Genetics of bipolar disorder: a review

Abstract

The present review provides a brief overview of both genetic epidemiological and molecular genetic studies of bipolar disorder. Twin studies have consistently shown an increased risk of bipolar disorder in monozygotic (identical) co-twins as compared to dizygotic (fraternal) co-twins of a proband with bipolar-I disorder, which indicates that a substantial proportion of the variance in the aetiology of bipolar disorder is likely to be attributable to genetic factors. The involvement of genetic factors in the development of bipolar disorder is also supported by the results of two adoption studies. According to family studies that included direct interviews of relatives as well as of a control group the risk ratio for bipolar disorder among relatives of bipolar patients has been estimated at around ten. However, family studies have revealed that the relatives of bipolar probands are not only at an increased risk for bipolar disorder, but also for unipolar depression. Regarding the morbidity risk for offspring of parents suffering from bipolar disorder, a meta-analysis revealed a 2.5-fold increased risk of developing any psychiatric disorder in children of bipolars as compared to those of non-psychiatric controls. Given the well-established familial aggregation of bipolar-I disorder as well as evidence that a substantial proportion of the variance in the aetiology of bipolar disorder is likely to be attributable to genetic factors, a series of linkage and association studies have attempted to identify the genes involved in the susceptibility to bipolar disorder. The findings of linkage studies are not consistent with the existence of a gene of major effect for the vulnerability for bipolar disorder, but several chromosomal regions have repeatedly been shown to be implicated. Two meta-analyses found evidence for susceptibility genes on chromosomes 8p22,9p22-21,10q21-22,13q32-34,14q24-32 and 22q11-22, as well as on regions on chromosome 18. Other regions of interest, identified by recent linkage studies are 6q16-22 and 12q23-24. Regarding candidate genes, for each of them there were usually some positive studies and generally an even greater number of negative replications. Meta-analyses of studies on these polymorphisms have provided some support for the implication of MAOA, COMT and 5HTT metabolism, all with modest effect sizes though. However, the strongest evidence currently supports the DAOA/G30 and the BDNF genes. The conflicting results obtained in psychiatry genetic research in the last decades are likely to be at least in part attributable to the heterogeneity of bipolar disorder. Therefore, the need to look for specific clinical indicators of bipolar disorder that could be used to identify more homogeneous subtypes of the disorder has frequently been highlighted. Recent studies that focused on early onset bipolar disorder or stratified the sample according to the age of onset have provided some interesting results. It is of interest that some of the regions identified in linkage studies of bipolar disorder overlap with regions implicated in schizophrenia and variations at the DAOA/G30 and the BDNF genes could predispose to both schizophrenia and bipolar disorder. The overlap in the biological basis between the two disorders could have implications for the classification of these major psychiatric disorders, which have been classified as distinct entities over the last 100 years.