Genetic projects Genetic research on mood disorders can be expected to make substantial contributions to our understanding of treatment mechanisms and, ultimately, to lead to more effective treatment options and disease management. Although there is substantial evidence that bipolar disorder has a genetic etiology, the mode of inheritance is unknown. Most researchers agree that bipolar disorder is a heterogeneous condition with distinct genetic mechanisms. As a result, molecular genetic approaches have not yet been successful. The first step towards identifying genes is developing a clear definition of the phenotype “bipolar disorder.” Definitions temporarily change and the extent of the phenotype spectrum in bipolar disorder is uncertain. Therefore, it may be advantageous to use other, intermediate phenotypes in genetic studies. The IGSLI developed the concept of homogenizing the sample of bipolar patients by limiting the sample to the phenotype of excellent lithium response. The response to lithium can be regarded as a factor independent of the underlying illness, and can be used for characterizing an illness subtype. In 1992, IGSLI started collecting blood samples from bipolar patients in the Canadian and European centres who had shown an excellent response to long-term lithium treatment. Extensive analysis revealed a positive association with the gene for phospholipase C gamma l (Turecki et al. 1998). Researchers also tested additional candidate genes for enzymes and receptors considered relevant to the etiology of bipolar disorder, but the findings were negative (Turecki et al. 1999, Alda et al. 2000, Duffy et al. 2000). Projects on the genetics of suicidal behaviour Only a subset of patients with affective disorder exhibit suicidal behaviour, another part does not. In addition suicidal behaviour seems to cluster in certain families, while other families are completely free of this trait. There is solid evidence suggesting that the predisposition to suicidal behaviour is, at least in part, modulated by genes. The genetic effect seems to be conditional on, but independent of, the familial loading of psychiatric morbidity, including affective disorders. IGSLI is currently investigating a sample of families ascertained through bipolar probands. These patients are classified according to positive or negative history of suicidal behaviour. Preliminary results from a smaller sample suggest that bipolar disorder and suicidal behaviour might arise from two correlated, but different genetic liability distributions. Future directions in genetic research Until now, there has been a lack of concrete data on the genetics of affective disorders, although a large number of studies from various research groups have contributed substantially to our understanding of the field. Further research may lead to more definitive results, provided that currently available methods are used in a complementary way and large samples of probands are accumulated, preferably by co-operation between research groups. More efforts need to be made to improve the definitions of phenotype and linkage, and association samples must be followed carefully to improve and update clinical information. IGSLI strives to be at the forefront of developments in genetic research. top >>