The current status and prospects for genetic studies of bipolar disorder

Family, twin, and adoption studies provide strong evidence for a genetic etiology in bipolar disorder (BPD). Early studies seeking to locate genes reported statistical evidence for linkage of BPD to DNA markers at several chromosomal sites. The earliest of these have not proven robust while several more powerful genome scans have had largely negative findings. Recurring, suggestively positive linkage findings on chromosomes 4p, 12q, 18p, 18q, and 21q have emerged as attractive candidate regions for further study. However, it is clear now that single gene forms of BPD, if they exist, must be uncommon. Clinical strategies for increasing the power of linkage and association studies include: (1) ascertaining very large family samples and (2) dividing the phenotypes and families into genetically meaningful subgroups to decrease heterogeneity. The Human Genome Project will soon provide the chromosomal location and DNA sequences for all genes. In doing so, it will make the identification of candidate genes for bipolar disorder a routine step in our studies. We summarize here the results of the current studies at Johns Hopkins to resolve the genetic causes of BPD related to the locus on 18q21-22. We have found that preferential transmission of paternal alleles to BPII offspring is the critical observation behind our linkage findings in this chromosomal region. Similar delineation of the individual and familial subtypes of BPD at the other candidate regions could lead to progress in isolation of the genes involved and to pathogenetic studies of the disease.