Previous results from our genetic analyses using pedigrees from a French Canadian population suggested that the interval delimited by markers on chromosome 12, D12S86 and D12S378, was the most probable genomic region to contain a susceptibility gene for affective disorders. Association studies with microsatellite markers using a case/control sample from the same population (n = 427) revealed significant allelic associations between the bipolar phenotype and marker NBG6. Since this marker is located in intron 9 of the P2RX7 gene, we analyzed the surrounding genomic region for the presence of polymorphisms in regulatory, coding and intron/exon junction sequences. Twenty four (24) SNPs were genotyped in a case/control sample and 12 SNPs in all pedigrees used for linkage analysis. Allelic, genotypic or family-based association studies suggest the presence of two susceptibility loci, the P2RX7 and CaMKK2 genes. The strongest association was observed in bipolar families at the non-synonymous SNP P2RX7-E13A (rs2230912, P-value = 0.000708), which results from an over-transmission of the mutant G-allele to affected offspring. This Gln460Arg polymorphism occurs at an amino acid that is conserved between humans and rodents and is located in the C-terminal domain of the P2X7 receptor, known to be essential for normal P2RX7 function.

We completed a genome-wide scan for susceptibility loci for bipolar affective disorders in families derived from a rather homogeneous population in the Province of Québec. The genetic homogeneity of this population stems from the migration of founding families into this relatively isolated area of Québec in the 1830s. A possible founder effect, combined with a prevalence of very large families, makes this population ideal for linkage studies. Genealogies for probands can be readily constructed from a population database of acts of baptism and marriage from the early 1830s up to the present time (the BALSAC register). We chose probands with a DSM III diagnosis of bipolar affective disorder and who may be grouped within large families having genealogical origins with the founding population of the Saguenay-Lac-St-Jean area. Living members (n approximately 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 multisource information (interview, medical records, family history) and pronounced best-estimate consensus diagnoses on all family members. Linkage, SimAPM, SimIBD, and sib-pair analyses have been performed with 332 microsatellite probes 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 confirmation of presumed linkages found in the region of chromosome 12q23-q24.

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SummaryWe have collected information about 118 children born to mothers who were given lithium treatment during the first trimester of pregnancy. The data show that the risk of teratogenic effects is lower than one might have expected from some of the studies carried out on rats and mice; they do not answer the question of whether or not lithium is teratogenic in man. The data were collected retrospectively and therefore overestimate rather than underestimate the risk of teratogenicity. Introduction It has been known for many years that lithium (lithium salts, lithium ions) added to the medium surrounding eggs of sea urchins, snails, and other lower organisms may interfere with morphogenesis so that monsters are produced (Herbst, 1893;Schou, 1957