Review of bipolar molecular linkage and association studies.

This paper reviews the history of molecular genetic linkage and linkage disequilibrium (LD) or association studies of bipolar disorder (BPD). The topic is introduced with a brief discussion of various genetic concepts, including linkage and linkage disequilibrium. It is emphasized that criteria for declaring linkage must include independent confirmation by multiple groups of investigators. Given that the inherited susceptibility for BPD is most likely explained by multiple genes of small effect, simulations indicate that universal confirmation of valid linkages cannot be expected due to sampling variation and genetic heterogeneity. With this background, several valid linkages of BPD to genomic regions are reviewed, including some which may be shared with schizophrenia. These results suggest that nosology must be changed to reflect the genetic origins of the multiple disorders which are collectively described by the term, BPD. The history of BPD LD studies is reviewed, using monoamine oxidase as as an example. Some suggestions of improving these BPD LD are offered.