelled association studies between PLA2 genes
and schizophrenia, as summarised in Table 3.
PLA2G4A
Deletion of a promotor CA microsatellite (numerous
repeats of the bases cytosine paired with an adenine)
increases PLA2G4A mRNA expression by 50%.86 One
CA allele, (140 repeats) has a frequency of 0.96,
PLA2s and schizophrenia
MH Law et al
Table 2
551
Available data for PLA2 genes on dbSNP85
Gene
Names
Locus
PLA2G2A
PLA2G4A
PLA2G6A
sPLA2
cPLA2
iPLA2
1q35
1q25
22q13.1
Exons
GWL < 10 cM
6
18
16
No
No
No
GWL > 10 cM
Variants/
Verified
Coding/
Verified
Untranslated/
Verified
1q42
1q21–23
22q11–12
50/40
726/407
494/299
8/4
5/5
10/8
21/17
63/27
91/47
Abbreviations: GWL, genomewide linkage studies; PLA2, phospholipases A2; PLA2G2A, phospholipase A2 Group 2 A;
PLA2G4A, phospholipase A2 Group 4 A; PLA2G6A, phospholipase A2 Group 6 A.
Table 3
Genetic analysis of PLA2 genes in psychotic disorders
Article
Modela
Hudson et al.90
Hudson et al.91
Hudson et al.91
Price et al.93
Doris et al.54
Wei et al.95
Wei et al.95
Peet et al.94
Ramchand et al.89
Chowdari et al.100
Chowdari et al.100
Chowdari et al.100
Frieboes et al.92
Junqueira.et al.101
Junqueira et al.101
Wei and Hemmings96
Yu et al.99
Pae et al.97
Tao et al.102
Wei and Hemmings98
CC
T
CC
CC
CC
CC
T
CC
CC
T
CC
T
T
CC
CC
T
T
CC
T
T
Case no.
65
44
20
58
35
193
50
36
52
86
86
159
328
240
240
118
168
97
240
132
Ethnicityb,c
Control no.
Ca/C, USA/C
Ca/C, R/C
Ca/C, USA/C
S/C
NR
NR/C
NR/C
I
I
USA/C, USA/Af
USA/C, USA/Af
I
E/C. M, T/A
B
B
UK/C
M/M
K/K
M/M
UK/C
65
88
20
56
40
101
100
27
48
130
94
283
426
312
312
236
336
117
480
262
Analysis methodd
Associated?
Poly(A)
Poly(A)
Poly(A), Niacin sensitivity
Poly(A)
Poly(A)
BanI
BanI
BanI
CA
Poly(A), BanI
Poly(A), BanI
BanI
Poly(A)
BanI
AvrII
BanI
BanI
BanI
BanI
BanI
Yes
Yes
Yes
No
No
No
Yes
Yes
No
No
No
No
No
No
Yes
Yes
No
Yes
No
Yes
a
CC, case/control test; T, transmission disequilibrium test.
NR, not recorded in paper.
c
Ethnicity is expressed as country of origin/ethnicity. (a) Country of origin shorthand: USA = United States of America,
Ca = Canada, S = Scotland, M = China, T = Taiwan, E = Europe, R = Italy, P = Poland, M = China, I = India, K = Korea, UK = United Kingdom. (b) Ethnicity shorthand – C = Caucasian, A = Asian, I = Indian, Af = African, B = Brazilian, M = Chinese,
K = Korean.
d
Poly(A), adenine repeat PLA2G4A promotor variant, CA, CA microsatellite in promotor of PLA2G4A, BanI, rs10798059 in
first intron of PLA2G4A, AvrII, rs4375 in fourth intron of PLA2G6A.
Abbreviation: PLA2, phospholipases A2.
b
Table 4
Range of Poly(A) alleles
Studies
Method
Hudson et al.90,91
Price et al.93
Doris et al.54
Chowdari et al.100
Frieboes et al.92
Electrophoresis vs
Electrophoresis vs
Electrophoresis vs
Direct sequencing
Electrophoresis vs
known allele
absolute size marker and sequencing.
absolute size marker
absolute size marker
Alleles
No. (A) repeats
10
24
10
26
14
41–60
22–57
136–156
17–52
?
Result
Yes
No
No
No
No
Abbreviation: Poly(A), PLA2G4A promotor adenine repeat variant.
requiring large sample sizes to achieve sufficient
statistical power to detect association.87,88 The one
reported study of the CA microsatellite found no
significant association with schizophrenia (Table 4).89
Hudson et al.90,91 reported the PLA2G4A promotor
adenine repeat variant (Poly(A)) (an adenine repeat)
occurred as 10 size alleles, termed A1–A10, ranging
from 41 to 60 repeats in length. The small differences
Molecular Psychiatry
PLA2s and schizophrenia
MH Law et al
552
between alleles, except for five bases between A6
and A7 made genotyping difficult, so analysis
was performed using A1–A6 vs A7–A10 groupings.
Association between schizophrenia and the A7–A10
group was detected under a case/control and a
transmission model.90,91 Additionally, niacin insensitivity was greater in patients with the A7–A10.91 Later
methods detected completely differing alleles, and
found association between schizophrenia and Poly(A)
(Tables 3 and 4).54,92,93
Alternative studies have used an adenine (A1, not
cut by restriction enzyme PLA2G4A, rs10798059,
intron one adenine/guanine variant (BanI)) or guanine
(A2, cut by BanI) variant in the first intron of
PLA2G4A, rs10798059 (BanI).94 The A2 allele of
BanI has been associated with schizophrenia under
both case/control and transmission disequilibrium
test (TDT) models (Table 3).94–98 Five additional
studies have not replicated any association
between the BanI locus and schizophrenia.96,99–102
Testing of markers across the chromosome region
containing PLA2G4A make it unlikely that association is due to linkage disequilibrium (LD) with a
nearby gene.96
PLA2G2A and PLA2G6A
A variant in the fourth intron of PLA2G6A rs4375 has
been used to test for association with schizophrenia.
Rs4375 is either a cytosine base that creates a cut site
for the AvrIII restriction enzyme or a noncut thymine.
Both a case/control and a TDT model in this Brazilian
population indicated association between the cysteine allele and schizophrenia.101 Although studies
have used alternative PLA2s, such as PLA2G1B, there
are no published association studies of PLA2G2A in
psychotic illnesses.90,92,101
Discussion
The three PLA2s regulate the levels of bound and free
AA that has key functions in processes such as brain
maturation, memory formation and synaptic remodelling all processes suggested to be important for
schizophrenia.5,6,11,103 An increasing body of evidence
suggests that AA is altered in schizophrenia in a
causative manner:
(a) In vivo 31P-MRS and post-mortem measurements
of AA levels of patients with schizophrenia
confirm that AA alterations are present in the
brain and peripheral tissues.48,52
(b) AA changes are present in drug naı̈ve patients
indicates that the relationship is independent of
drug treatment and associated with the onset of
disease.49–51
(c) Chronic haloperidol administration in rats reduced AA levels specifically in dopaminergic
neurons, possibly due to interactions with dopamine receptors and their downstream targets, the
PLA2 enzymes.57
Molecular Psychiatry
(d) Increased calcium-independent PLA2 activity has
been replicated in both peripheral and CNS tissue,
and in drug naı̈ve patients (Table 1).62,72,76,78
(e) Higher calcium-independent PLA2 activity correlates significantly with greater severity of psychopathology, suggesting a direct relationship
between the degree of PLA2G6A activity and
disease progression.72
(f) Though numbers were small, the work of Tavares
et al.62 supports the concept of antipsychotic
efficacy through modulating PLA2 activity.
(g) Niacin sensitivity requires PLA2G4A- and PLA2G2A-mediated AA release from cellular membranes. Membrane AA levels are maintained by
PLA2G6A, and the separate associations of
reduced AA levels and increased calcium-independent activity with niacin insensitivity is
intriguing.20,23
(h) The strengthening of association between schizophrenia and a variant in the PLA2G4A gene after
stratification by niacin sensitivity is promising,
but not replicated.90 Yet increased calcium-dependent PLA2 activity, which includes PLA2G4A,
was not associated with niacin insensitivity.
Rather it was the patient group with normal
sensitivity to niacin that possessed increased
calcium-dependent activity.64 Low participant
numbers may explain this unexpected result, or
as reported by the authors, the niacin insensitive
group had the greatest activity variation, with a
standard deviation twice that of the other
groups.64 A repeat of this experiment in a larger
population using direct measures of PLA2G4A
protein level is required before further conclusions can be made.
That there are no GWL peaks for schizophrenia
within the suggested 10 cM of PLA2 loci is not
absolute proof of noninvolvement (Table 2).104
The population needed to detect GWL increases
dramatically as the relative risk (RR) conferred by
variants at that loci decrease.87 The RR estimated
from replicated associations of variants in dopamine
and serotonin receptors as well as the neuregulin 1
gene range from 1.2 to 2.4.105,106 If the RR of PLA2
variants is two or more, then thousands to tens
of thousands of families are required to detect GWL,
and if the RR is lower millions of families
are needed.87 All that can be concluded is that
these PLA2 genes, like neuregulin or dopamine
receptors, do not contribute a high (4 þ ) risk for
schizophrenia.
The different allele profiles found for the Poly(A)
site in the PLA2G4A promotor may be due to method
of size detection, as there was the greatest consistency
in allele profiles when direct sequencing was used
(Table 4). Interestingly the Poly(A) and BanI variants
are in significant LD, supporting the concept that
association is due to an adjacent causative variant(s).100 Although the absence of the repressive CA
microsatellite has a functional effect, it is not clear if a
PLA2s and schizophrenia
MH Law et al
change in CA repeat numbers also modifies expression. Genotyping in sufficiently large populations to
overcome the high frequency of one of the alleles
would be interesting.
The association between schizophrenia and either
of PLA2G4A variants in populations of different
ethnicity and alternative statistical models is promising (Table 4). Yet many studies have not replicated
these associations. There are a number of possible
reasons for this inconsistency.
(a) The associations so far may have been false
positives due to population heterogeneity.
(b) The tested variants may not be in perfect LD with
the causative variant(s), increasing false negatives.
Using a population large enough to detect association under varying models of LD and RR, and utilising
niacin sensitivity or RBC AA levels to reduce
heterogeneity should limit these problems.
Additionally, replication inconsistency may be due
to the underlying spectrum of disease variants. The
association studies discussed have followed the
common disease, common variant (CDCV) hypothesis
that for each ‘disease’ gene there are one or few risk
variants with minor allele frequency > 10%.87,107 The
alternative common disease, rare variant (CDRV)
hypothesis proposes that there a large pool of rare
(minor allele frequency < 10%) or even unique risk
variants.108–110 Interestingly, association between a
common variant and a disease can be due to LD with
high penetrance rare variants present in only a few of
the total study population.111
It is likely that both paradigms contribute, as a
spectrum of common and rare deleterious variants has
been seen in both Mendelian and complex disorders.112–114 However most studies do not characterise
the rare variants present in the study population nor
have the statistical power to test them.87
Conclusion
The collected evidence discussed point towards the
involvement of AA and PLA2s in the pathogenesis of
schizophrenia. The reported aberrations in AA levels,
PLA2 enzyme activities and in vivo brain membrane
breakdown specific to schizophrenia are biological
processes mediated by PLA2G6A, PLA2G4A and
PLA2G2A. As AA levels and metabolism is tightly
associated with the activity of PLA2G4A, PLA2G2A
and PLA2G6A, measurement of AA may reduce
schizophrenia heterogeneity (‘a PLA2s-AA endophenotype’). The topical Niacin skin flush test or RBC AA
level measurements have the potential to identify
such an endophenotype.45,61,64,115,116
As reported, these three PLA2 enzymes lie downstream of activation of neurotransmitter pathways
implicated in schizophrenia, such as dopaminergic,
serotoninergic or glutamatergic systems. It is plausible that antipsychotic efficacy can be modulated by
PLA2 genetic variants. Feedback may occur, as
changes in AA release by PLA2s will alter the
membrane saturated:unsaturated fats ratio, altering
neurotransmitter receptors dynamics.12,13 Thus, PLA2
genetic variants with altered activity have implications in both the release and the reception of neuronal
signals. Environmental modification of AA metabolism could, in a background of deleterious PLA2
variants, lead to a run away failure of brain function and development. Detection of these variants
will ultimately require models that take into account
both rare and common risk variants. If sampling of
variation occurs in a large study population, association tests using the variants found should allow
evaluation of both the CDCV and CDRV hypotheses.
In summary, the PLA2G4A gene has been associated with schizophrenia and reduced niacin sensitivity. There are as yet to be replicated studies
indicating PLA2G4A protein levels and specific
activity are increased in, and the PLA2G6A gene is
associated with, schizophrenia. That mice null for
PLA2G2A and PLA2G4A genes are viable could
explain the relative high frequency of schizophrenia,
as negative variants in these genes would be under
reduced selective pressure due to compensation by
other PLA2s. The lack of normal inflammation in
these mice indicates that this compensation is
incomplete, and such PLA2 activity shortfalls in
humans may result in schizophrenia.
553
Abbreviations
AA, arachidonic acid; AMPAR, glutamate receptor;
BanI, PLA2G4A, rs10798059, intron one adenine/
guanine variant; bp, DNA base pairs; CDCV, common
disease common variant; CDRV, common disease rare
variant; CNS, central nervous system; EFA, essential
fatty acids; G-proteins, guanosine triphosphate binding proteins; GWL, genomewide linkage studies; LD,
linkage disequilibrium; LTP, long-term potentiation;
mRNA, messenger RNA; PLA2, phospholipase A2;
PLA2GIVA, PLA2G4A, phospholipase A2 Group 4 A;
PLA2GIIA, PLA2G2A, phospholipase A2 Group 2 A;
PLA2GVIA, PLA2G6A, phospholipase A2 Group 6 A;
Poly(A), PLA2G4A promotor adenine repeat variant;
PUFA, polyunsaturated fatty acid; 31P MRS, 31phosphorus magnetic resonance imaging; RBC, red
blood cells; TDT, transmission disequilibrium test.
Acknowledgments
We wish to thank R Purcell for editing and proofreading assistance.
Web Resources
The URLs for data presented herein is as follows
dbSNP, http://www.ncbi.nlm.nih.gov/SNP/
References
1 Piomelli D, Pilon C, Giros B, Sokoloff P, Martres MP, Schwartz JC.
Dopamine activation of the arachidonic acid cascade as a basis for
D1/D2 receptor synergism. Nature 1991; 353: 164–167.
Molecular Psychiatry
PLA2s and schizophrenia
MH Law et al
554
2 Meiri KF, Saffell JL, Walsh FS, Doherty P. Neurite outgrowth
stimulated by neural cell adhesion molecules requires growthassociated protein-43 (GAP-43) function and is associated with
GAP-43 phosphorylation in growth cones. J Neurosci 1998; 18:
10429–10437.
3 Negre-Aminou P, Pfenninger KH. Arachidonic acid turnover and
phospholipase A2 activity in neuronal growth cones. J Neurochem 1993; 60: 1126–1136.
4 St-Gelais F, Menard C, Congar P, Trudeau LE, Massicotte G.
Postsynaptic injection of calcium-independent phospholipase A2
inhibitors selectively increases AMPA receptor-mediated synaptic transmission. Hippocampus 2004; 14: 319–325.
5 Garcia MC, Kim HY. Mobilization of arachidonate and docosahexaenoate by stimulation of the 5-HT2A receptor in rat C6
glioma cells. Brain Res 1997; 768: 43–48.
6 Mounier CM, Ghomashchi F, Lindsay MR, James S, Singer AG,
Parton RG et al. Arachidonic acid release from mammalian cells
transfected with human groups IIA and X secreted phospholipase
A(2) occurs predominantly during the secretory process and with
the involvement of cytosolic phospholipase A(2)-alpha. J Biol
Chem 2004; 279: 25024–25038.
7 Six DA, Dennis EA. The expanding superfamily of phospholipase
A(2) enzymes: classification and characterization. Biochimica et
Biophysica Acta 2000; 1488: 1–19.
8 Balsinde J, Dennis EA. Function and inhibition of intracellular
calcium-independent phospholipase A2. J Biol Chem 1997; 272:
16069–16072.
9 Winstead MV, Balsinde J, Dennis EA. Calcium-independent
phospholipase A(2): structure and function. Biochimica et
Biophysica Acta 2000; 1488: 28–39.
10 Shimizu T, Wolfe LS. Arachidonic acid cascade and signal
transduction. J Neurochem 1990; 55: 1–15.
11 Kurrasch-Orbaugh DM, Parrish JC, Watts VJ, Nichols DE. A
complex signaling cascade links the serotonin2A receptor to
phospholipase A2 activation: the involvement of MAP kinases.
J Neurochem 2003; 86: 980–991.
12 Yao JK, van Kammen DP. Red blood cell membrane dynamics in
schizophrenia. I. Membrane fluidity. Schizophr Res 1994; 11:
209–216.
13 Farkas E, de Wilde MC, Kiliaan AJ, Meijer J, Keijser JN, Luiten
PG. Dietary long chain PUFAs differentially affect hippocampal
muscarinic 1 and serotonergic 1A receptors in experimental
cerebral hypoperfusion. Brain Res 2002; 954: 32–41.
14 Clark JD, Milona N, Knopf JL. Purification of a 110-kilodalton
cytosolic phospholipase A2 from the human monocytic cell line
U937. Proc Natl Acad Sci USA 1990; 87: 7708–7712.
15 Murakami M, Kambe T, Shimbara S, Yamamoto S, Kuwata H,
Kudo I. Functional association of type IIA secretory phospholipase A(2) with the glycosylphosphatidylinositol-anchored heparan sulfate proteoglycan in the cyclooxygenase-2-mediated
delayed prostanoid-biosynthetic pathway. J Biol Chem 1999;
274: 29927–29936.
16 Murakami M, Shimbara S, Kambe T, Kuwata H, Winstead MV,
Tischfield JA et al. The functions of five distinct mammalian
phospholipase A2S in regulating arachidonic acid release. Type
IIa and type V secretory phospholipase A2S are functionally
redundant and act in concert with cytosolic phospholipase A2.
J Biol Chem 1998; 273: 14411–14423.
17 Kuwata H, Yamamoto S, Miyazaki Y, Shimbara S, Nakatani Y,
Suzuki H et al. Studies on a mechanism by which cytosolic
phospholipase A2 regulates the expression and function of
type IIA secretory phospholipase A2. J Immunol 2000; 165:
4024–4031.
18 Han WK, Sapirstein A, Hung CC, Alessandrini A, Bonventre JV.
Cross-talk between cytosolic phospholipase A2 alpha (cPLA2
alpha) and secretory phospholipase A2 (sPLA2) in hydrogen
peroxide-induced arachidonic acid release in murine
mesangial cells: sPLA2 regulates cPLA2 alpha activity that is
responsible for arachidonic acid release. J Biol Chem 2003; 278:
24153–24163.
19 Bonventre JV, Huang Z, Taheri MR, O’Leary E, Li E, Moskowitz
MA et al. Reduced fertility and postischaemic brain injury in
mice deficient in cytosolic phospholipase A2. Nature 1997; 390:
622–625.
Molecular Psychiatry
20 Rosenberger TA, Villacreses NE, Contreras MA, Bonventre JV,
Rapoport SI. Brain lipid metabolism in the cPLA(2) knockout
mouse. J Lipid Res 2003; 44: 109–117.
21 Balsinde J, Dennis EA. Function of calcium-independent phospholipase A2 in arachidonic acid metabolism in P388D1
macrophages. Adv Exp Med Biol 1997; 407: 99–103.
22 Atsumi G, Murakami M, Kojima K, Hadano A, Tajima M, Kudo I.
Distinct roles of two intracellular phospholipase A2s in fatty acid
release in the cell death pathway. Proteolytic fragment of type
IVA cytosolic phospholipase A2alpha inhibits stimulus-induced
arachidonate release, whereas that of type VI Ca2 þ -independent
phospholipase A2 augments spontaneous fatty acid release. J Biol
Chem 2000; 275: 18248–18258.
23 Balsinde J, Balboa MA, Dennis EA. Antisense inhibition of group
VI Ca2 þ -independent phospholipase A2 blocks phospholipid
fatty acid remodeling in murine P388D1 macrophages. J Biol
Chem 1997; 272: 29317–29321.
24 Weinberger DR. Implications of normal brain development for the
pathogenesis of schizophrenia. Arch Gen Psychiatry 1987; 44:
660–669.
25 Murray RM, Lewis SW. Is schizophrenia a neurodevelopmental
disorder? Br Med J (Clin Res Ed) 1987; 295: 681–682.
26 Gilman AG. G proteins: transducers of receptor-generated signals.
Annu Rev Biochem 1987; 56: 615–649.
27 Clapham DE, Neer EJ. G protein beta gamma subunits. Annu Rev
Pharmacol Toxicol 1997; 37: 167–203.
28 Balsinde J, Balboa MA, Dennis EA. Functional coupling between
secretory phospholipase A2 and cyclooxygenase-2 and its
regulation by cytosolic group IV phospholipase A2. Proc Natl
Acad Sci USA 1998; 95: 7951–7956.
29 Murakami M, Nakatani Y, Kuwata H, Kudo I. Cellular components that functionally interact with signaling phospholipase
A(2)s. Biochim Biophys Acta 2000; 1488: 159–166.
30 Li S, Okamoto T, Chun M, Sargiacomo M, Casanova JE, Hansen
SH et al. Evidence for a regulated interaction between
heterotrimeric G proteins and caveolin. J Biol Chem 1995; 270:
15693–15701.
31 Carman CV, Lisanti MP, Benovic JL. Regulation of G proteincoupled receptor kinases by caveolin. J Biol Chem 1999; 274:
8858–8864.
32 Wolf MJ, Izumi Y, Zorumski CF, Gross RW. Long-term potentiation requires activation of calcium-independent phospholipase
A2. FEBS Lett 1995; 377: 358–362.
33 Barbour B, Szatkowski M, Ingledew N, Attwell D. Arachidonic
acid induces a prolonged inhibition of glutamate uptake into glial
cells. Nature 1989; 342: 918–920.
34 Bernard J, Chabot C, Gagne J, Baudry M, Massicotte G. Melittin
increases AMPA receptor affinity in rat brain synaptoneurosomes. Brain Res 1995; 671: 195–200.
35 Gaudreault SB, Chabot C, Gratton JP, Poirier J. The caveolin
scaffolding domain modifies 2-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor binding properties by inhibiting
phospholipase A2 activity. J Biol Chem 2004; 279: 356–362.
36 Tournois C, Mutel V, Manivet P, Launay JM, Kellermann O. Crosstalk between 5-hydroxytryptamine receptors in a serotonergic
cell line. Involvement of arachidonic acid metabolism. J Biol
Chem 1998; 273: 17498–17503.
37 Schaeffer EL, Gattaz WF. Inhibition of calcium-independent
phospholipase A(2) activity in rat hippocampus impairs acquisition of short- and long-term memory. Psychopharmacology
(Berlin) 2005; 181: 392–400.
38 Cao Y, Pearman AT, Zimmerman GA, McIntyre TM, Prescott SM.
Intracellular unesterified arachidonic acid signals apoptosis.
Proc Natl Acad Sci USA 2000; 97: 11280–11285.
39 Shinzawa K, Tsujimoto Y. PLA2 activity is required for nuclear
shrinkage in caspase-independent cell death. J Cell Biol 2003;
163: 1219–1230.
40 Kim SJ, Gershov D, Ma X, Brot N, Elkon KB. I-PLA(2) activation
during apoptosis promotes the exposure of membrane lysophosphatidylcholine leading to binding by natural immunoglobulin
M antibodies and complement activation. J Exp Med 2002; 196:
655–665.
41 Lauber K, Bohn E, Krober SM, Xiao YJ, Blumenthal SG,
Lindemann RK et al. Apoptotic cells induce migration of
PLA2s and schizophrenia
MH Law et al
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
phagocytes via caspase-3-mediated release of a lipid attraction
signal. Cell 2003; 113: 717–730.
Clemens JA, Stephenson DT, Smalstig EB, Roberts EF, Johnstone
EM, Sharp JD et al. Reactive glia express cytosolic phospholipase
A2 after transient global forebrain ischemia in the rat. Stroke
1996; 27: 527–535.
Stephenson D, Rash K, Smalstig B, Roberts E, Johnstone E, Sharp
J et al. Cytosolic phospholipase A2 is induced in reactive glia
following different forms of neurodegeneration. Glia 1999; 27:
110–128.
Gilroy DW, Newson J, Sawmynaden P, Willoughby DA, Croxtall
JD. A novel role for phospholipase A2 isoforms in the checkpoint
control of acute inflammation. FASEB J 2004; 18: 489–498.
Berger GE, Wood SJ, Pantelis C, Velakoulis D, Wellard RM,
McGorry PD. Implications of lipid biology for the pathogenesis of
schizophrenia. Aust NZ J Psychiatry 2002; 36: 355–366.
Horrobin DF. Schizophrenia as a prostaglandin deficiency
disease. Lancet 1977; 1: 936–937.
Horrobin DF. The membrane phospholipid hypothesis as a
biochemical basis for the neurodevelopmental concept of
schizophrenia. Schizophr Res 1998; 30: 193–208.
Yao JK, Stanley JA, Reddy RD, Keshavan MS, Pettegrew JW.
Correlations between peripheral polyunsaturated fatty acid
content and in vivo membrane phospholipid metabolites. Biol
Psychiatry 2002; 52: 823–830.
Yao JK, van Kammen DP, Welker JA. Red blood cell membrane
dynamics in schizophrenia. II. Fatty acid composition. Schizophr
Res 1994; 13: 217–226.
Khan MM, Evans DR, Gunna V, Scheffer RE, Parikh VV, Mahadik
SP. Reduced erythrocyte membrane essential fatty acids and
increased lipid peroxides in schizophrenia at the never-medicated first-episode of psychosis and after years of treatment with
antipsychotics. Schizophr Res 2002; 58: 1–10.
Arvindakshan M, Sitasawad S, Debsikdar V, Ghate M, Evans D,
Horrobin DF et al. Essential polyunsaturated fatty acid and lipid
peroxide levels in never-medicated and medicated schizophrenia
patients. Biol Psychiatry 2003; 53: 56–64.
Horrobin DF, Manku MS, Hillman H, Iain A, Glen M. Fatty acid
levels in the brains of schizophrenics and normal controls. Biol
Psychiatry 1991; 30: 795–805.
Yao JK, van Kammen DP, Gurklis J. Red blood cell membrane
dynamics in schizophrenia. III. Correlation of fatty acid
abnormalities with clinical measures. Schizophr Res 1994; 13:
227–232.
Doris AB, Wahle K, MacDonald A, Morris S, Coffey I, Muir W et
al. Red cell membrane fatty acids, cytosolic phospholipase-A2
and schizophrenia. Schizophr Res 1998; 31: 185–196.
Strassnig M, Singh Brar J, Ganguli R. Dietary fatty acid and
antioxidant intake in community-dwelling patients suffering
from schizophrenia. Schizophr Res 2005; 76: 343–351.
Hibbeln JR, Makino KK, Martin CE, Dickerson F, Boronow J,
Fenton WS. Smoking, gender, and dietary influences on
erythrocyte essential fatty acid composition among patients with
schizophrenia or schizoaffective disorder. Biol Psychiatry 2003;
53: 431–441.
Myers CS, Contreras MA, Chang MC, Rapoport SI, Appel NM.
Haloperidol downregulates phospholipase A(2) signaling in rat
basal ganglia circuits. Brain Res 2001; 896: 96–101.
Pettegrew JW, Keshavan MS, Panchalingam K, Strychor S, Kaplan
DB, Tretta MG et al. Alterations in brain high-energy phosphate
amd membrane phospholipid metabolism in first-episode, drugnaive schizophrenics. A pilot study of the dorsal prefrontal
cortex by in vivo phosphorous 31 nuclear magnetic resonance
spectroscopy. Arch Gen Psychiatry 1991; 48: 563–568.
Fukuzako H, Fukuzako T, Hashiguchi T, Kodama S, Takigawa M,
Fujimoto T. Changes in levels of phosphorus metabolites in
temporal lobes of drug-naive schizophrenic patients. Am J
Psychiatry 1999; 156: 1205–1208.
Morrow JD, Awad JA, Oates JA, Roberts II LJ. Identification of
skin as a major site of prostaglandin D2 release following oral
administration of niacin in humans. J Invest Dermatol 1992; 98:
812–815.
Hudson CJ, Lin A, Cogan S, Cashman F, Warsh JJ. The niacin
challenge test: clinical manifestation of altered transmembrane
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
signal transduction in schizophrenia? Biol Psychiatry 1997; 41:
507–513.
Tavares H, Yacubian J, Talib LL, Barbosa NR, Gattaz WF.
Increased phospholipase A2 activity in schizophrenia with
absent response to niacin. Schizophr Res 2003; 61: 1–6.
Shah SH, Vankar GK, Peet M, Ramchand CN. Unmedicated
schizophrenic patients have a reduced skin flush in response to
topical niacin. Schizophr Res 2000; 43: 163–164.
Hudson CJ, Gotowiec A, Seeman M, Warsh J, Ross BM. Clinical
subtyping reveals significant differences in calcium-dependent
phospholipase A2 activity in schizophrenia. Biol Psychiatry
1999; 46: 401–405.
Waldo MC. Co-distribution of sensory gating and impaired niacin
flush response in the parents of schizophrenics. Schizophr Res
1999; 40: 49–53.
Turenne SD, Seeman M, Ross BM. An animal model of nicotinicacid-induced vasodilation: effect of haloperidol, caffeine and
nicotine upon nicotinic acid response. Schizophr Res 2001; 50:
191–197.
Ross BM, Hughes B, Turenne S, Seeman M, Warsh JJ. Reduced
vasodilatory response to methylnicotinate in schizophrenia as
assessed by laser Doppler flowmetry. Eur Neuropsychopharmacol 2004; 14: 191–197.
Smesny S, Berger G, Rosburg T, Riemann S, Riehemann S,
McGorry P et al. Potential use of the topical niacin skin test in
early psychosis – a combined approach using optical reflection
spectroscopy and a descriptive rating scale. J Psychiatr Res 2003;
37: 237–247.
Smesny S, Rosburg T, Klemm S, Riemann S, Baur K, Rudolph N
et al. The influence of age and gender on niacin skin test results –
implications for the use as a biochemical marker in schizophrenia. J Psychiatr Res 2004; 38: 537–543.
Glen AI, Cooper SJ, Rybakowski J, Vaddadi K, Brayshaw N,
Horrobin DF. Membrane fatty acids, niacin flushing and clinical
parameters. Prostag Leukot Essent Fatty Acids 1996; 55: 9–15.
Horrobin DF. Schizophrenia: a biochemical disorder? Biomedicine 1980; 32: 54–55.
Ross BM, Hudson CJ, Erlich J, Warsh JJ, Kish SJ. Increased
phospholipid breakdown in schizophrenia. Evidence for the
involvement of a calcium-independent phospholipase A2. Arch
Gen Psychiatry 1997; 54: 487–494.
Macdonald DJ, Boyle RM, Glen AC, Ross BM, Glen AI, Ward PE et
al. The investigation of cytosolic phospholipase A2 using ELISA.
Prostag Leukot Essent Fatty Acids 2004; 70: 377–381.
Noponen M, Sanfilipo M, Samanich K, Ryer H, Ko G, Angrist B et
al. Elevated PLA2 activity in schizophrenics and other psychiatric patients. Biol Psychiatry 1993; 34: 641–649.
Gattaz WF, Kollisch M, Thuren T, Virtanen JA, Kinnunen PK.
Increased plasma phospholipase-A2 activity in schizophrenic
patients: reduction after neuroleptic therapy. Biol Psychiatry
1987; 22: 421–426.
Gattaz WF, Hubner CV, Nevalainen TJ, Thuren T, Kinnunen PK.
Increased serum phospholipase A2 activity in schizophrenia: a
replication study. Biol Psychiatry 1990; 28: 495–501.
Lasch J, Willhardt I, Kinder D, Sauer H, Smesny S. Fluorometric
assays of phospholipase A2 activity with three different substrates in biological samples of patients with schizophrenia. Clin
Chem Lab Med 2003; 41: 908–914.
Ross BM, Turenne S, Moszczynska A, Warsh JJ, Kish SJ.
Differential alteration of phospholipase A2 activities in brain of
patients with schizophrenia. Brain Res 1999; 821: 407–413.
Katila H, Appelberg B, Rimon R. No differences in phospholipase-A2 activity between acute psychiatric patients and controls.
Schizophr Res 1997; 26: 103–105.
Gattaz WF, Schmitt A, Maras A. Increased platelet phospholipase
A2 activity in schizophrenia. Schizophr Res 1995; 16: 1–6.
Albers M, Meurer H, Marki F, Klotz J. Phospholipase A2 activity
in serum of neuroleptic-naive psychiatric inpatients. Pharmacopsychiatry 1993; 26: 94–98.
Brzustowicz LM, Hodgkinson KA, Chow EW, Honer WG, Bassett
AS. Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21–q22. Science 2000; 288: 678–682.
Gurling HM, Kalsi G, Brynjolfson J, Sigmundsson T, Sherrington
R, Mankoo BS et al. Genomewide genetic linkage analysis
555
Molecular Psychiatry
PLA2s and schizophrenia
MH Law et al
556
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
confirms the presence of susceptibility loci for schizophrenia, on
chromosomes 1q32.2, 5q33.2, and 8p21–22 and provides support
for linkage to schizophrenia, on chromosomes 11q23.3–24 and
20q12.1–11.23. Am J Hum Genet 2001; 68: 661–673.
Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I
et al. Genome scan meta-analysis of schizophrenia and bipolar
disorder, part II: schizophrenia. Am J Hum Genet 2003; 73: 34–48.
Sherry ST, Ward M, Sirotkin K. dbSNP-database for single
nucleotide polymorphisms and other classes of minor genetic
variation. Genome Res 1999; 9: 677–679.
Dolan-O’Keefe M, Chow V, Monnier J, Visner GA, Nick HS.
Transcriptional regulation and structural organization of the
human cytosolic phospholipase A(2) gene. Am J Physiol Lung
Cell Mol Physiol 2000; 278: L649–L657.
Risch N, Merikangas K. The future of genetic studies of complex
human diseases. Science 1996; 273: 1516–1517.
Tay A, Maxwell P, Li Z, Goldberg H, Skorecki K. Isolation of
promoter for cytosolic phospholipase A2 (cPLA2). Biochim
Biophys Acta 1994; 1217: 345–347.
Ramchand CN, Wei J, Lee KH, Peet M. Phospholipase A2 gene
polymorphism and associated biochemical alterations in schizophrenia. Phospholipid Spectrum Disorder in Psychiatry. Carnforth: Marius Press, 1999; 1999: 31–38.
Hudson CJ, Kennedy JL, Gotowiec A, Lin A, King N, Gojtan K et
al. Genetic variant near cytosolic phospholipase A2 associated
with schizophrenia. Schizophr Res 1996; 21: 111–116.
Hudson CJ, Lin A, Horrobin DF. Phospholipases: in search of a
genetic base of schizophrenia. Prostag Leukot Essent Fatty Acids
1996; 55: 119–122.
Frieboes RM, Moises HW, Gattaz WF, Yang L, Li T, Liu X et al.
Lack of association between schizophrenia and the phospholipase-A(2) genes cPLA2 and sPLA2. Am J Med Genet 2001; 105:
246–249.
Price SA, Fox H, St Clair D, Shaw DJ. Lack of association between
schizophrenia and a polymorphism close to the cytosolic
phospholipase A2 gene. Psychiatr Genet 1997; 7: 111–114.
Peet M, Ramchand CN, Lee J, Telang SD, Vankar GK, Shah S et al.
Association of the Ban I dimorphic site at the human cytosolic
phospholipase A2 gene with schizophrenia. Psychiatr Genet
1998; 8: 191–192.
Wei J, Lee KH, Hemmings GP. Is the cPLA2 gene associated with
schizophrenia? Mol Psychiatry 1998; 3: 480–481.
Wei J, Hemmings GP. A study of a genetic association between the
PTGS2/PLA2G4A locus and schizophrenia. Prostag Leukot
Essent Fatty Acids 2004; 70: 413–415.
Pae CU, Yu HS, Lee KU, Kim JJ, Lee CU, Lee SJ et al. BanI
polymorphism of the cytosolic phospholipase A2 gene may
confer susceptibility to the development of schizophrenia. Prog
Neuropsychopharmacol Biol Psychiatry 2004; 28: 739–741.
Wei J, Hemmings GP. A study of the combined effect of the
CLDN5 locus and the genes for the phospholipid metabolism
pathway in schizophrenia. Prostag Leukot Essent Fatty Acids
2005; 73: 441–445.
Yu YQ, Tao R, Wei J, Xu Q, Liu SZ, Ju GZ et al. No association
between the PTGS2/PLA2G4A locus and schizophrenia in a
Chinese population. Prostag Leukot Essent Fatty Acids 2004; 71:
405–408.
Chowdari KV, Brandstaetter B, Semwal P, Bhatia T, Deshpande S,
Reddy R et al. Association studies of cytosolic phospholipase A2
Molecular Psychiatry
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
polymorphisms and schizophrenia among two independent
family-based samples. Psychiatr Genet 2001; 11: 207–212.
Junqueira R, Cordeiro Q, Meira-Lima I, Farid Gattaz W, Vallada H.
Allelic association analysis of phospholipase A2 genes with
schizophrenia. Psychiatr Genet 2004; 14: 157–160.
Tao R, Yu Y, Zhang X, Guo Y, Shi J, Xie L et al. Cytosolic PLA2
genes possibly contribute to the etiology of schizophrenia. Am J
Med Genet B Neuropsychiatr Genet 2005; 137: 56–58.
Farooqui AA, Yang HC, Rosenberger TA, Horrocks LA. Phospholipase A2 and its role in brain tissue. J Neurochem 1997; 69:
889–901.
Niculescu III AB, Segal DS, Kuczenski R, Barrett T, Hauger RL,
Kelsoe JR. Identifying a series of candidate genes for mania and
psychosis: a convergent functional genomics approach. Physiol
Genom 2000; 4: 83–91.
Craddock N, O’Donovan MC, Owen MJ. The genetics of
schizophrenia and bipolar disorder: dissecting psychosis. J Med
Genet 2005; 42: 193–204.
Stefansson H, Sarginson J, Kong A, Yates P, Steinthorsdottir V,
Gudfinnsson E et al. Association of neuregulin 1 with schizophrenia confirmed in a Scottish population. Am J Hum Genet
2003; 72: 83–87.
Reich DE, Lander ES. On the allelic spectrum of human disease.
Trends Genet 2001; 17: 502–510.
Fearnhead NS, Wilding JL, Winney B, Tonks S, Bartlett S,
Bicknell DC et al. Multiple rare variants in different genes
account for multifactorial inherited susceptibility to colorectal
adenomas. Proc Natl Acad Sci USA 2004; 101: 15992–15997.
Cohen JC, Kiss RS, Pertsemlidis A, Marcel YL, McPherson R,
Hobbs HH. Multiple rare alleles contribute to low plasma levels
of HDL cholesterol. Science 2004; 305: 869–872.
Pritchard JK. Are rare variants responsible for susceptibility to
complex diseases? Am J Hum Genet 2001; 69: 124–137.
Hopper JL, Hayes VM, Spurdle AB, Chenevix-Trench G, Jenkins
MA, Milne RL et al. A protein-truncating mutation in CYP17A1
in three sisters with early-onset breast cancer. Hum Mutat 2005;
26: 298–302.
Wen G, Mahata SK, Cadman P, Mahata M, Ghosh S, Mahapatra
NR et al. Both rare and common polymorphisms contribute
functional variation at CHGA, a regulator of catecholamine
physiology. Am J Hum Genet 2004; 74: 197–207.
Wright AF, Hastie ND. Complex genetic diseases: controversy
over the Croesus code. Genome Biol 2001; 2: COMMENT2007.1–
COMMENT 2007.8.
Knoblauch H, Bauerfeind A, Toliat MR, Becker C, Luganskaja T,
Gunther UP et al. Haplotypes and SNPs in 13 lipid-relevant genes
explain most of the genetic variance in high-density lipoprotein
and low-density lipoprotein cholesterol. Hum Mol Genet 2004;
13: 993–1004.
Nakatani N, Uozumi N, Kume K, Murakami M, Kudo I,
Shimizu T. Role of cytosolic phospholipase A2 in the production
of lipid mediators and histamine release in mouse bone-marrowderived mast cells. Biochemical Journal. 2000; 352(Part 2):
311–317.
Fujishima H, Sanchez Mejia RO, Bingham III CO, Lam BK,
Sapirstein A, Bonventre JV et al. Cytosolic phospholipase A2 is
essential for both the immediate and the delayed phases of
eicosanoid generation in mouse bone marrow-derived mast cells.
Proc Natl Acad Sci USA 1999; 96: 4803–4807.