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Abstracts for the IXth World Congress of Psychiatric Genetics, Saint Louis, Missouri

2001; Wiley; Volume: 105; Issue: 7 Linguagem: Inglês

10.1002/ajmg.1593

1096-8628

Child and Adolescent Psychosocial and Emotional Development

American Journal of Medical GeneticsVolume 105, Issue 7 p. 579-595 Abstract Abstracts for the IXth World Congress of Psychiatric Genetics, Saint Louis, Missouri First published: 23 October 2002 https://doi.org/10.1002/ajmg.1593Citations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract VII. Bipolar Disorder Genome-Scans and Overlap With Schizophrenia O55 DIFFERENT INHERITANCE MODELS BY AGE OF ONSET IN BIPOLAR I DISORDER Grigoroiu-Serbanescu M1, Martinez M2, Nöthen MM3, Grinberg M4, Sima D4, and Propping P5 1Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Psychiatric Hospital, Sos. Berceni, 10, O.P. 8 R-75622, Bucharest, Romania, Phone: 40-1-332.39.29; 40-1-683.57.62; Fax: 40-1-334.71.64; E-mail: mserban@dnt.ro 2I.N.S.E.R.M., Unité 358, EPI 06, Paris, France 3Department of Medical Genetics, University of Antwerp, Belgium 4Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Psychiatric Hospital, Bucharest, Romania 5Institute of Human Genetics, University of Bonn, Germany In bipolar affective disorder, where the majority of linkage studies have produced conflicting results, studies reporting clinical characteristics and familial occurrence of disease have suggested that age of onset might serve as an indicator for identifying more homogenous subgroups of disease. Our study was the first to examine this hypothesis by the means of segregation analysis. We investigated a sample of 177 bipolar I probands recruited from consecutive admissions and their first- and second-degree relatives (2,407 subjects). Probands were subdivided into an early-onset (N=107) and a late-onset group (N=70) using an age of onset of 25 as a cut-off point. This age was chosen because the observed age of onset distribution was bimodal with a cut-off of 25 years. Morbid risks for affective disorder were found significantly higher (P=.01) in relatives of probands with an early-onset than in probands with late-onset of disease. The segregation analysis showed that the disease is transmitted differently in early- and late-onset groups. In the early-onset group a non-Mendelian major gene with a polygenic component was favored while the data in the late-onset group were compatible with a multifactorial model. This result may have important implications for molecular studies. O56 THE RISK FOR SCHIZOPHRENIA AND BIPOLAR DISORDER IN SIBLINGS TO PROBANDS WITH SCHIZOPHRENIA AND BIPOLAR DISORDER Ösby U, Brandt L, and Terenius L Department of Clinical Neuroscience Karolinska Institutet 171 75 Stockholm, Sweden, Phone: 46 70 772 70 93; Fax: 46 8 27 70 76; E-mail: urban.osby@nvso.sll.se All patients in Sweden with an inpatient diagnosis of schizophrenia or bipolar disorder from 1973 to 1995 were identified from the Swedish patient register. All siblings were identified by the second-generation register and their inpatient diagnoses were determined from the patient register. Standardized incidence ratios (SIR) for full and half siblings were calculated in 5-year age and calendar time classes. There were 13,870 schizophrenia probands with 23,223 full and 8,369 half siblings, and 5,400 bipolar disorder probands with 8,846 full and 2,758 half siblings. In siblings to schizophrenia probands, SIR for schizophrenia was 7.4 for full and 4.4 for half siblings, and 3.6 for full and 2.8 for half siblings for bipolar disorder. In siblings to bipolar probands, SIR for bipolar disorder was 12.8 for full and 8.1 for half siblings, and 4.4 for full and 2.2 for half siblings for schizophrenia. If both parents were affected, the risk increased for full siblings in both schizophrenia and bipolar disorder. One affected parent increased the risk in bipolar disorder only. When the first admission for the proband was before age 25, the risk increased for schizophrenia in full siblings to schizophrenia probands but not for bipolar disorder in full siblings to bipolar probands. O57 A SEARCH FOR SPECIFIC AND COMMON SUSCEPTIBILITY LOCI FOR SCHIZOPHRENIA AND BIPOLAR DISORDER Mérette C, Phaneuf D, Fournier A, Roy MA, Cliche D, Dion C, and Maziade M Centre de recherche Université Laval Robert-Giffard, 2601, de la Canardière Beauport, PQ G1J 2G3 Canada, Phone: 418-663-5741; Fax: 418-663-9540; E-mail: chantal.merette@psa.ulaval.ca Schizophrenia (SZ) and bipolar disorder (BP) are prevalent major psychoses underlain by complex genetic components. To identify the susceptibility loci contributing to these disorders, we have undertaken a two-stage genome wide scan on 480 individuals from 21 multigenerational pedigrees of Eastern Québec. Here we report the second stage based on 220 microsatellite markers. In addition to testing susceptibility loci specific to each disorder, we also tested the hypothesis that some susceptibility loci might be common to both SZ and BP using an affection status that included both disorders. Two-point and multipoint model-based linkage analyses were performed and the resulting mod scores will be reported. In the first stage of the genome scan targetting 13 candidate chromosomes, the strongest linkage signals were detected at D18S1145 (in 18q12; Lod=4.03) for BP, and at D6S334 (net Lod=3.47; theta=0.66) for SZ. The 18q12 result met the Lander & Krugliak (1995) criterion for a genome wide significant linkage and, moreover, provided support for a susceptibility region that may overlap SZ and BP. Three other chromosomal areas (3q, 10p, and 21q) yielded positive linkage signals. Chromosomes 4p, 5q, 6q, 8p, 11q, and 22q showed no evidence of linkage. O58 ASSOCIATION OF CAG REPEAT LOCI ON CHROMOSOME 22 WITH SCHIZOPHRENIA AND BIPOLAR DISORDER Jain S, Saleem QP, Dash D, Gandhi C, Benegal V, Mukherjee O, and Brahmachari SK Department of Psychiatry, Molecular Genetics Laboratory, National Institute of Mental Health and Neuro-Sciences, Hosur Road, Bangalore, Karnataka 560029 India, Centre for Biochemical Technology, Delhi University Campus, Mall Road, Delhi 110007 Chromosome 22 has been implicated in schizophrenia and bipolar disorder in a number of studies. CAG repeat expansion may also be involved in these diseases. To explore the involvement of CAG repeats on Chr.22, we created an integrated map of all CAG repeats >5 on this chromosome together with microsatellite markers associated with these diseases. Of the 52 CAG repeat loci identified, four repeat stretches in regions previously implicated by linkage analyses were chosen for further study. Three of the four repeat containing loci were found in the coding region with the CAG repeats coding for glutamine, and were expressed in the brain. All the loci studied showed varying degrees of polymorphism, and one locus had two alleles of 7 and 8 CAG repeats. The 8 repeat allele was significantly over represented in patient groups when compared to ethnically matched controls, while alleles at the other three loci did not show any difference. The repeat lies within a gene that shows homology to an androgen receptor related apoptosis protein in rat. We also identified other candidate genes in the vicinity of this locus. Our results suggest that the repeats within this gene or other genes in the vicinity of this locus are likely to be implicated in bipolar disorder and schizophrenia. O59 LINKAGE ANALYSIS USING QUANTITATIVE PHENOTYPES IN BIPOLAR DISORDER: A GENOME SCAN OF A SIB-PAIR SAMPLE O'Mahony E, Corvin A, Craddock N, and Gill M Dept of Psychiatry, Trinity Centre for Health Sciences, St James Hospital Dublin 8, Ireland, Phone: 353 1 608 2465; Fax: 353 1 608 3405; E-mail: omahonep@tcd.ie In a previous sibling-pair study of bipolar illness the authors investigated the degree of familial aggregation of a number of demographic and clinical features: age at onset; frequency of manic and depressive episodes; proportion of manic to depressive episodes; dimension scores for mania, depression, psychosis and incongruence of psychotic symptoms with mood. Of these, intra-pair Spearman correlations were most significant for dimension scores for psychosis (r=0.332, P<0.001) and age at onset (r=0.293, P 1 or P 3.0 and three loci with a LOD score>2.0 were observed on 1q31.1, 16p11.1 and at Xq25, a locus already earlier identified in one Finnish extended pedigree. Total of thirteen loci; 1q43, 2pq, 3p12.2, 3q13.31, 3q26.31, 5p12, 7p14, 8p22, 8q24.3, 9p21, 11pq, 14q21, 14pq the two-point LOD score exceeded 1.0. Interestingly, regions of 1q31 (Zmax=2.3; D1S1660), 4q28.3 (Zmax=3.3; D4S1629), 5p13.3 (Zmax=1.6; D5S1470), 12q23.2 (Zmax=3.0 PAH), 16p11.1 (Zmax= 2.9; D16S769) have provided evidence for linkage also in previous studies from other populations. We are currently fine mapping these regions to establish conclusive evidence for their involvements in the genetic background of bipolar disease in Finland. O62 THE WELLCOME TRUST UK-IRISH BIPOLAR SIB-PAIR GENOME SCREEN: SECOND STAGE PROGRESS REPORT: CHROMOSOMES 4, 7 AND X Middle F, Bennett PP, Jones II, Heron JJ, Gill MM, and Craddock NN University of Birmingham, Department of Psychiatry, Queen Elizabeth Psychiatric , Birmingham, 0 B15 2QZ UK Phone: 0121 414 3838; Fax: 0121 414 8025; E-mail: f.a.middle@bham.ac.uk The Wellcome Trust UK-Irish Bipolar Sib-pair Study is a two-stage collaborative genome screen funded by the Wellcome Trust involving the University of Birmingham, UK, and Trinity College, Dublin, Eire. The first stage screening sample included 509 subjects, consisting of 154 narrowly defined affected pairs (DSMIV BPI) and 258 broadly defined affected pairs (DSMIV BPI, BPII, SA BP, BP NOS or MDD(R)). Analysis of genotyping data from ∼ 200 markers (∼ 10 cM spacing) covering the 11 chromosomes under investigation in Birmingham confirmed the presence of 7 chromosomal regions exceeding our second stage inclusion criterion, namely a MLS>0.74 under the narrow diagnostic model. In particular, regions on chromosomes 4 (D4S419-D4S1597; MLS 0.79 at D4S405), 7 (D7S516-D7S515; MLS 1.40 at D7S630), and X (DXS1060-DXS1001; MLS 1.18 at DXS990) have now undergone further detailed study. This has involved both increasing marker density (to ∼ 5 cM) and the addition of a second stage sample set containing 360 further individuals (giving a total of 220 narrowly defined affected pairs and 396 broadly defined affected pairs). An interim analysis, involving all new markers for the first stage sample set as well as a number of markers for the second stage sample set, supports results originally obtained for chromosomes 4 and 7, while those for chromosome X are less consistent. A detailed analysis including all markers and those individuals in the second stage sample set will be presented at the 2001 World Congress. VIII. PHARMACOGENETIcS O63 GENETIC PREDICTORS OF OLANZAPINE RESPONSE Arranz MJ, Staddon S, Mata I, Beperet M, Munro J, Osborne S, and Kerwin RW Clinical Neuropharmacology, Institute of Psychiatry, London, UK SE5 8AF Phone: 44 (0)20 7848 0343; E-mail: m.arranz@iop.kcl.ac.uk In a previous study we showed that clinical response to the potent antipsychotic clozapine could be predicted using a combination of genotypes from neurotransmitterreceptors (Arranz et al., 2000). In this study we try to predict response to the drug olanzapine using a similar strategy. Olanzapine is an atypical antipsychotic which resembles clozapine in its affinity for 5-HT2A, 5-HT2C, 5-HT6, Histamine-1 and Muscarine-1 receptors. However, olanzapine has a relatively higher affinity for D2 and D3 receptors than clozapine and a lower affinity for Histamine-2 receptors. We have investigated known genetic variants in these receptors and their contribution to treatment outcome. Preliminary results in a sample of 70 schizophrenic patients of British and Spanish origin and treated with olanzapine show that a combination of polymorphisms in 5-HT2A, 5-HT2C, 5-HT6, and D3 receptor genes and in the serotonin transporter 5-HTT could result in a level of prediction of 78% (P=ns, sensitivity 75%, specificity=81%). This level of prediction was higher (83%, P= 0.04) on a subset of Spanish patients of Basque origin (Sensitivity=90%, specificity=71%). The validity of these results is being investigated in a larger sample. O64 PHARMACOGENETIC DISSECTION OF CENTRAL AND PERIPHERAL CANDIDATE GENES IN ATYPICAL ANTIPSYCHOTIC-INDUCED WEIGHT-GAIN Vincenzo S Basile,* Mario Masellis, Vincenzo DeLuca, Herbert Y Meltzer, Jeffrey A Lieberman, and James L Kennedy Neurogenetics Section, Clarke Division, Centre for Addiction and Mental Health (CAMH), University of Toronto, 250 College Street, Toronto (ON) M5T 1R8, Canada (vincebasile@ica.net) A drawback to the treatment of schizophrenia with atypical antispsychotics (AAs) is the occurrence of weight gain. Variability exists among individuals regarding this weight gain and genetic predisposition has been suggested. AAs may potentially disrupt both central mechanisms regulating appetite and peripheral mechanisms governing energy expenditure to cause weight gain. Evidence supports a role for the serotonin 2C and histamine H1 receptors in central hypothalamic regulation of food intake and consequently for AA induced weight gain. There is also support for peripheral AA disruption of thermogenesis and metabolic rate via TNFα, β3 and α1adrenergic receptors. We investigated these candidate genes in 77 patients with DSM-IIIR diagnoses of schizophrenia that were prospectively assessed for clozapine-induced weight gain. ANCOVA analyses correcting for covariates were utilized to detect differences among genotypes. Although results were predominantly negative, trends were noted for TNFα (F[2,72]=2.58, P=0.12; means per genotype of 7.4 ± 3.7, 2.3 ± 4.1 and 3.9 ± 4.5) and the α1adrenergic receptor (F[2,57]=1.45, P=0.24; Arg/Arg=3.24 ± 3.1; Arg/Cys =4.89 ± 4.9; Cys/Cys=0.85 ± 3.4). These candidate genes may be involved in clozapine induced weight gain, although replication is necessary. O65 INVESTIGATION OF AN ASSOCIATION BETWEEN A CYP1A2 5′ FLANKING SNP (T-3591G) AND RESPONSE TO CLOZAPINE Aitchison KJ, Zhao JH, Munro J, Collier DA, Makoff AJ, and Kerwin RW Institute of Psychiatry, Section Clinical Neuropharmacology, 1 Windsor Walk, Denmark Hill, London, SE5 8AF UK, Phone: 44 (0)207 848 0034/0793; Fax: 44 (0)207 848 0051/0059; E-mail: k.aitchison@iop.kcl.ac.uk The cytochrome P450 enzyme CYP1A2 is involved in the metabolism of several psychotropic agents, including clozapine (1,2). There is wide interindividual variation in CYP1A2 activity (1), and several polymorphisms in CYP1A2 have been identified, including SNPs in the 5′ flanking region (3). We have determined the frequency of one of these SNPs (T-3591G) by PCR-RFLP analysis (3), in 194 patients treated with clozapine. Prescribing consultants provided information regarding the patients’ response to clozapine. Analysing the genotyping results under a recessive model, Fisher's exact test gave a 1-tailed P value of 0.16; while analysing the results by allele, Fisher's exact test gave a 1-tailed P value of 0.10. The results show a trend towards an excess of the mutant (G-3591) allele in those with a relatively poor response to clozapine. Although this SNP has been shown to be nonfunctional, it is possible that it is in linkage disequilibrium with a functional CYP1A2 polymorphism, and genotyping for this SNP, in addition to other genetic markers, could be useful in predicting response to clozapine. References: 1 Aitchison et al. Drug Metab Drug Interactions 2000;16: 15–38. 2 Aitchison et al. J Psychopharmacol 2000; 14: 353– 359. 3 Aitchison et al. Pharmacogenetics 2000; 10: 695– 704. O66 QUANTITATIVE GENETICS OF MONOAMINE METABOLITES IN PEDIGREED BABOONS, PAPIO HAMADRYAS Rogers J, Comuzzie AG, Martin L, Mann JJ, and Kaplan JR Southwest Reg. Primate Research Center, 7620 N.W. Loop, 410 San Antonio, TX 78245, Phone: 210-258-9532; Fax: 210-670-3344; E-mail: jrogers@darwin.sfbr.org The monoamine neurotransmitters serotonin, dopamine and norepinephrine are related to a number of fundamental neurophysiological processes, as well as to psychiatric diseases such as depression, anxiety disorders, bipolar disorder and risk of suicide. While it is clear that genetic variation among people influences levels of neurotransmitters found in the cerebrospinal fluid, the details of this genetic control are not understood. In an effort to learn more about the genetics of monoamine levels, we measured levels of metabolites for these monoamines (5-HIAA, HVA and MHPG) in 270 pedigreed baboons. All study animals can be linked into a single large pedigree, providing unique opportunities to examine quantitative genetic parameters. All three compounds exhibit significant heritability (5-HIAA h2=0.30, HVA h2=0.50, MHPG h2=0.36). Bivariate genetic correlations calculated using variance components methods reveal that the genetic correlation between MHPG and HVA is rho=0.91, indicating that 83% of the genetic variance is shared between these two traits. In addition, it has long been known that HVA and 5-HIAA are phenotypically correlated in humans. Our results show that in baboons the genetic correlation is 0.50 and environmental correlation 0.71, both statistically significant. This means the common phenotypic correlation of HVA and 5-HIAA is due both to shared genes and shared environmental effects. A genome scan is planned to locate specific loci controlling monoamine levels in the baboons. O67 MICROARRAY STUDIES OF CHANGES IN GENE EXPRESSION IN MOUSE BRAIN INDUCED BY ANTI-MANIC DRUGS Adams LJ and Schofield PR Garvan Institute, 384 Victoria Street Darlinghurst, Sydney, Phone: 61 2 9295 8287; Fax: 61 2 9295 8281; E-mail: l.adams@garvan.org.au Genes found to be regulated by one or more anti-manic drugs are candidates that may have a role in the etiology of bipolar disorder. We are using the mouse as a model to investigate the biology underlying susceptibility to this disorder through the use of microarray studies in which we can monitor changes in gene expression. We have validated treatment doses in mice for both lithium and valproate, and are currently expanding this to include other anti-manic drugs such as carbamazepine and lamotrigine. We have obtained brains from mice treated for seven days with either valproate (400 mg/kg/day, n=10), lithium (340 mg/kg/day) which have high (0.8–1.2 mM; n=10) or medium (0.4–0.7 mM; n=10) serum levels, or saline controls (n=10). Our initial experiments were undertaken using Affymetrix Murine U74A GeneChips, each containing approximately 12,000 genes and ESTs, and mice (n=5) with high lithium serum levels (mean ± SD =0.94 ± 0.03 mM) or saline controls (n=5). Analysis of these GeneChips identified 20 transcripts that are expressed at least two-fold more, and two genes that are expressed at least two-fold less in the treated animals. These represent members of different gene families, including protein kinases, transcription proteins, and integral membrane proteins. O68 IDENTIFICATION OF POTENTIAL GLUCOCORTICOID RESPONSE ELEMENTS IN REGULATORY REGIONS OF CANDIDATE GENES FOR SUSCEPTIBILITY TO BIPOLAR DISORDER Tremblay S, Tremblay M, Harvey M, and Barden N CHUL Research centre, 2705 Blvd. Laurier Sainte-Foy, Qc G1V 4G2 Canada, Phone: 418 654 2152; Fax: 418 654 2753, E-mail: sophie_tremblay@hotmail.com We have identified the chromosome 12q24.11–24.31 region as a site for bipolar disorder susceptibility gene(s). Since stress often precipitates manic or depressive episodes and the hypothalamic-pituitary-adrenal axis has been shown to be functionally disturbed in depression, we have developed a method to identify glucocorticoid sensitive sites in genes. A fusion-protein, GST-DBD-hGRa (glutathione-S-transferase/DNA-binding-domain of the human glucocorticoid receptor a), was produced, coupled to sepharose 4B-glutathione and used to enrich genomic DNA fragments containing GRE sequences. Experimental conditions were developed using the MMTV GRE (5′-GATTACAaacTGTTCT-3′). DBD-hGRa showed high affinity for GRE sequences and competition assays against other hormone response elements (PRE/GRE, ERE, RXR, etc) confirmed the DBD-hGRa/GRE binding specificity. Method validation was performed using human genes known to contain GRE sequence and cloned in BACs. The DBD-hGRa/GRE interaction permitted enrichment of these gene fragments and we are currently using this strategy to identified regulatory GREs in the chromosome 12 linkage region as potential sites for mutations. O69 CHRONIC ANTIDEPRESSANT TREATMENT EFFECTS ON KINASE GENE EXPRESSION PATTERNS Rausch JL, Fei Y, Johnson ME, Jackson B, Ganapathy V, Hobby HM, and Leibach FH Veterans Administration, The Medical College of Georgia, 1515 Pope Ave. Augusts, GA 30912, Phone: 706 721-7793; Fax: 706 721-7796; E-mail: jeffreyr@mail.mcg.edu The serotonin transporter, SERT, is a phosphoprotein whose function is determined by its phosphorylation state via multiple kinase pathways. At least two fundamental phosphorylation mechanisms may regulate SERT activity. Phosphorylation through protein kinases may serve both to regulate sequestration of SERT from the cell membrane, and also down-regulate SERT expression. Ligand occupancy has been recently shown to affect this system, with SSRIs blocking 5-HT's ability to inhibit phosphorylation-mediated sequestration of SERT. Consequently, the kinases may serve to regulate extracellular 5-HT concentrations with SERT upregulation in response to increased 5-HT, and down regulation of SERT in response to SSRIs. If this were true, then we might expect to see differences in protein kinase expression in response to SSRI treatment. To investigate this possibility, we studied 5 groups of rats 5 rats in each group (N=25, males). Rats were assigned randomly to osmotic mini-pump treatment with placebo 3 days, placebo 21 days, fluoxetine 3 days, fluoxetine 21 days, or citalopram 21 days. Total RNA was isolated and labeled as cRNA, and incubated with Affymetrix gene chip and stained with Streptavidin-phycoerythrin conjugate, and read for changes in the kinase expression system as a result of antidepressant treatment. The results indicated that expression of several protein kinases increased with acute and decreased with chronic antidepressant treatment. The results are consistent with homeostasis of SERT function through a decrease in PK manufacture, in response to antidepressant treatment. The results suggest that gene variation in this system may underlie differences in response to antidepressant treatment since kinase down-regulation would counterbalance the SSRI effect, by lessening inhibition of SERT function, in response to treatment. O70 A COMMON P-GLYCOPROTEIN POLYMORPHISM IS ASSOCIATED WITH NORTRIPTYLINE-INDUCED POSTURAL HYPOTENSION IN PATIENTS TREATED FOR MAJOR DEPRESSION Kennedy MA, Roberts RL, Joyce PR, and Mulder RT University of Otago, Christchurch School of Medicine, University of Otago, PO Box 4345, Christchurch, New Zealand Department of Pathology, Christchurch School of Medicine, P.O. Box 4345 Christchurch, SI 8015 New Zealand, Phone: 640-3641222; Fax: 640-3640525; E-mail: martin.kennedy@AEA-chmeds.ac.nz The human multi-drug resistance gene ABCB1 encodes the P-glycoprotein (P-gp) that regulates movement of many substances across the blood-brain barrier. Evidence from a knockout mouse lacking P-gp suggests that the TCA amitriptyline and its metabolites are substrates for P-gp. In these mice penetration of amitriptyline, but not the SSRI fluoxetine, into the brain is enhanced. We reasoned that polymorphisms of P-gp may affect responses of patients to antidepressant drugs. A polymorphism of ABCB1 (3435C+AD4-T) was recently correlated with expression levels and in vivo function of P-gp. We developed a DNA test for this SNP, and genotyped 165 Caucasian patients with major depression enrolled in a randomized antidepressant treatment trial of nortriptyline and fluoxetine. We observed a significant association between nortriptyline-induced postural hypotension (NIPH) and 3435C+AD4-T (chi-square +AD0- 6.75, df +AD0- 2.73, p+AD0-0.034). Of nortriptyline-treated patients, 25+ACU- (4 of 16) who were TT and 7+ACU- (3 of 43) who were heterozygous suffered symptomatic NIPH. None of the 17 patients who were CC and no fluoxetine-treated patients experienced postural hypotension. Our results suggest that presence of one or more T alleles at the 3435C+AD4-T polymorphism of ABCB1 is a risk factor for occurrence of NIPH. O71 EFFECTS OF THE -1438-A/G SEROTONIN 2A RECEPTOR PROMOTOR POLYMORPHISM ON EXPRESSION Parsons MJ, D'Souza U, Makoff A, Arranz MJ, and Kerwin R Institute of Psychiatry De Crespigny Park Denmark Hill, London, United Kingdom SE5 8AF, Phone: 011442087610953; E-mail: spklmjp@iop.kcl.ac.uk The 5-HT2A-receptor (5-HT2A-R) promoter polymorphism -1438-A/G is associated with psychiatric disorders and plays a potential role in clozapine response. The -1438-A/G polymorphism was found to affect the degree of radioligand affinity for the 5-HT2A receptor, suggesting that the polymorphism may have functional consequences on 5-HT2A-R gene expression. Conversely, the two -1438-A/G variants had equal levels of basal expression. In order to clarify whether the polymorphism has functional effects, either at the promoter or enhancer level, we cloned part of the 5-HT2A-R promoter (-1536 to -536) for both -1438-A/G variants into the following vectors: pCAT-basic, negative control; pCAT-enhancer, to test for promoter activity; and p-CAT-promoter, to test for enhancer affects. The pCAT-control vector was used as a positive control. These vectors were transformed into SHSY-5Y cells (neuroblastoma cells) and CAT activity was determined using a CAT ELISA kit. Our preliminary findings suggest that the expression levels were lower for the -1438-G variant within pCAT enhancer. There appears to be no other differences. Though further replication is required, these results suggest that the -1438-G variant decreases basal promoter activity, but may not disrupt an enhancer element. IX. Manifestations of Known Genetic Disorders/Anorexia O72 AN ANALYSIS OF HUNTINGTON'S DISEASE MUTATIONS IN INDIA SUGGESTS PREVALENCE RATES CLOSER TO THE WEST AND MULTIPLE ORIGINS FOR THE DISEASE MUTATION Padiath QS, Roy S, Murgood U, Muthane U, Verma IC, Saxena R, Jain S, Anand A, and Brahmachari SK Centre for Biochemical Technology CBT (CSIR), Mall Rd., Delhi University Campus, Delhi 110 007 NCBS, T