The aim of the present application is to characterize restriction fragment length polymorphisms (RFLP's) in DNA which are associated with the trait of bipolar affective disorders. The success of such studies is dependent, to a large extent, on the homogeneity of the population from which the probands are drawn and on the size of their family pedigrees. The population found in the Saguenay-lac-St-Jean area is unique in the whole of N.America. The history of the settlement of this area dates from the 1840's and most of the population now living in this region stems form a founding 100-150 families. The genomic constitution of this population is very homogeneous - and essential factor for RFLP linkage studies. The total population, of the order of 225,000, is served by a central psychiatric facility,l'Institut Roland Saucier. Registries of all acts of baptism and marriage for this population exist from the founding families in the early 1800's up to present time. An investigator associated with this project, Dr G Bouchard, has computerized all this information and can readily construct genealogies for all probands. We have chosen 58 probands with a DSM III diagnosis of bipolar affective disorder and who may be grouped within 9 large families having genealogical origins with the founding population of the Saguenay-Lac-St-Jean area. These large families, because of genetic homogeneity and a founder effect, greatly increase the chance and discriminatory factor for finding linkage between genetic markers and bipolar affective disorders. Genetic transmission of bipolar affective disorders is well establish, although the precise mode of transmission remains uncertain. Recent studies have demonstrated genetic linkage between manic depressive illness and a Taql polymorphism at coagulation factor IX locus at Xq27 and also, in a different population, with a PvuII polymorphism at the HRASl locus at 11p15.5. Neither of these linkages could be demonstrated in other populations. We will start by confirming or infirming these linkages in our population. A very close relationship exists between biological mechanisms causing, or at least present, in the depressed state and those responsible for regulation of the brain-pituitary-adrenal axis. We have probes recognizing many of the components implicated in the control of the brain-pituitary-adrenal axis and, if necessary, a search for other RFLP's linked to depression could take good advantage of these. A multi-disciplinary approach to this project is necessary and associated investigators regroup specialists in molecular biology, demographic history, psychiatry and genetics. Collaboration with the Clinical Neurogenetics Branch, NIMH has also been established. Identification of polymorphisms, which could be used as markers for the disease, will also permit prediction concerning familial inheritance of the disease and, ultimately,can aid in the identification of genomic defects present in the disease.
