wider phenotype (NIMH Center for Genetic Studies; http://zork.wustl.edu/nimh). Risch and Merikangas54

have estimated that for a genetic risk ratio of λ=1.5, approximately 500 sib pairs will be necessary to have adequate power of mapping a disease gene in an outbred population such as that of the United States, Cell Cycle inhibitor although they acknowledge that in a more homogeneous population the number of Inhibitors,research,lifescience,medical sib pairs needed may be less. The difficulty of obtaining such samples may be the most, important limiting factor in confirming linkage analysis of BP, as evidenced by recent efforts to develop multicenter collaborations for pedigree collections for both SC55 and BP.12 Nevertheless, there have been a number of linkages reported to BP spectrum diseases, as described in the next section. Linkage studies Pedigree-based linkage analyses have been quite successful in identifying the genes for hundreds of simple Mendelian diseases (like Huntington’s disease), Inhibitors,research,lifescience,medical and for a few complex diseases (like early-onset Alzheimer’s and early-onset breast Inhibitors,research,lifescience,medical cancer). Although a few groups have focused on a small number of large, extended pedigrees,27,56 due to

the difficulty of obtaining large multiplex families, genome-wide scans using dense maps of polymorphic markers in small pedigrees have become the

standard strategy for finding bipolar genes through linkage.57 To circumvent, problems Inhibitors,research,lifescience,medical inherent, in complex diseases, nonparametric methods have recently been utilized, where mode of inheritance, allele frequency, or penetrance parameters (currently unknown for bipolar disorder) are not needed to assess linkage between phenotype and genotype. In what may be a preview of things to come, investigators from several countries recently pooled their genotypic information from 11 different genome-wide linkage scans, (with a total sample of 5179 individuals from 1067 families), Inhibitors,research,lifescience,medical and found successful, genome-wide significant evidence of linkage to chromosomes 6q and 8q. Table 1 summarizes key findings from a number of linkage analyses performed over the last 20 years, indicating the chromosomal regions, phenotypes focused on, and the LOD scores for each region. Farnesyltransferase As we increase our sample sizes (mainly through collaborative efforts from multiple sites), improve the phenotypic definition of bipolar disorder (possibly through endophenotype discoveries) and discover improved meta-analysis tools, it is hoped that linkage analyses will assist, the field in better understanding where the most critical loci for bipolar disorder (predisposition genes of moderate effect) arc located in the human genome.