Analysis of GNAZ Gene Polymorphism in Bipolar Affective Disorder

American Journal of Medical Genetics (Neuropsychiatric Genetics) 88:324–328 (1999) Analysis of GNAZ Gene Polymorphism in Bipolar Affective Disorder T...
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American Journal of Medical Genetics (Neuropsychiatric Genetics) 88:324–328 (1999)

Analysis of GNAZ Gene Polymorphism in Bipolar Affective Disorder Takuya Saito,1 Demitri F. Papolos,1 Danielle Chernak,1 Mark H. Rapaport,2 John R. Kelsoe,2 and Herbert M. Lachman1* 1

Department of Psychiatry, Program of Behavioral Genetics, Albert Einstein College of Medicine, Bronx, New York Department of Psychiatry, University of California at San Diego, San Diego, California


Evidence for a bipolar disorder (BPD) susceptibility locus on chromosome 22q11 has been provided in several studies. One candidate gene that maps to this region is the G-protein ␣ subunit gene G␣z (GNAZ). We have identified a common silent polymorphism in GNAZ exon 2 by single strand conformation polymorphism analysis. The frequency of this polymorphism was determined in a control population (n=84) and in patients with BPD (n=88). The data showed a statistical trend toward a difference in the distribution of alleles in patients with BPD compared with control subjects (chi square=3.2, 1 df, P=0.073, two-tailed). No significant difference was detected when the GNAZ polymorphism was analyzed in control subjects and schizophrenia patients (n=63, P=0.92). These data continue to provide some support for a BPD susceptibility gene on 22q11, possibly in linkage disequilibrium with the GNAZ 309 polymorphism. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:324–328, 1999. © 1999 Wiley-Liss, Inc. KEY WORDS: bipolar disorder; G-protein; chromosome 22; manic depression; manic depressive illness

Part of this work was presented at the annual American Psychiatry Association meetings (Toronto, 1998). Contract grant sponsor: Scottish Rite Schizophrenia Research; Contract grant sponsor: American Psychiatric Association; Contract grant sponsor: National Institute of Mental Health; Contract grant number: MH47612; Contract grant sponsor: Novartis. *Correspondence to: Herbert M. Lachman, Department of Psychiatry, Program of Behavioral Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461. E-mail: [email protected] Received 24 April 1998; Accepted 9 October 1998

© 1999 Wiley-Liss, Inc.

INTRODUCTION Bipolar disorder (BPD) is a common psychiatric condition characterized by periods of depression alternating with mania (BPI) or hypomania (BPII). Family, twin, and adoption studies show that genetic factors play an important role in its development [Bertelson et al., 1977; Craddock and McGuffin, 1993; Mendlewicz and Rainer, 1977; Nurnberger et al., 1994]. However, despite a decade of intensive research, mapping BPD susceptibility genes to specific chromosomal loci has been very difficult. Although early genetic linkage studies using parametric lod score determinations provided strong evidence for loci on chromosomes X and 11, the results were not replicated [Baron et al., 1987; Berretini et al., 1990; Egeland et al., 1987; Gershon, 1991; Kelsoe et al., 1989; Mendlewicz et al., 1987]. In the past few years several loci including 18p, 18q, 4p, 13q, 15q, and 21q have been mapped using model-free, nonparametric methods of statistical analysis that are more useful for complex nonmendelian traits [Berretini et al., 1994; Blackwelder and Elston, 1985; Blackwood et al., 1996; DeBruyn et al., 1995; Detera-Wadleigh et al., 1997; Freimer et al., 1996; Gurling et al., 1995; Risch, 1990; Stine et al., 1995; Stine et al., 1997; Straub et al., 1994; Suarez et al., 1978; Weeks and Lange, 1988]. Recently, we have also used parametric and nonparametric multipoint analyses in 17 multiplex pedigrees to map a possible BPD susceptibility locus on chromosome 22q11 [Lachman et al., 1997a]. A maximum lod of 2.51 was obtained under a dominant model and 50% heterogeneity at marker D22S303. Similar findings were subsequently reported by Edenberg et al. [1997], who obtained a maximum lod score of 2.46 for marker D22S533, which also maps to 22q11. One gene that maps near D22S303 is GNAZ, a member of the G-protein family of signal transducers [Fields and Casey, 1997; Fong et al., 1988; Matsuoka et al., 1988; Matsuoka et al., 1990]. G-proteins are heterotrimeric proteins, composed of ␣, ␤ and ␥-subunits that are critical cellular signal transducers involved in the activation of adenyl cyclase, phosphoinositide metabolism, and calcium and potassium channel function [Casey et al., 1990; Guderman et al., 1997; Simon et al.,

GNAZ Gene Polymorphism in Bipolar Affective Disorder

1991]. One function reported for GNAZ is agonist mediated inhibition of adenyl cyclase, similar to G␣i. However, it differs from the G␣i family of proteins in that it is not inhibited by pertussis toxin [Fields and Casey, 1997]. We and others have previously suggested that G-proteins are very feasible candidate genes in BPD [Avissar et al., 1988; Lachman and Papolos, 1989]. Lithium, the major drug used in the treatment of BPD, has been found in some studies to inhibit Gprotein activation [Avissar et al., 1988]. Differences in G-protein levels and in agonist stimulated GTP binding have been detected in mononuclear leukocytes of patients with BPD [Avissar et al., 1997]. Lithium also appears to have an affect at a level distal to G-protein activation since it inhibits forskolin and calmodulin stimulated adenyl cyclase [Mork and Geisler, 1987; Mork and Geisler, 1995]. More than two dozen genes encoding various ␣, ␤, and ␥ G-protein subunits have been identified. The capacity of G-protein subunits to mix and match components and couple to different neurotransmitter receptors, thereby providing the opportunity for a single defective subunit protein to interact with multiple neurotransmitter/signal transduction pathways, is a particularly suggestive property for a candidate gene in an illness characterized by mood extremes. GNAZ has unique properties that make it an interesting candidate gene to consider in BPD. First, it is expressed at relatively high levels in the brain compared with other tissue [Matsuoka et al., 1988]. Second, GNAZ has a relatively slow rate of GTP hydrolysis compared with other ␣-subunits, requiring a G-protein activating protein (GAP) for maximal activity [Casey et al., 1990]. A delay in GTP hydrolysis caused by reduced GTPase activity would lead to enhanced effector target activation. Third, GNAZ is inhibited by nanomolar concentrations of Mg++, a property that could present a specific target for lithium since Li+1 and Mg+2 compete with each other at some targets, including sites necessary for G-protein guanine nucleotide exchange [Avissar et al., 1991; Casey et al., 1990]. Fourth, GNAZ is coupled to receptors that are activated by neurotransmitters and neuropeptides implicated in affective disorders including the ␣1-adrenergic, 5-HT1A, mu and kappa opioid, melatonin, and dopamine DRD2 receptors [Ammer and Schulz, 1993; Butkerait et al., 1995; Ho and Wong, 1997; Lai et al., 1995; Yung et al., 1995]. Finally, GNAZ is an excellent substrate for protein kinase C (PKC)-mediated phosphorylation; PKC has been suggested as a potential target of lithium [Ho and Wong, 1997; Manji and Lenox, 1994]. The 22q11 linkage findings and the experimental and theoretical considerations described in the preceding paragraphs led us to examine GNAZ as a potential candidate gene for BPD. A preliminary scan of the gene by single strand conformation polymorphism (SSCP) analysis identified a silent C→T transition at codon 103 (henceforth referred to as the 309 polymorphism). This polymorphism was used in an association study conducted on 88 patients with BPD and 84 control subjects. The data show a statistical trend toward an increase in 309T in patients with BPD compared with controls.


METHODS Subjects Patients with BPD were diagnosed on the basis of either a schedule for affective disorder and schizophrenia-life-time version for bipolar spectrum disorder (SADS)-LB interview or structured clinical interview for Diagnostic and Statistical Manual of Mental Disorders (DSM-III R) diagnosis [Endicott and Spitzer, 1978]. There were 54 patients with BPI and 34 with BPII in the study; 60 (68%) were female. All patients were Caucasians of European ancestry. Included in the analysis were 14 probands from our BPD linkage study. The mean age was 44.8±11.7. Control subjects (n⳱84) were Caucasian individuals of European ancestry drawn from hospital and medical school staff and students matched for geographical location, age, and gender with the patient population. Fifty-two controls were female (62%) with a mean age of 42.9±12.8. No formal testing procedure was used to screen for underlying psychiatric illness. However, subjects were excluded as controls if they had a personal or family history of BPD, severe depression or schizophrenia. Schizophrenic subjects (n⳱63) were diagnosed by Research diagnostic criteria (RDC) and DSM-III R criteria based on information obtained from a SADS interview or from semistructured interview and chart review [Spitzer et al., 1978]. The patients were Caucasians of European ancestry matched for age with the control and BPD populations (42.6±9.4). The schizophrenic subjects, however, were not matched for gender since there was a predominance of males in the patient population available for analysis (19/63 female subjects). Genotype GNAZ coding exons (2 and 3) were screened in 10 subjects with BPI for mutations by SSCP analysis using published sequence information [Fong et al., 1988; Matsuoka et al., 1988; Matsuoka et al., 1990]. In addition, the GTPase domain in the 5⬘ portion of exon 2 was screened by direct sequencing of polymerase chain reaction (PCR)-amplified fragments. The subjects analyzed were probands from the families that provided the highest lod scores for 22q11 in our linkage study [Lachman et al., 1997a]. SSCP and DNA analysis was performed on overlapping PCR fragments. For SSCP, 32 P-labeled PCR products were generated in a 20-␮L volume using the following primers that spanned GNAZ coding regions in exons 2 and 3: GTGTCCCCTGTGGCAAGAGG (primer 1) and TGCGGGTCAGCGAGTCGATG (−70 to 250, translation start site is position 1); CTCAGGATCGACTTCCACAA and CGATGCGCTCCAGGTCGTTC (270–490); ACAGGCCTGCTTCAGCCCGCT and CACTTACTGTCTGGTTATCC (primer 2)(411–723/intron 2); CCAGAGTCGGATGGCAGA and GTCTCCTTGTTGCGGTTCAG (intron 2/724–950); GCTGTCTACATCCAGCGGCA and TGGATTGGGCCTCTCTAGCA (901–1150) [Matsuoka et al., 1988; Matsuoka et al., 1990]. Five microliters of PCR product was added to 7 ␮L of denaturing buffer (90% formamide, 0.01N NaOH, 0.5X TBE, 0.25% xylene cyanol and 0.25% bromocresol purple). The samples were denatured by heating to 9°C for 5 min


Saito et al.

and then quenched at 4°C prior to loading. An aliquot (3 ␮L) was loaded onto a 5% acrylamide gel containing 5% glycerol and 0.5×TBE. Nondenatured PCR product was loaded on each gel. The DNA was separated by electrophoresis at constant power (30 watts) at room temperature with constant fanning until the xylene cyanol dye migrated a distance of 45 cm. Following electrophoresis, the gel was dried and exposed to X-ray film at room temperature without intensifying screens for 24–72 hr. Band shifts signifying allelic differences were observed by visual inspection of the autoradiograms. SSCP genotypes were read independently by two investigators (H.M.L and T.S.). A region approximately encompassing the translation start and position 290, which includes the GTP hydrolytic site, was analyzed by DNA sequence analysis. A PCR product was generated using primers 1 and 2 (see above) and treated with shrimp alkaline phosphatase and exonuclease I to remove unused primer (United States Biochemical). A sequence ladder was generated using Sequenase and the reverse primer CGGGGCCCGTCAGCGCAAAG (position 350). Data Analysis Allele frequencies were organized in a 2 × 2 contingency table comparing genotype and phenotype (control versus BPD and control versus schizophrenia). A chi-square analysis (with Yate’s correction) was performed. RESULTS The GTPase domain is commonly mutated in functional alterations of G-protein ␣-subunits and Ras. However, DNA sequence analysis did not reveal any polymorphisms in the GNAZ GTPase domain in the 10 subjects analyzed (not shown). Screening by SSCP revealed a band shift in eight out of 10 subjects when primers spanning positions 270–490 were used. DNA sequence analysis showed that the SSCP band was due to a C→T transition at position 309. Although the polymorphism creates a restriction fragment length polymorphism (RFLP) for the enzyme Hga I, genotyping by PCR-RFLP was difficult because of partial digestion caused by the loss of Hga I activity after a short period of incubation at 37°C. Consequently, all genotypes were determined by SSCP analysis. Under the conditions described in Methods, both DNA strands and both alleles generated by the 309 polymorphism could be separated on the same SSCP gel. The frequency of the 309 polymorphism was determined in a population of patients with BPD and control subjects. As seen in Table I, the frequency of 309T was 0.318 in patients with BPD and 0.226 in controls. There was a statistical trend toward a difference in allele frequencies between controls and patients with BPD (P⳱0.073, two-tailed). The number of 309T homozygotes was too small to obtain meaningful data by chi-square analysis of genotypes. However, when the genotypes were pooled to increase the number of subjects in each cell of the contingency table the findings continued to show a statistical trend. Among patients with BPD, 50/88 (56.8%) had one or two 309T alleles compared with 36/84

TABLE I. Distribution of GNAZ 309 Alleles* Allele frequency (n) Subjects [n]** BPD [88] CONT [84] SCH [63]

Genotype frequency (n)






(56) .318 (38) .226 (27) .214

(120) .682 (130) .774 (99) .784

(6) .068 (2) .024 (4) .063

(44) .500 (34) .405 (19) .302

(38) .432 (48) .571 (40) .635

*Allele frequency: BPD vs control: chi square ⳱ 3.2, 1 df, p ⳱ 0.037, one-tailed, p ⳱ 0.073, two-tailed, relative risk ⳱ 1.41. SCH vs control frequency: chi square ⳱ 0.01, 1 df, p ⳱ 0.92. Genotype: BP vs control: all subjects with one or two 309T alleles compared with all homozygotes for 309C (chi-square ⳱ 2.82, 1 df, p ⳱ 0.047, one-tailed, p ⳱ 0.093, two-tailed, relative risk ⳱ 1.33. **Bipolar disorder (BPD), schizophrenia (SCH), controls (CONT) T and C are GNAZ 309 alleles.

(42.9%) controls (P⳱0.093, two-tailed). Interestingly, there was no difference in the frequency of 309T in patients with BPI and BPII (0.310 and 0.329 respectively, not shown). We also analyzed a group of 63 schizophrenic subjects since there have been reports of linkage to chromosome 22q12 by some investigators [Coon et al., 1994; Gill et al., 1996; Vallada et al., 1995]. The frequency of 309T in chronic schizophrenics was similar to controls (0.214) and a comparison by chi-square showed no significant difference (P⳱0.92). DISCUSSION There are indications that chromosome 22q11 may contain one or more BPD susceptibility genes. This region was investigated initially as a result of work we and others have conducted on velo cardio facial syndrome (VCFS), a congenital disorder caused by a chromosome 22q11 microdeletion. The disorder is characterized by a typical facial appearance, cleft palate, cardiac defects, learning disabilities, and psychiatric illness [Morrow et al., 1995; Papolos et al., 1996; Scambler et al., 1992; Shprintzen et al., 1978; Shprintzen et al., 1992]. Papolos et al. [1996] found that a high percentage of patients fulfilled criteria for BP spectrum disorders, in particular rapid cycling BPD. The clinical and genetic findings in VCFS suggest that ‘loss of function‘ of a gene or genes in the deleted region increases the susceptibility to develop BPD and other psychiatric problems. One gene that maps to the deleted region is catechol O-methyltransferase (COMT), which encodes one of the major enzymes involved in catecholamine metabolism [Axelrod and Tomchick, 1958; Morrow et al., 1995; Scambler et al., 1992]. COMT activity is subject to a common genetic polymorphism that leads to enzyme variants with either high or low activity [Boudikova et al., 1990; Lachman et al., 1996a; Lotta et al., 1995; Weinshilboum and Raymond, 1977]. We have provided some evidence that ultra rapid cycling BPD in patients with VCFS is associated with the COMT allele encoding the low enzyme activity variant [Lachman et al., 1996b]. However, it appears that genetic factors other than COMT also play a role in the development of the psychiatric problems found in VCFS [Lachman et al., 1996b]. COMT may also increase the cycling fre-

GNAZ Gene Polymorphism in Bipolar Affective Disorder

quency in patients with BPD resulting in an ultra ultra rapid cycling pattern [Papolos et al., 1998; Kirov et al., 1998]. However, COMT does not appear to exert a ‘‘major gene effect’’ in the pathogenesis of BPD [Gutierrez et al., 1997; Lachman et al., 1997b]. The findings in VCFS prompted our analysis of 22q11 in 17 multiplex families. Using parametric methods of analysis under a dominant model, we obtained a maximum lod of 2.51 at marker D22S303, which maps approximately 8 cm telomeric to the VCFS deleted region [Lachman et al., 1997a]. Similar results were provided by Edenberg et al. [1997] for marker D22S533. Since mapping of complex traits is not precise [Terwilliger et al., 1997], it is conceivable that the putative BPD susceptibility gene identified in these studies may be the same gene that causes BPD when deleted in patients with VCFS. However, arguing against this idea is our finding of strongly negative lod scores obtained in the linkage study using markers flanking the VCFS deleted region [Lachman et al., 1997a]. GNAZ maps to a YAC clone adjacent to D22S303 (unpublished observations). Based on its map location near D22S303 and the theoretical considerations outlined in the introduction, GNAZ has to be viewed as a feasible candidate gene for involvement in BPD. Scanning GNAZ exons by SSCP analysis identified a common nonfunctional polymorphism at position 309. Using a case control design we now report a trend toward an increase in the frequency of GNAZ 309T in patients with BPD. The screening for allelic differences should be considered preliminary since only 20 alleles were analyzed and SSCP may miss 20–30% of mutations when only a single electrophoresis condition is used. Furthermore, analysis of the intron-exon borders was limited because intron sequence data that could be used to generate a PCR product that encompassed the two relevant intron-exon borders was unavailable. The modest trend toward an association found in this study could be a type I error caused by population stratification, a common problem in association studies. However, the finding that the distribution of alleles in schizophrenic subjects was similar to that found in control subjects argues against this idea. Additional analysis in other populations of BPD patients is necessary, preferentially using family-based association studies. If an association between BPD and 309T is established, it would suggest that the polymorphism is in linkage disequilibrium with a disease causing functional alteration located in GNAZ or in a nearby gene. REFERENCES Ammer H, Schulz R. 1993. Alterations in the expression of G-proteins and regulation of adenylate cyclase in human neuroblastoma SH-SY5Y cells chronically exposed to low-efficiency mu-opioids. Biochem J 295: 263–271. Avissar S, Schreiber G, Danon A, Belmaker RH. 1988. Lithium inhibits adrenergic and cholinergic increases in GTP binding in rat cortex. Nature 331:440–442. Avissar S, Murphy DL, Schreiber G. 1991. Magnesium reversal of lithium inhibition of ␤-adrenergic and muscarinic receptor coupling to G proteins. Biochem Pharmacol 41:171–175. Avissar S, Nechamkin Y, Roitman G, Schreiber G. 1997. Differential G


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