Genetics Behind Mood Disorders - Candidate Gene Studies of Bipolar and Major Depressive Disorders

Mood disorders are complex psychiatric disorders that are the leading cause of disability to work in Finland. They include major depressive disorder (MDD) and bipolar disorder (BD). Both are highly heritable, i.e. the variance between individuals is, in MDD partly and in BD mostly, explained by genetic factors. Their specific genetic background, however, remains widely unknown. Previous linkage and association studies have revealed some potential candidate genes and genomic areas that seem to predispose to mood disorders, at least in some populations and subsamples. Recent genome wide association (GWA) studies have revealed some novel susceptibility genes and risk variants as the field has moved into the era of genome-wide genotyping of huge samples sizes from collaborative studies. The risk variants revealed with this approach, however, cover only a small fraction of the total heritability of these diseases. Thus, it is still highly relevant to study samples from more genetically and environmentally homogenous populations, since the amount of risk variants that are enriched in isolated populations is smaller than in more confounded populations. Detailed characterization of the phenotype has also become an important factor in psychiatric genetics, since the psychiatric disease phenotypes themselves are so broad and heterogeneous. The principal goal of this work was to survey functionally relevant candidate genes for mood disorders and risk variants revealed from the first GWA studies in a Finnish bipolar family sample and in clinical cohorts for mood disorders collected from the metropolitan area of Finland. The bipolar family sample comprises 723 individuals (227 affected for BD) collected utilizing nation-wide registers to identify all individuals born between 1940 and 1969 and hospitalized for bipolar disorder type I (BDI) between 1969 and 1991. Part of this sample has been characterized in more detail enabling the search for genetic susceptibility genes for potential endophenotypes of mood disorders. The clinical cohort sample is comprised of 272 MDD and 178 BD patients, who were characterized for clinical comorbidities and followed for long term clinical outcome. In the bipolar family sample, the highly studied variant val66met of BDNF was found to be associated with BD with the allelic replication observed in previous association studies. SLC6A4 allelic variants also showed some association with BD among males, whilst variants of P2RX7 associated with both BD and neuropsychiatric test results used to assess executive function. The most statistically significant result demonstrated the association of variants of the DAOA gene and the general intellectual function of visuospatial ability. The clinical cohort sample revealed statistically significant association of two functional variants from P2RX7 gene with familial form of mood disorder, and both variants affected also the clinical outcome of the patients by lengthening the time of illness. Our effort to replicate the results from the first GWA studies in the bipolar family sample revealed five genomic areas that associated with mood disorder also in Finland. Most of these variants also associated with some potential mood-disorder endophenotype, such as neurocognitive trait or seasonality in fluctuation of sleep, social activity, or mood. In conclusion, the use of detailed characterized samples may provide an advantage to the genetic studies, since it increases the possibility of finding the susceptibility genes behind more homogenous phenotypes. This work has also revealed some potential endophenotypes, or trait features, that might convey the effect of the susceptibility genes to the end diagnosis of mood disorder.