A linkage study between the GABAA β2 and GABAA γ2 subunit genes and major psychoses

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Abstract
Alterations of the gamma-aminobutyric acid (GABA) system have been implicated in the pathophysiology of major psychoses. Restriction fragment length polymorphisms associated with the human gamma-aminobutyric acid type A (GABAA) beta2 and GABAA gamma2 subunit genes on chromosome 5q32-q35 were tested to determine whether they confer susceptibility to major psychoses. Thirty-two schizophrenic families and 25 bipolar families were tested for linkage. Results: Nonparametric linkage (NPL) analysis performed by GENEHUNTER showed no significant NPL scores for both genes in schizophrenia (GABAA beta2: NPL narrow= -0.450; NPL broad= -0.808; GABAA gamma2: NPL narrow=0.177; NPL broad= -0.051) or bipolar disorder (GABAA beta2: NPL narrow=0.834; NPL broad=0.783; GABAA gamma2: NPL narrow= -0.159; NPL broad=0.070). Linkage analysis does not support the hypothesis that variants within the GABAA beta2 and GABAA gamma2 genes are significantly linked to major psychoses in a Portuguese population.
A Linkage Study Between the GABA
A
β
2
and GABA
A
γ
2
Subunit Genes
and Major Psychoses
By Alda M. Ambrósio, PhD, James L. Kennedy, MD,
Fabio Macciardi, MD, PhD, Nicole King, BSc, Maria H. Azevedo, MD, PhD,
Catarina R. Oliveira, MD, PhD, and Carlos N. Pato, MD
Dr. Ambrósio is research assistant professor and head of the Unit of Clinical and Molecular Genetics of National Institute of Legal
Medicine in the Faculty of Medicine at the University of Coimbra in Portugal. Dr. Kennedy and Dr. Macciardi are associate professors
in the Section of Neurogenetics in the Department of Psychiatry at the Clarke Institute of Centre for Addiction and Mental Health at
the University of Toronto in Canada. Ms. King is research assistant in the Section of Neurogenetics in the Department of Psychiatry at
the Clarke Institute of Centre for Addiction and Mental Health at the University of Toronto. Dr. Azevedo is professor in the Department
of Psychiatry in the Faculty of Medicine at the University of Coimbra. Dr. Oliveira is professor in the Department of Neurochemistry at the
Center for Neuroscience of Coimbra in the Faculty of Medicine at the University of Coimbra. Dr. Pato is associate professos at the Center
for Psychiatric and Molecular Genetics at the State University of New York Upstate Medical University and at the Behavioral Health Care
Line at the Veterans Affairs Medical Center in Syracuse, New York.
Disclosure: This work was supported by Medical Research Council of Canada, National Institute of the Mental Health and Fundação para
a Ciência e a Tecnologia. This article was submitted on May 22, 2003, and accepted on August 13, 2003.
Please direct all correspondence to: Alda M. Ambrósio,
Unit of Clinical and Molecular Genetics of National Institute of Legal Medicine, Largo
da Se Nova
, 3000-213 Coimbra, Portugal; Tel: 351-239-854230, Fax: 351-239-836470; E-mail: aldachico@yahoo.com
.
57
Volume 10 – Number 1 © MBL Communications Inc. CNS Spectrums – January 2005
Original Research
FOCUS POINTS
The involvement of the gabaergic system in
major psychoses has been suggested by a large
body of evidence.
Nonparametric linkage analysis is a useful tool to
identify genes that play a role in major psychoses.
The use of homogenous populations in the
genetic studies of complex disorders allows to
minimize genetic heterogeneity.
lar disorder (GABA
A
β
2
: NPL narrow=0.834; NPL
broad=0.783; GABA
A
γ2: NPL narrow=0.159;
NPL broad=0.070).
Conclusion: Linkage analysis does not support the
hypothesis that variants within the GABA
A
β
2
and
GABA
A
γ
2
genes are significantly linked to major
psychoses in a Portuguese population.
CNS Spectr. 2005;10(1):57-61
INTRODUCTION
There is accumulated evidence that heredity is
a major factor in the pathogenesis of major psycho-
ses. This hypothesis is supported by findings from
family, twin, and adoption studies. The mode of
inheritance is still unknown and may depend on
a few (oligogenic) or many (polygenic) genes
1,2
in
combination with different environmental factors,
although genes with a major effect may be present
in some multiplex families.
The increasing availability of polymorphic DNA
markers has greatly expanded their potential utility
in the identification of genes for susceptibility to
the disease by applying linkage or association strat-
egies. However, the application of linkage analysis
to complex diseases such as schizophrenia and bipolar
disorder has many difficulties, including reduced
penetrance, unknown mode of inheritance, pheno-
ABSTRACT
Background: Alterations of the γ-aminobutyric acid
(GABA) system have been implicated in the pathophysi-
ology of major psychoses.
Objective: Restriction fragment length polymorphisms
associated with the human γ-aminobutyric acid type A
(GABA
A
) β
2
and GABA
A
γ
2
subunit genes on chromo-
some 5q32-q35 were tested to determine whether they
confer susceptibility to major psychoses.
Methods: Thirty-two schizophrenic families and 25
bipolar families were tested for linkage.
Results: Nonparametric linkage (NPL) analysis per-
formed by GENEHUNTER showed no significant NPL
scores for both genes in schizophrenia (GABA
A
β
2
: NPL
narrow=0.450; NPL broad=0.808; GABA
A
γ
2
:
NPL narrow=0.177; NPL broad=0.051) or bipo-
copies, and genetic heterogeneity.
2,3
Nonparametric
linkage (NPL) analysis was developed to avoid
some of these problems.
4
It is considered the most
important method for linkage analysis of complex
disorders because NPL analysis is independent of
the mode of inheritance. Although linkage studies
can be performed using chromosomal regions, these
studies are particularly important when applied to
specific candidate genes of known biological func-
tion implicated in the disease, identified within the
candidate chromosomal region by linkage studies.
5
Based on several linkage studies,
6-10
a number of
genomic regions that include the 5q region (which
might harbor genes predisposing to schizophrenia
and bipolar disorder) have been proposed to be
either linked or implicated in these disorders.
Alterations in γ-aminobutyric acid (GABA) neu-
rotransmission have been indirectly implicated in
the etiology of schizophrenia,
11-15
and bipolar I disor-
der.
16,17
Because GABA is the major inhibitory neu-
rotransmitter in the central nervous system (CNS),
primarily synthesized by interneurons in the cere-
bral cortex, hippocampus, and limbic structures,
18
changes in the GABAergic activity may cause
perturbation in other neurotransmitter pathways,
as, for example, dopamine, serotonin (5-HT) and
noradrenaline, which also have been implicated in
these disorders. About 20% to 50% of all neuronal
synapses use GABA as a transmitter,
19
and most of
the physiological actions of GABA are produced via
GABA A (GABA
A
) receptors. Based on their phar-
macologic action, it was concluded that GABA
A
receptors are involved in controlling the excitability
of the brain
20,21
and in the modulation of anxiety,
22
cognition, vigilance, memory, and learning.
23,24
Molecular cloning studies have revealed the
existence of 16 mammalian subunits (α
1-6
, β
1-4
,
γ
1-4
, ρ
1-2
, ε
1-2
) for ionotropic GABA
A
receptors.
25
Chromosomal mapping indicates that GABA
A
subunit genes are often clustered in the genome.
For example, GABA
A
α
1
, GABA
A
α
6
, GABA
A
β
2
, and GABA
A
γ
2
have been localized to chromo-
some 5q32-q35.
26-29
GABA
A
receptors are chlo-
ride ion channels that can be opened by GABA
and can be modulated by a variety of pharmaco-
logically and clinically important drugs, such as
barbiturates, steroids, anesthetics, anticonvulsants,
and benzodiazepines (BZs).
30,31
In clinical practice, BZs are routinely prescribed
in schizophrenia and in acute psychotic states,
although mostly in combination with neurolep-
tics. The benefit of such therapy appears to be the
reduction of the dose of neuroleptics and increased
responsiveness to therapy, particularly in neurolep-
tic-resistant patients.
12
BZs produce at least part of
their clinically relevant effects by interacting with
distinct allosteric binding sites on GABA
A
recep-
tors.
32
Alterations in the density of these receptors
in the dorsolateral prefrontal cortex from schizo-
phrenia subjects and alterations in the number of
BZ binding sites on the GABA
A
receptors have
been reported.
14
Also, BZs can ameliorate symp-
toms of mania.
33
The antimanic and antidepres-
sant effects of lithium, carbamazepine, and valproic
acid may be partly achieved by their actions on
GABAergic neurotransmission.
34,35
BZ binding to GABA
A
receptors is modulated
by γ
2
receptor subunit, and this subunit, along with
α and β subunits, is the principal contributors to
most native GABA
A
receptors.
36
The subunits α are
responsible for the selectivity of the receptor for BZs,
whereas the β
2
subunit is essential for high affin-
ity BZ binding. Based on the aforementioned evi-
dence, GABA
A
receptor genes, such as GABA
A
β
2
and GABA
A
γ
2
subunit genes, are located in
chromosomal regions implicated in schizophrenia
and bipolar disorder by linkage analysis are excel-
lent candidate genes for these disorders. Therefore,
the present linkage study investigates the hypothesis
that allelic variants of GABA
A
β
2
and GABA
A
γ
2
genes confer susceptibility to major psychoses in a
Portuguese population.
METHODS
Subjects
The families used in this study were ascertained
from Azores and mainland Portugal and contained
at least two affected members. The overall sample
consisted of 32 schizophrenia families (including
66 schizophrenia, 9 unipolar, and 123 unaffected
family members) and 25 bipolar families (includ-
ing 51 bipolar, 23 unipolar, 3 schizophrenia, and
92 unaffected family members). Local ethical com-
mittee approval and written consent from each
subject were obtained. All probands and available
relatives were personally interviewed by a clinician
with a extensive training. All participants were
administered the Diagnostic Interview for Genetics
Studies,
37
Portuguese version
38
and rated with
the Operational Criteria checklist. Best estimate
diagnosis were made according to the Diagnostic
and Statistical Manual of Mental Disorders, Fourth
Edition.
39
Ascertainment and diagnostic methods for
these families have been described elsewhere.
40,41
Original Research
58
Volume 10 – Number 1 © MBL Communications Inc. CNS Spectrums – January 2005
Original Research
GABA
A
β
2
and GABA
A
γ
2
Polymorphisms
Blood samples were collected by venous punc-
ture in test tubes containing ethylenediaminetet-
raacetic acid as the anticoagulant, and genomic
DNA was prepared using the standard method,
42
with slight modifications. polymerase chain reac-
tion (PCR) restriction fragment length polymor-
phism analysis of BanI and NciI polymorphisms of
the GABA
A
β
2
and GABA
A
γ
2
genes was carried
out according to Loh and colleagues,
43
with slight
modifications. For polymorphism BanI, amplifica-
tion reactions were carried out in a volume of 25
µl, containing 100 ng genomic DNA as template,
200 µM dinucleotides, 1µM of each primer, 10
mM Tris-HCL (pH=8.3), 1.67 mM MgCl2, and 1
unit of Taq polymerase. After initial denaturation
at 9C for 5 minutes, 40 cycles of PCR reaction
were performed under conditions of denaturation
at 9C for 30 seconds, annealing at 56°C for 30
seconds, and extension at 72°C for 30 seconds.
Amplification products were digested with BanI
restriction enzyme, separated by electrophoresis
in a 3% agarose gel, and visualized with ethidium
bromide staining under ultraviolet light.
The polymorphism NciI in the intronic region
of the GABA
A
γ
2
was determined by PCR in a
final volume of 25 µl, containing 100 ng genomic
DNA as template, 200 µM dinucleotides, 1 µM of
each primer, 10 mM Tris-HCL (pH=8.3), 2.5 mM
MgCl
2
, and 1 unit of Taq polymerase. PCR ampli-
fication was initiated at 95°C for 4 minutes and
performed for 40 cycles each, consisting of 95°C for
30 seconds, 5C for 30 seconds, and 7C for 40
seconds. PCR products were digested using enzyme
NciI. The digested fragments were separated in
2.5% agarose gel and were visualized by ethidium-
bromide staining.
Statistical Analysis
Single-point NPL analysis was performed using
GENEHUNTER (Version 1.2) program,
4
which
allows NPL analysis of moderately sized pedigrees.
This is a model-free test
of the exact probability of
observed identical by descent marker allele sharing
among affected individuals in each pedigree. Two
diagnostic phenotypes were tested in linkage analy-
sis. Concerning schizophrenia, the narrow pheno-
type included only schizophrenia and the broad
phenotype included schizophrenia and unipolar
disorder. Relatively to bipolar disorder, the narrow
phenotype included bipolar disorder, and the broad
phenotype included bipolar disorder, unipolar dis-
order and schizophrenia.
FINDINGS
Thirty two schizophrenic families and 25 bipo-
lar families with at least two affected members
were recruited in this study. Concerning schizo-
phrenia, we performed linkage analysis with
GENEHUNTER and the results are presented in
Table 1 for polymorphism BanI of GABA
A
β
2
gene
and polymorphism NciI situated in the intronic
region of the GABA
A
γ
2
gene. For polymorphism
BanI of the GABA
A
β
2
gene (narrow and broad
disease phenotype), the NPL score was 0.450
(P=.703) and 0,808 (P=.823), respectively, and
for polymorphism NciI GABA
A
γ
2
gene (narrow
and broad disease phenotype) the NPL score was
0.177 (P=.412) and 0.051 (P=.517), respectively.
Similarly, single-point NPL analysis performed
with GENEHUNTER used the 25 bipolar families.
The results for both genes are presented in Table
2. For polymorphism BanI of the GABA
A
β
2
gene
the NPL score was no significant for both narrow
(0.834, P=.169) and broad (0.783, P=.189) diag-
noses. For polymorphism NciI of the GABA
A
γ
2
gene the NPL score for the narrow disease phe-
notype was –0.159 (P=.563) and for broad disease
phenotype was 0.070 (P=.458).
DISCUSSION
We tested two genes from GABAergic system,
and we did not find evidence for linkage between
the polymorphisms examined in these genes and
both schizophrenia and bipolar disorder, following
the guidelines proposed by Lander and Krugylak.
44
To our knowledge, no association and linkage stud-
ies between the polymorphism BanI of GABA
A
β
2
gene or polymorphism NciI of GABA
A
γ
2
gene and
schizophrenia have been reported. Although we
did not find any evidence for linkage, we cannot
exclude the involvement of GABA receptors in
the etiology of schizophrenia. Indeed, it has been
TABLE 1. NPL ANALYSIS FOR GABA
A
β
2
AND
GABA
A
γ
2
GENES AND SCHIZOPHRENIA FAMILIES
Phenotype
definition
GABA
A
β2 gene
GABA
A
γ2 gene
NPL
score
P
value
NPL
score
P
value
Narrow –0.450 .703 0.177 .412
Broad –0.808 .823 –0.051 .517
NPL=nonparametric linkage; GABA
A
=γ-aminobutyric acid type A.
Ambrósio AM, Kennedy JL, Macciardi F, King N, Azevedo MH,
Oliveira CR, Pato CN. CNS Spectr. Vol 10, No 1. 2005.
59
Volume 10 – Number 1 © MBL Communications Inc. CNS Spectrums – January 2005
reported an increase in the density of GABA
A
receptors in the dorsolateral prefrontal cortex from
schizophrenic subjects.
45
Conversely, a reduction
or no change in the number of BZ binding sites
on the GABA
A
receptor in schizophrenia has also
been reported.
46,47
It was also shown that glutamic
acid decarboxylase mRNA levels are reduced in the
prefrontal cortex of schizophrenia patients without
loss of neurons.
48,49
Concerning bipolar disorder these findings
extended the results of other negative molecu-
lar genetic studies of the GABAergic system,
including GABA
A
α
1
, GABA
A
α
3
, GABA
A
α
5
,
GABA
A
β
2
1 and GABA
A
β
3
genes.
50-54
Conversely,
Papadimitiou and colleagues
55
showed association
between GABA
A
α
5
gene and bipolar disorder, but
case control association studies can generate false
positives as a result of population stratification.
Several methods have been proposed for linkage
analysis of complex traits with unknown mode of
inheritance, including maximum likelihood-based
methods and nonparametric approaches, such as
NPL statistics.
4
The maximum likelihood method
uses all the data available and is the most power-
ful method available when the true model is used.
NPL analysis is less powerful when detecting link-
age than parametric analyses,
56
but does not require
specification of a mode of inheritance. Both meth-
ods are still limited by heterogeneity and definitive
conclusions cannot be drawn from this study due to
the small sample size, the low marker heterozygosity
and consequently limited statistical power. The use
of the Portuguese population, which can be consid-
ered a highly homogenous population,
57
allows us
to minimize the problem of genetic heterogeneity.
Our findings cannot completely exclude a role of
the GABA
A
β
2
and GABA
A
γ
2
genes in major psy-
choses. GABAergic neurons are widely distributed
in the CNS, and their action influences the effects
of other neurotransmitters such as dopamine, 5-
HT, and norepinephrine.
58
For example, it was
recently shown that the second intracellular loop
of the GABA
A
γ
2
(short) receptor subunit interacts
directly with the dopamine D
5
carboxy-terminal
domain.
59
Failure to detect linkage with GABA
A
β
2
and GABA
A
γ
2
genes cannot exclude the possibil-
ity that there might be mutations in these genes
that play a role in schizophrenia and bipolar disor-
der, for instance, potentially via interaction with
genetic variation of the dopamine D
5
. In linkage
analyses of genetically complex traits, the inherent
methodological difficulties may make it difficult to
detect the presence of a rare or minor gene effect.
CONCLUSION
Although our results do not provide evidence
for a role of the GABA
A
β
2
and GABA
A
γ
2
genes
in the susceptibility to major psychoses in the
Portuguese population, further work on larger sam-
ples is warranted. In addition, the potential role of
gene-gene interaction between several neurotrans-
mitter systems may be of particular interest.
CNS
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TABLE 2. NPL ANALYSIS FOR GABA
A
β
2
AND
GABA
A
γ
2
GENES AND BIPOLAR FAMILIES
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β
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Volume 10 – Number 1 © MBL Communications Inc. CNS Spectrums – January 2005
    • "Several new candidate genes have recently been identified, involving signal transduction cascades, intracellular signaling, or neuronal networks . These genes include TPH2, HTR3B [145], ADRA2C [146], PIK3C3 [147], GABA A Beta2, GABA A Gamma2 [148], PCDH11Y [149], and GSK3Beta [150] [151]. Most of these genes have shown negative results, but positive associations were reported in HTR3B and PIK3C3. "
    [Show abstract] [Hide abstract] ABSTRACT: Polycystic Ovary Syndrome (PCOS) is a polygenic disorder caused by the interaction of susceptible genomic polymorphisms with environmental factors. PCOS, characterized by hyperandrogenism and menstrual abnormalities, has a higher prevalence in women with Bipolar Disorder (BD). Theories explaining this high prevalence have included the effect of PCOS itself or the effect of drugs such as Valproate, which may cause PCOS either directly or indirectly. Incidentally, metabolic abnormalities are observed in both bipolar and PCOS patients. Endophenotypes such as insulin resistance, obesity, and hyperglycemia are common among BD and PCOS patients, suggesting some degree of pathophysiological overlap. Since both BD and PCOS are complex polygenetic diseases, the endophenotype overlap may be the result of common genetic markers. This paper postulates that shared clinical endophenotypes between PCOS and BD indicate common pathophysiological platforms and will review these for the potential of genetic overlap between the two disorders.
    Full-text · Article · Jul 2009
  • [Show abstract] [Hide abstract] ABSTRACT: Diss. -- Helsingin yliopisto.
    Full-text · Article · · Psychiatry and Clinical Neurosciences
  • [Show abstract] [Hide abstract] ABSTRACT: In this review, all papers relevant to the molecular genetics of bipolar disorder published from 2004 to the present (mid 2006) are reviewed, and major results on depression are summarized. Several candidate genes for schizophrenia may also be associated with bipolar disorder: G72, DISC1, NRG1, RGS4, NCAM1, DAO, GRM3, GRM4, GRIN2B, MLC1, SYNGR1, and SLC12A6. Of these, association with G72 may be most robust. However, G72 haplotypes and polymorphisms associated with bipolar disorder are not consistent with each other. The positional candidate approach showed an association between bipolar disorder and TRPM2 (21q22.3), GPR50 (Xq28), Citron (12q24), CHMP1.5 (18p11.2), GCHI (14q22-24), MLC1 (22q13), GABRA5 (15q11-q13), BCR (22q11), CUX2, FLJ32356 (12q23-q24), and NAPG (18p11). Studies that focused on mood disorder comorbid with somatic symptoms, suggested roles for the mitochondrial DNA (mtDNA) 3644 mutation and the POLG mutation. From gene expression analysis, PDLIM5, somatostatin, and the mtDNA 3243 mutation were found to be related to bipolar disorder. Whereas most previous positive findings were not supported by subsequent studies, DRD1 and IMPA2 have been implicated in follow-up studies. Several candidate genes in the circadian rhythm pathway, BmaL1, TIMELESS, and PERIOD3, are reported to be associated with bipolar disorder. Linkage studies show many new linkage loci. In depression, the previously reported positive finding of a gene-environmental interaction between HTTLPR (insertion/deletion polymorphism in the promoter of a serotonin transporter) and stress was not replicated. Although the role of the TPH2 mutation in depression had drawn attention previously, this has not been replicated either. Pharmacogenetic studies show a relationship between antidepressant response and HTR2A or FKBP5. New technologies for comprehensive genomic analysis have already been applied. HTTLPR and BDNF promoter polymorphisms are now found to be more complex than previously thought, and previous papers on these polymorphisms should be treated with caution. Finally, this report addresses some possible causes for the lack of replication in this field.
    Full-text · Article · Mar 2007
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