(GABRA3) in bipolar patients - Nature

Molecular Psychiatry (2002) 7, 201–207  2002 Nature Publishing Group All rights reserved 1359-4184/02 $25.00 www.nature.com/mp

ORIGINAL RESEARCH ARTICLE

Excess of allele1 for ␣3 subunit GABA receptor gene (GABRA3) in bipolar patients: a multicentric association study I Massat1, D Souery1, J Del-Favero2, L Oruc3, MM Noethen4, D Blackwood5, M Thomson5, W Muir5, GN Papadimitriou6, DG Dikeos6, R Kaneva7, A Serretti8, R Lilli8, E Smeraldi8, M Jakovljevic9, V Folnegovic9, M Rietschel10, V Milanova11, F Valente12, C Van Broeckhoven2 and J Mendlewicz1 1

Department of Psychiatry, University Clinics of Brussels, Erasme Hospital, Free University of Brussels, Belgium; Department of Molecular Genetics, Flanders Interuniveristy Institute for Biotechnology (VIB), University of Antwerp (UIA), Antwerpen, Belgium; 3Psychiatry Clinic, University of Sarajevo, Sarajevo, Bosnia and Herzegovina; 4Institute of Human Genetics, University of Bonn, Germany; 5Department of Psychiatry and the Department of Medical Science, University of Edinburgh, UK; 6Athens University Medical School, Department of Psychiatry and University Mental Health Research Institute, Athens, Greece; 7Laboratory of Molecular Pathology, University Hospital of Obstetrics, Medical University, Sofia, Bulgaria; 8Instituto Scientifico H San Raffaele, Department of Neuroscience, University of Milano School of Medicine, Milan, Italy; 9Department of Psychiatry, University Hospital ‘REBRO’, University of Zagreb, Zagreb, Croatia; 10Department of Psychiatry, University of Bonn, Bonn, Germany; 11First Psychiatric Clinic, Department of Psychiatry, Alexander University Hospital, Sofia, Bulgaria; 12Department of Statistics, School of Public Health, Free University of Brussels, Belgium 2

Keywords: GABRA3; association study; candidate gene; chromosome X; bipolar disorder The available data from preclinical and pharmacological studies on the role of gamma amino butyric acid (GABA) support the hypothesis that a dysfunction in brain GABAergic system activity contributes to the vulnerability to bipolar affective disorders (BPAD). Moreover, the localization of the ␣3 subunit GABA receptor GABRA3 gene on the Xq28, a region of interest in certain forms of bipolar illness, suggests that GABRA3 may be a candidate gene in BPAD. In the present study, we tested the genetic contribution of the GABRA3 dinucleotide polymorphism in a European multicentric case-control sample, matched for sex and ethnogeographical origin. Allele and genotype (in females) frequencies were compared in 185 BPAD patients and 370 controls. A significant increase of genotype 1–1 was observed in BPAD females compared to controls (P = 0.0004). Furthermore, when considering recessivity of allele 1 (females with genotype 1–1 and males carrying allele 1), results were even more significant (P = 0.00002). Our findings suggest that the GABRA3 polymorphism may confer susceptibility to or may be in linkage disequilibrium with another gene involved in the genetic etiology of BPAD. Molecular Psychiatry (2002) 7, 201–207. DOI: 10.1038/ sj/mp/4000953

The hypothesis that bipolar affective disorder (BPAD) is transmitted through a gene on the X-chromosome was first proposed by Rosanoff et al in 1935.1 Several linkage studies have investigated the region Xq26–28 in BPAD2–28 (see Table 1). Among them, the largest pedigree series reported a high Lod score (z) confirming linkage (z = 8.1 at ␪ = 0.15) to color blindness (CB) in 17 North American families.4 This finding was further

supported by additional studies in different populations showing linkage to CB2–5,11,23 and glucose-6phosphate dehydrogenase (G6PD).9,11,23 In more recent studies, genome-wide scans using highly polymorphic DNA markers in large numbers of pedigrees have provided conflicting evidence for X-linkage in BPAD. Negative linkages,26,28 and modest but not significant evidence for linkage to Xq26–28, may be indicative of loci of modest susceptibility.25,27 Conversely, conclusive evidence for linkage from a Finnish pedigree24 was reported with a maximum Lod score (Zmax) of 3.54 at ␪ = 0, for DXS994 at Xq25–q26. These controversial results support the notion that genetic heterogeneity and ethnic differences may be a possible source of divergent results. Replication was reported in different populations, that makes the Xq26–X28 region particularly interesting for applying other methodologies. Because the two regions of positive linkage (Xq26 and Xq28) are separated by a genetic distance of 15–30 cM, there may be more than one susceptibility locus for BPAD in that area. More recent hypotheses of mode of inheritance of BPAD focus on complex heredity.29 Consequently, true positive linkage is difficult to replicate in disorders that are predisposed to by the combined action of several genes of minor or moderate effect.29 The allelic association strategy offers a powerful means of identifying such genes in realistically sized samples of unrelated cases by the study of polymorphisms within candidate genes and/or regions. To further explore the presence of a vulnerability gene for BPAD in the Xq28 region, we selected the dinucleotide repeat (CA) polymorphism of the ␣3 subunit of gamma-aminobutyric acid receptor gene (GABRA3), located near the 3⬘ end of the gene in

GABRA3 and bipolar affective disorders I Massat et al

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Table 1

Linkage studies for Xq26–28 region in BPAD

Study

Pedigree: number (origin)

Chromosomal location

Marker

Winokur, 19692 Reich, 19693 Mendlewicz, 19744 Baron, 19775 Gershon, 19796 Mendlewicz, 19797 Reading, 19798 Mendlewicz, 19809 Del Zompo, 198410

2 (US) 17 (US) 1 (US) 6 (US) 8 (Belgium) 1 (Australia) 1 (Iran) 2 (Sardinia)

Xq28 Xq28 Xq28 Xq28 Xq28 Xq28 Xq28 Xq28 Xq28

Baron, 198711

5 (Israel)

Xq28

Mendlewicz, 198712 Berretini, 199013

11 (Belgium) 9 (US)

Xq26.3–27.1 Xq28

Gejman, 199014

7 (US)

Xq27.1–27.2

Neiswanger, 199015 Mendlewicz, 199116 Lucotte, 199217 Gill, 199218 Bredbacka, 199319 Baron, 199320 Jeffries, 199321

3 1 1 1

De bruyn, 199422

9 (Belgium)

Mendelbaum, 199523

23 (Belgium) 1 11

CB CB CB CB CB CB CB G6PD CB G6PD CB G6PD F9 DXS52, DXS15 CB G6PD F8 F9 DXS98, DXS105 GABRA3 DXS52 fragile X F9 F9 F9 F8, G6PD X fragile F9 F9 DXS52 GABRA3 F8 CB G6PD F9

⬍0 + 3.91 0.9 ⬍0 ⬍0/2 ⬍0 2.2 1.12 1.12 0.28 1.19 7.35 2.9 2.07

Pekkarinen, 199524

1 (Finland)

Stine, 199725 (NIMH)

97 (US)

Smyth, 199726

23 (Ireland and UK)

Liu, 199727

57 (US and Israe¨ l)

Xq27.3 Xq28 Xq26.3 Xq26

Vallada, 199828

43 (Europe and Brazil)

Xq24–27.1

F9 DXS994 F8 DXS1047 GATA31E08 FRAX.AC2 F8 DXS102 DXS1192 DXS1187 DX51227, DXS1062

0.42 3.54 ⬍0 1.23 1.27 ⬍0 ⬍0 ⬍0 1.95 1.22 0

(US) (Belgium) (France) (UK)

3 (Israel) 1 (USA)

Xq28 Xq28 Xq27 Xq27.1–27.2 Xq27.1–27.2 Xq27.1–27.2 Xq27–28 Xq27.3Xq27.1–27.2 Xq27 Xq28 Xq28 Xq28 Xq28 Xq28 Xq24–27.1 Xq27.1–27.2 Xq24–27.1 Xq25–26 Xq2 region Xq26–28

the 8 intron for carrying out a case-control association study in a large European multicentric sample. A total of 555 subjects were recruited, including 185 BPAD patients, each matched with two controls (n = 370) for sex and ethnogeographical origin (see Table 2). To our knowledge, only three association studies have examined the role of GABRA3 in BPAD, and didn’t report significant findings30–32 (Table 3). Three other genes have been investigated in the same region: FMR1 implicated in the fragile X syndrome in Xq27.333 Molecular Psychiatry

Lod score (Zmax) 3.3 3.3 8.1 2.3 ⬍0 1.6 0.4 4 1 4.75 2.94 3.1 ⬍0 ⬍0 ⬍0 ⬍0 ⬍0 ⬍0

reported negative findings, G6PD in Xq2834–37 reported positive results in two different populations. Finally, a recent preliminary study38 reported a trend of association between BPAD males and the SYBL1 gene (Xq28) involved in synaptic vesicle function. Pathophysiological arguments for selecting GABRA3 as a candidate gene are summarized as follows: gamma amino-butyric acid (GABA) is the principal inhibitory aminoacid in the vertebrate brain. Emrich et al39 in 1980 formulated the so-called ‘GABA hypothesis of


Table 2 Contribution of each center to the recruitment of case controls sample Centers

BPAD

Controls

Males Females Total Males Females Total Brussels Sofia Zagreb Athens Milan Edinburgh Bonn Total (n = 555)

Table 3

10 7 11 13 19 0 9 69

14 22 25 8 17 20 10 116

24 29 36 21 36 20 19 185

20 14 22 26 38 0 18 138

28 44 50 16 34 40 20 232

48 58 72 42 72 40 38 370

affective disorder’ in which valproic acid was presumed to correct a GABA deficit in BPAD. Since then, several lines of evidence from preclinical and clinical studies have lent support to the involvement of GABA in AD (see Massat et al40 for a review). GABA (type A) receptor is an ionotropic receptor with a hetero-oligomeric structure composed of five distinct classes ␣, ␤, ␥, ␦ and ␳ (divided into subunits) organized as a channel. These subunit types differ with respect to their sensitivity for GABA and recognition sites for drugs, that is relevant to the pharmacological differences observed between drugs, such as benzodiazepines (BZDs), which interact with GABAA receptors. Receptors that are composed of ␣3 subunits yield much greater responses to BZD than do receptors, which contain ␣1 or ␣2 subunits.41 Mutations are also known to alter the binding characteristics of the GABAA receptor. Especially for the ␣3 subunit, a single amino acid substitution increases by 10 the affinity of certain compounds for the BZD site.42

203

Case control association studies for the Xq27–28 region in BPAD

Study

Walsh, 199230 Puertellano, 199531 Oruc, 199632 Craddock, 199433 Bocchetta, 199434 Bocchetta, 199935 Kalsi, 199936 Bocchetta, 200037 Saito, 200038

Number of patients

Chromosomal location

Marker

Association

60 BP (UK) 59 BP (Spanish) 38 BP (Croatian) 79 BP (UK) 267 BP (Sardinian) 274 BP and parents (Sardinian) 279 BP (English, Irish and Scottish 111 BP and parents (Sardinian) 53 males BP (Japanese)

Xq28 Xq28 Xq28 Xq27.3 Xq28 Xq28 Xq28 Xq28 Xq28

GABRA3 GABRA3 GABRA3 FRA(X)CGG G6PD G6PD G6PD G6PD-med SYBL1

− − − − + + + +(BP2) trend

Table 4 Genotype and allelic distributions between BPAD patients and controls, by centers (A1 = 169 bp, A2 = 167 bp, A3 = 165 bp, A4 = 163 bp) Genotypes (females) 1–1 Brussels Sofia Zagreb Athens Milan Edinburgh Bonn

BP C BP C BP C BP C BP C BP C BP C Total

10 19 17 15 17 25 6 9 14 20 17 28 8 15 220

(71.4%) (67.9%) (77.3%) (34.1%) (68%) (50%) (75%) (56%) (82.4%) (58.8%) (85%) (70%) (80%) (75%) (63.2%)

1–2 1 2 1 2 2 3

1–3

1 7 4 23 6 18 2 3 3 3 13 2 2 6 1 1 2 17(4.9) 91(26.1)

1–4

Allelic distribution (males and females) 2–3

3–3

4–4

2

2

2

4 1 1 2

1

1

8(2.3)

1(0.3)

3 10(2.9)

1(0.3)

A1 32 64 46 65 52 92 26 45 45 77 36 66 26 49

(84.2) (84.2) (90.2) (63.7) (85.2) (75.4) (89.7) (77.6) (84.9) (72.6) (90) (82.5) (89.7) (84.5) (79.8)

A2

A3

A4

1 5 0 2 10 0 1 4 0 3 32 2 2 7 0 3 23 4 0 3 0 4 9 0 0 25 0 2 8 2 0 4 0 3 9 2 1 2 0 0 9 0 (2.4) (16.6) (1.1)

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No significant deviation from HWE was observed in female BPAD patients and control populations. When considering centers separately, a heterozygote deficit was noted in the Bonn control sample (P = 0.008) and Brussels BPAD sample (P = 0.02). The initial focus of our analysis was to detect differences between BPAD patients and controls in the distribution of genotypes, and alleles (see Table 4 for a description). Results are shown in Table 5 and Figure 1. The genotype distribution (after collapsing genotypes with a frequency less than 3%) showed an overall significant difference between BPAD and control females (P = 0.0024), with a level of significance of 0.03 for the genotype 1–1. When the presence or absence of genotype 1–1 was tested separately, significance increased (P = 0.0004, OR = 2.5 (1.5–4.3)). The relatively narrow confidence interval suggested precision in the estimate of the magnitude of the association. Comparison of allelic distribution (after collapsing allele 2 and allele 4 in the same group) between BPAD and matched controls showed an overrepresentation of allele 1 in BPAD patients (P = 0.002, OR = 1.8 (1.2–2.7)). In order to examine the allele 1 recessive hypothesis, we carried out an analysis that compared groups of BPAD patients and controls, according to genotype 1–1 homozygote females and allele 1 hemizygote males. Robust statistical differences emerged (P = 0.00002, OR = 2.5 (1.6–3.9)). When comparing the number of copies of allele 1 in BPAD females, we found that there was a significant difference between 1 and 2 copies (two copies of allele 1 were present in 78.8% of BPAD patients and 58.7% of controls, P = 0.0012 after bonferroni corrections). However, there was no statistical difference between 0 and 2 copies (two copies of allele 1 were present in 96.7% of BPAD patients and 93.6% of controls) and 0 and 1 copy (one copy was present in 88.9% of BPAD patients and 91.1% of controls): power was too low to detect significant results. Effect modification of center and sex (tested separately) didn’t show any significant difference (see Figure 1). The allelic distribution of our overall control population did not differ significantly from data in ‘Genome Database-http://www.gdb.org/’. In this multicentric European study, a robust association was found in favor of allele 1 recessive hypothesis of a (CA)n polymorphism43 in GABRA3, in BPAD patients. The involvement of GABRA3 may be related to a direct effect of the polymorphism on the disease. Microsatellites may alter DNA structure, which has been implicated in the regulation of transcription and translation. Altered binding of transcription and translation factors may compromise RNA editing.44,45 Another possibility is that the association may reflect an indirect effect of another gene close to GABRA3, in linkage disequilibrium. Our results are not in line with some previous association studies testing the same GABRA3 (CA)n repeat polymorphism.30–32 However, samples used in previous studies didn’t have a sufficient statistical power for detecting association, if we consider a minor or moderate effect of genetic variant


Table 5 Comparison of genotypes, genotype 1–1 distributions, and alleles, allele 1 recessive hypothesis at the GABRA3 locus, between bipolar patients (BPAD), and controls Conditional logistic regression (dependant variable: diagnosis) Predictor

Sig

Genotype* n = 116 trios 1–1 1–2 1–3

Odds ratio (95% CI)

0.0024 0.03 0.25 0.47

4.2 (1.1–15.4) 2.5 (0.5–12.6) 1.6 (0.4–6.5)

Genotypes 1–4, 2–2, 2–3, 3–3, 4–4 were collapsing because the frequency was less than 3%. 0.0004a

Genotype 1–1 n = 116 trios

2.5 (1.5–4.3)

a Significant after Bonferroni correction (two tests): P = 0.0008.

Alleles (males and females) n = 301 trios Allele 1 Collapsing allele 4 and 2

0.001 0.002 0.465

1.8 (1.2–2.7) 0.7 (0.26–1.8)

Recessivity of allele 1 n = 185 trios

0.00002

2.5 (1.6–3.9)

Number of copies of allele 1 in females n = 116 trios 0 copy 2 copies Comparison between 1 and 2 copies n = 113 trios Comparison between 0 and 1 copy n = 27 trios Comparison between 0 and 2 copies n = 92 trios

0.001

b Significant P = 0.0012.

after

Bonferroni

0.845 0.001 0.0003b

1.6 (0.3–5.1) 2.6 (1.5–4.4) 2.6 (1.5–4.6)

0.76

0.7 (0.1–4.6)

0.547

1.5 (0.4–6.7)

correction

(four

tests):

at this polymorphism. Furthermore, our present investigation supports DNA studies that have reported positive association findings for G6PD enzyme deficiency (Xq28) in BPAD patients in two populations.34–37 In light of previous positive linkage findings in this region,2–5,7,9,11,23 together with the present results implicating the GABRA3 candidate gene in BPAD, we suggest further investigation of the GABRA3 (CA)n


205

Figure 1 Allele 1 recessivity hypothesis (%) in BPAD and controls: stratification by centers and by sex. Stratification analysis: (a) Strata = centers. Breslow Day (Homogeneity test) ␹2 = 5.9, df 6, P = 0.43. (b) Strata = sex. Breslow Day (Homogeneity test) ␹2 = 0.002, df 1, P = 0.97.

repeat in other populations, using family-based association methods, to further explore the genetics of BPAD. Additionally, it would be of interest to investigate other GABA receptor genetic markers, such as Snps in the vicinity of GABRE (GABA receptor epsilon) and GABR␤4 (GABA ␤4 subunit) in Xq28 region. Finally, the positive association found in this multicentric European study between BPAD patients and allele 1 of GABRA3 (CA)n repeat polymorphism, underlines the interest of investigating further this genetic marker in controlled pharmacogenetic studies evaluating the treatment response of BPAD patients to anticonvulsants with primary activity at the GABA system.

Methods Subjects The present sample has been recruited within the Biomedical European (BIOMED 1) European Collaborative Project on Affective Disorders (ECPAD) (European Community Grant CT92–1217, project leader J Mendlewicz) and BIOMED 2 (European Collaborative Study on Molecular Genetics in Affective Disorders, Contract No: BMH4-CT-97-2307). This network was established within the framework of the European Commission. The objectives and the detailed methodology of the project were described previously.46 A total of seven clinical centers participated in the present study (Brussels, Sofia, Zagreb, Bonn, Athens, Milan and Edinburgh, see Table 2). All subjects were interviewed using standard diagnostic interviews, such as the Schedule for Affective Disorders and Schizophrenia–Lifetime Version (SADS-LA47) and the schedule for the Clinical Assessment of Neuropsychiatry (SCAN48). One of the two diagnostic interviews was used for all patients and controls recruited for the project. The decision to adopt two instruments arose out of different research experience within individual research teams having their own preferences and expertise with the two interviews. Comparability between SADS and SCAN instruments is inferred from data published by the European Science Foundation

ESF showing good concordance between the two instruments.49 Patients met the diagnosis of BPAD according to RDC, DSM-III-R and DSM-IV classification systems. Within the control group, subjects with a positive personal or familial history of psychiatric disorder were excluded. Informed consent was obtained from patients and controls. Genotyping Standard procedures were used for DNA extraction. The GABRA3 (CA)n polymorphism was identified using hot-start polymerase chain reaction (PCR). The primers employed were those described by Hicks et al.43 Cross-examination of DNAs ensured identical allele assignments between centers. The 169-bp dinucleotide was named allele 1, 167-bp allele 2, the 165bp allele 3 and the 163-bp allele 4 in our analyses. Statistical analysis The overall sample, as well as the samples of all centers separately, were tested for Hardy–Weinberg equilibrium (HWE) in female patients and control populations by using the exact HW test and the GENEPOP, 3.d program-updated version of GENEPOP.50 Matching in the design was utilized to control for potential confounding factors, sex and especially ethnogeographical origin, a complex nominal variable which represents a wide and undefinable range of environmental and genetic factors difficult to quantify and thus to control by other means. Because of the matched design with two controls individually matched to cases, conditional logistic regression was used to assess the association between BPAD and some predictors, and to derive odds ratios and 95% confidence intervals after adjustment for potential confounding factors. However, the limitation of matching is the inability to evaluate the effect of matching factor on risk of the outcome. To evaluate the possible effect modification of center, a stratified analysis was performed (match ignoring) and odds ratios (OR) and confidence intervals (95% CI) were calculated. The Breslow Day test was applied to test the homogeneity of the stratum-specific estimates Molecular Psychiatry


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(center and sex for strata and allele 1 recessivity as exposition). Bonferroni corrections were applied when necessary. Acknowledgements This work was supported by the Association for Mental Health Research (AESM), the European Community Biomed Grant (Grant No. CT 92–1217), the National Fund for Scientific Research (NFSR), and the Fund for Scientific Research Flanders-Belgium (FWO).

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21

22

23

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Correspondence: I Massat, MD, Department of Psychiatry, University Clinics of Brussels, Erasme Hospital, Free University of Brussels, 808 route de Lennik, B-1070, Brussels, Belgium. E-mail: imassat얀ulb.ac.be Received 7 December 2000; revised 23 April 2001; accepted 27 April 2001
