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

Abstract VII. Bipolar Disorder Genome‐Scans and Overlap With Schizophrenia O55 DIFFERENT INHERITANCE MODELS BY AGE OF ONSET IN BIPOLAR I DISORDER Grigoroiu‐Serbanescu M 1 , Martinez M 2 , Nöthen MM 3 , Grinberg M 4 , Sima D 4 , and Propping P 5 1 Biometric 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 2 I.N.S.E.R.M., Unité 358, EPI 06, Paris, France 3 Department of Medical Genetics, University of Antwerp, Belgium 4 Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Psychiatric Hospital, Bucharest, Romania 5 Institute 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 <0.001). On the basis of the hypothesis that different aspects of the bipolar phenotype may be primarily influenced by different genes we have sought to apply a quantitative scale to phenotype assignment in our study of familial bipolar illness. We used 398 highly polymorphic microsatellite markers with an average inter‐marker distance of 9.6cM to genotype all individuals and GENEHUNTER 2.0 was used for non‐parametric analysis of the quantitative phenotype data. We identified 8 regions, suggestive of linkage for the ‘age at onset’ phenotype; These were on chromosomes 1q, 2p, 3p, 4q, 7p, 10p, 16p and 20p. With regard to the ‘psychosis dimension’ phenotype, we identified 6 regions suggestive of linkage; on 1p, 2p, 5p, 10p, 13q and 18p. O60 GENOME‐WIDE GENETIC LINKAGE STUDIES IN BIPOLAR DISORDER: A REVIEW Segurado R and Gill M Trinity College, University of Dublin, Department of Genetics, Dublin, IE Dublin, 2 Ireland, Phone: 353 1 608 2444; Fax: 353 1 679 8558; E‐mail: seguradr@tcd.ie Genetic linkage studies are prone to publication bias, as are genome scans which have been published in incomplete form, sometimes before the completion of genotyping and analysis across the entire genome. In order to overview genetic link

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