Abstracts S96 229. ASSOCIATION BETWEEN ALLELIC VARIATION the U.K. blood transfusion service. Genotyping was done IN THE SEROTONIN TRANSPORTER GENE AND PER- on an ABI 373 DNA sequencer using the ABI GENESCAN VASIVE DEVELOPMENTAL DISORDER. 1Zwaigenbaum and GENOTYPER software. Patient and control data were L, 2Mejia J, 1Szatmari P, 2Palmour R, 3Jones MB, 2Paliouras analysed by CLUMP vs 1.1 and 2 × 2 contingency tables G, 1Bryson SE, 1Bartolucci G, 1Mahoney W.. 1Centre for were analysed by Pearson chi square test. Studies of Children at Risk, Department of Psychiatry, Alleles containing 3 and 4 repeats were most fre- McMaster University, Hamilton, Ontario; 2Department of quent, making up 35% and 62% of the sample respect- Human Genetics and Psychiatry, McGill University, Mon- ively. No significant differences were observed in allele treal, Quebec; 3Department of Behavioural Science, Penn frequency between patients and controls, p=0.188. When State, Hershey, Pennsylvania. the alleles were grouped into high and low expression, Serotonin has long been suggested to play a role in again no significant differences were observed, ␹2=1.81, the pathophysiology of autism/pervasive developmental p=0.25. Male and female data were also analysed separ- disorder (PDD). Cook and colleagues (1997) first reported ately (male, n=108; female, n=46), with no significant dif- an preliminary evidence of linkage and association ferences. between autism and the serotonin transporter (5HTT) gene (short variant of the second intron of the promoter region). Subsequent efforts have failed to replicate this finding, 1 Sabol et al. (1998): Hum Genet 103: 273–279 although one group has found preferential transmission of 2 Williams et al. (1998): Am J Med Genet (Neuropsychiatric Genet) the opposite (long) variant in a PDD sample (Klauck et al., 81: 453 1997). The purpose of this study is to further assess 5HTT 3 Norton et al. (1998): Am J Med Genet (Neuropsychiatric Genet) as a candidate gene in trios consisting of probands with 81: 529 PDD and both parents. We have collected DNA samples from 116 families for TDT analysis. Probands were diag- nosed with PDD by consensus best estimate. Preliminary analysis considreted on 76 families shows a non-signifi- 231. EXCESS OF LONG MONOAMINE OXIDASE A cant trend towards preferential transmission of the long GENE PROMOTER ALLELES IN FEMALE PATIENTS variant of the 5HTT promoter to PDD probands (TDT chi- = = = WITH PANIC DISORDER: FUNCTIONAL CHARAC- squared 2.13, d.f. 1, p 0.14). We will complete the TERIZATION AND REPLICATION. Deckert J, Catalano M, analysis on the entire sample, and assess for genetic het- Syagailo YV, Bosi M, Okladnova O, DiBella D, No¯then erogeneity on the basis on gender, I.Q., and PDD subtype MM, Maffei P, Franke P, Fritze J, Maier W, Propping P, (autism vs. non-autism). Beckmann H, Bellodi L and Lesch KP.. Departments of Psychiatry, Universities of Wu¨ rzburg and Bonn, Institute Cook EH Jr, Courchesne R, Lord C et al. (1997). Evidence of linkage between the serotonin transporter and autistic disorder. Molecular of Human Genetics Bonn, Germany and IRCCS H San Raf- Psychiatry, 2, p247–250. faele Milan, Italy. Klauk SM, Poustka F, Benner A et al. (1997). Serotonin transporter Increased frequency of the longer of several monoam- gene variants associated with autism? Human Molecular Genetics, ine oxidase A gene promoter alleles has been observed 6, p2233–8. among female patients in a German sample (Am J Med Genet 81/6, 514, 1998). To probe the relevance of this observation we performed a functional characterization of the different promoter alleles and complemented the orig- 3. Monomine Oxidase inal finding by a replication study in an independent Ital- ian sample. Panic disorder was diagnosed according to DSMIII-R 230. NO EVIDENCE FOR ASSOCIATION BETWEEN using as interviews SADS-LA, CIDI and DIS-R (total n=209, 80 German and 129 Italian). Controls were of the SCHIZOPHRENIA AND MAO-A PROMOTER POLYMOR- = PHISM. Norton N,. Bray NJ, Williams NM, Cardno AC, same ethnic background (total n 190, 80 German and 110 Murphy KC, Jones LA, Sanders RD, McCarthy G, McGuffin Italian). Genotyping was performed as previously P, and Owen MJ.. Department of Psychological Medicine, described. In addition, functional characterization of the University of Wales College of Medicine, Heath Park, Car- different promoter alleles (3, 3a, 4 and 5 repeats) was per- diff, CF4 4XN. formed in SH-SY5Y cells by means of a luciferase assay. Monoamine Oxidase, (MAO-A), is a mitochondrial As in the German sample higher frequency of the longer enzyme which preferentially oxidizes serotonin and nore- alleles (3a, 4 and 5) and of genotypes containing only piniphrine. The gene encoding MAO-A maps to longer alleles was observed among females in the Italian = = Xp11.23–11.4. sample (p 0.01 and p 0.05 respectively). Combining the Sabol et al, 19981, reported a VNTR polymorphism two female subsamples increased significance to p=0.001 within the promoter of MAO-A, whereby alleles with 3.5 for the allele distribution and p=0.01 for the genotype dis- and 4 repeat elements produced a significantly higher tribution. Functional characterization demonstrated transcription rate than alleles containing 3 and 5 repeat approximately 50% higher activity of the longer alleles in elements as determined by gene fusion and transfection comparison with the short allele. experiments. MAO-A inhibitors are an effective treatment for Following the highest lod score of 1.6 in the region patients with panic disorder, in particular females. This Xp11 from our schizophrenia affected sib pair genome clinical observation is consistent with our finding that scan2,3, we tested for allelic association of the MAO-A homozygosity for monoamine oxidase A gene promoter VNTR polymorphism and schizophrenia. 154 caucasian, alleles with high expression of monoamine oxidase A may DMS-IV schizophrenia patients from the U.K. were age constitute a vulnerability factor in the pathogenesis of and sex matched with 154 control subjects collected from panic disorder. Abstracts S97 232. GENOTYPE OF THE MAO A PROMOTER-ASSO- with 4 copies of the allele, (Fisher’s PSLD-test; p = 0.026, CIATED VNTR AND CELLULAR MAO A ACTIVITY IN p = 0.018, p = 0.010, respectively). HUMAN MALE SKIN FIBROBLASTS. Denney RM, Koch The present results suggest that the structure of the HG and Craig IW.. MAOA promoter might be one factor underlying the SGDP Research Centre, Institute of Psychiatry, De expression of certain personality characteristics in Cauca- Crespigny Park, Denmark Hill, London, UK and Depart- sian males, possibly by influencing transcription of the ment of HBC and G, University of Texas Medical Branch, MAOA gene, and thereby the amount of active enzyme Galveston, TX. AVNTR located 1.2 kb upstream from molecules. MAO A exon 1 (uVNTR) is reportedly associated with panic disorder and compulsive eating disorder in females, and antisocial behavior in male alcoholics. Two labora- 234. ASSOCIATION ANALYSIS BETWEEN A FUNC- tories have shown that the three repeat allele at this locus TIONAL VNTR POLYMORPHISM IN THE PROMOTER confers lower promoter activity than the four repeat allele REGION OF MONOAMINE OXIDASE-A GENE AND when tested by transient expression in cultured cell lines. MOOD DISORDERS. Ishida S1, Kunugi H1, Kato T2, Tats- We report that uVNTR genotype has a quantitatively simi- umi M3, Sakai T3, Hattori M1, Hirose T1, Nanko S1. lar effect on cellular MAO A activity in cultured human 1Department of Psychiatry, Teikyo University School of skin fibroblasts. MAO A specific activity was significantly Medicine, Tokyo, Japan 2Department of Neuropsychiatry, lower in cultures with three repeats than that in cultures Faculty of Medicine, University of Tokyo, Tokyo, Japan with four (1.6 ± 1.1 and 13 ± 12 nmol/hr/mg, respectively; 3Department of Psychiatry, Showa University School of P = 0.032). Immunofluorescence microscopy and flow Medicine, Tokyo, Japan. cytometry showed that MAO A expression was confined Sabol and colleagues (Hum Genet 103: 273–9, 1998) to a cell sub population varying in size from 0.5–85% of identified a common polymorphism of a variable number cells in different cultures. This variability was not associa- tandem repeat (VNTR) in the promoter region of the ted with genotype, and generated additional variation in monoami oxidase-A (MAOA) gene, which was shown to activity within genotypes and overlap between genotypes. be associated with MAOA transcriptional activity. We Mean specific activity in MAO A+ cells (whole culture examined whether this functional polymorphism is asso- specific activity divided by the proportion of immunopos- ciated with the risk of developing mood disorders in a itive cells) again was lower for cells with three repeats Japanese sample of 161 patients with bipolar disorder, 98 than for cells with four (7.2 ± 3.1 and 23.9 ± with unipolar depression, and 258 controls. For the par- 9.5 nmol/hr/mg protein, respectively; P = 0.0013), with ticipation in the study, written informed consent was much less variation within and no overlap in activity obtained from each subject. We found a novel allele which between genotypes. Finding low fibroblast MAO A was not described by Sabol et al (1998), although its fre- activity in cells with three repeats is consistent with tran- quency was rare. Excluding this allele from the analyses, sient expression data, and suggests that uVNTR genotype there was no significant genotypic or allelic association, may be a major source of individual differences in sero- suggesting that the functional VNTR polymorphism in the tonin and norepinephrine oxidizing capacity. MAOA gene is unlikely to play a major role in the patho- genesis of bipolar disorder or unipolar depression in the Japanese sample. In addition, we found no significant 233. MAOA PROMOTER GENOTYPE IS RELATED TO association between the polymorphism and a history of PERSONALITY TRAITS.