Genome-wide search for linkage of bipolar affective disorders in a very large pedigree derived from a homogeneous population in Quebec points to a locus of major effect on chromosome 12q23-q24

We completed a genome-wide scan for susceptibility loci for bipolar affecti ve disorders in families derived from a rather homogeneous population in th e Province of Quebec. The genetic homogeneity of this population stems from the migration of founding families into this relatively isolated area of Q uebec in the 1830s. A possible founder effect, combined with a prevalence o f very large families, makes this population ideal for linkage studies. Gen ealogies for probands can be readily constructed from a population database of acts of baptism and marriage from the early 1830s up to the present tim e (the BALSAC register). We chose probands with a DSM III diagnosis of bipo lar affective disorder and who may be grouped within large families having genealogical origins with the founding population of the Saguenay-Lac-St-Je an area. Living members (n -120) of a very large pedigree were interviewed using the Structured Clinical Interview for DSM III (SCID I), SCID II, and with a family history questionnaire. A diagnostic panel evaluated multisour ce information (interview, medical records, family history) and pronounced best-estimate consensus diagnoses on all family members. Linkage, SimAPM, S imIBD, and sib-pair analyses have been performed with 332 microsatellite pr obes covering the entire genome at an average spacing of 11 cM, GENEHUNTER and haplotype analyses were performed on regions of interest. Analysis of a second large pedigree in the same regions of interest permitted confirmati on of presumed linkages found in the region of chromosome 12q23-q24. (C) 19 99 Wiley-Liss, Inc.