Strategies to identify genes for complex disorders: a focus on bipolar disorder and chromosome 16p.

Bipolar disorder, also termed manic-depression, is a genetically based neuropsychiatric disorder with heritability estimates of 80%. Over 25 genome-wide linkage studies have been completed for bipolar disorder and results are not all randomly distributed but appear to converge on several chromosomal regions. Recently, several genome-wide association studies have been reported using thousands of cases and controls and meta-analyses of combined studies have implicated at least two common alleles predisposing to illness. Taken together, genome-wide linkage and genome-wide association results indicate that both rare and common variants likely underlie the genetic architecture of bipolar disorder. Larger genome-wide association studies using tens of thousands of cases and controls will be required to map additional common loci that presumably have smaller effect sizes. Although genome-wide sequencing using thousands of cases and controls (at least 2000 cases and 2000 controls) will likely be needed to map the full range of rare variants predisposing to bipolar disorder, it is not currently technically or financially feasible for most groups using 'third generation' technology. Advances in sequencing and annotation methods are anticipated, however, and 'fourth generation' methods should make large-scale high throughput sequencing feasible for most investigators. In the meantime, however, high throughput sequencing can be used to scan tens-to-hundreds of genes mapping under linkage peaks or around association signals. We review the linkage evidence implicating the chromosome 16p region in bipolar disorder. Although linkage regions are by nature relatively large (approximately 10-20 Mb) for complex disorders it is currently possible to sequence all coding and proximal regulatory regions. Systematic re-sequencing under linkage peaks could be a valuable strategy for mapping some rare variants underlying bipolar disorder. Advantages of this approach, compared to large case-control sequencing samples, include smaller sample sizes, enrichment of certain alleles in the study group, and the ability to check for co-segregation.