Molecular and genetic analysis of lithium responsive bipolar disorder

Bipolar disorder is a major psychiatric condition that affects up to 1% of the general population and results in episodes of mania and depression. Genetic epidemiologic studies have consistently shown that genetic factors play an important role in the etiology of bipolar disorder, however, the precise mechanisms that increase the susceptibility to this condition are not known. In the past three decades, several studies have been carried out hoping to identify major genes. However, conflicting results between and within studies that do not replicate previous findings have constituted a major problem. It is believed that part of this problem is related to genetic heterogeneity. We have attempted to reduce heterogeneity by selecting patients responsive to longterm lithium treatment. There is compelling evidence that selecting patients according to lithium response may help define a more genetically homogeneous subgroup of bipolar patients. This evidence is based on the fact that lithium is more effective in bipolar patients with classical symptomatology and the absence of comorbidity. Similarly, nonresponders to lithium treatment are different with respect to neuroendocrine responses and family history from responders, who are more likely to have relatives affected with bipolar disorder than lithium nonresponders. Using association and linkage designs, we have studied 31 lithium responsive bipolar families and 138 unrelated lithium responsive bipolar patients and 163 normal controls. We used a candidate gene as well as a whole-genome scan approach. In the genome scan study, significant evidence for linkage was found with a locus on chromosome 15q14, and suggestive linkage with a locus on 7q11. In the candidate gene studies, we found preliminary evidence suggesting that a variant of PLCG1, a gene that codes for phospholipase C gamma 1, is associated with bipolar disorder. Our results provide evidence that these loci may confer susceptibility to lithium responsive bi