Genetic factors in the etiology of bipolar disorder

Twin and adoption studies have clearly established the heritability of bipolar disorder, estimated to be between 60% and 80%, with evidence of concordance between monozygotic twins ranging between 45% and 75%. Based on this imperfect concordance rate, it is clear that gene x environment interactions play a key role in the risk and onset of bipolar disorder. Following years of efforts toward discerning the etiology of bipolar disorder, recent large genome-wide association studies (GWAS) have made significant progress in identification of susceptibility genes. These studies show that bipolar disorder is a complex polygenic disorder caused by the combination of multiple common variants, individually of small effect, that account for approximately 30% of the heritability seen in bipolar disorder. Like in schizophrenia and many other complex disorders, these bipolar disorder susceptibility alleles may be disease-associated in only a subgroup of individuals; different individuals may harbor different mutations, either in the same gene or in different genes that act on similar biological pathways. The additive effect of these mutations, when combined with particular environmental factors, leads to a specific clinical manifestation. In addition, the latest advances in molecular genetic studies have also validated earlier epidemiological studies showing that bipolar disorder segregates among families with other psychiatric disorders, particularly depression and schizophrenia, and that it is influenced by some of the same underlying genetic factors. In this chapter, we describe the latest advances in the efforts to identify susceptibility genes for bipolar disorder, focusing on genome-wide studies.