Genetics of bipolar disorder: successful start to a long journey

doi:10.1016/j.tig.2008.12.002

Trends in Genetics

Volume 25, Issue 2, February 2009, Pages 99-105

https://doi.org/10.1016/j.tig.2008.12.002 Get rights and content

Family and twin studies attest to the importance of genetic factors influencing susceptibility to bipolar disorder and to its genetic and phenotypic complexity. Although linkage and candidate gene association studies have repeatedly implicated some chromosome regions and certain genes, they have not produced the level of unambiguous support required to confirm the involvement of any specific gene or sequence variant in the pathogenesis of bipolar disorder. However, strong associations have recently been reported in meta-analyses of genome-wide association studies and the systematic study of structural variation is ongoing. These findings indicate that the study of large, phenotypically well-characterized samples will make an important contribution to delineating the etiology and pathogenesis of bipolar disorder and thereby pave the way for major improvements in clinical management.

Section snippets

Bipolar disorder: phenotypic and genotypic complexity

Bipolar disorder (BD; manic depressive illness) refers to an episodic, recurrent pathological disturbance in mood (affect), ranging from extreme elation (mania) to severe depression and is usually accompanied by disturbances in thinking and behavior; psychotic features (delusions and hallucinations) often occur [1]. The definition of BD phenotype is based solely on clinical features because, as yet, validating diagnostic tests do not exist. Current diagnostic practice distinguishes two major

Classical genetic epidemiology

Family, twin and adoption studies conducted during the past 30–40 years have provided an impressive and consistent body of evidence supporting the existence of genes determining predisposition to bipolar disorder. The studies also show a gradation of risk of mood disorder as the genetic relatedness to a proband diminishes [2]. There are methodological impediments to precise quantification, but the approximate lifetime risks of narrowly defined bipolar disorder in relatives of a bipolar proband

Linkage findings in bipolar disorder

Many systematic genome screens have been conducted in samples ranging from large, densely affected pedigrees in genetic isolates to large numbers of affected sib pairs. As with linkage studies in most common familial disorders (both psychiatric and non-psychiatric), the pattern of findings is consistent with there being no gene of major effect to explain most cases of bipolar disorder.

In the recent combined collaborative analysis of 11 bipolar linkage scans, two regions showed genome wide

Candidate gene association studies

Most of the earlier association studies of bipolar disorder used modestly sized samples (at most, a few hundred individuals) and tested polymorphisms within functional candidate genes. Given that choice of candidates inevitably depends upon the prevailing hypotheses about disease pathophysiology, most of these studies focused on neuro-transmitter systems influenced by medications employed in the management of the disorder, namely, the dopamine, serotonin and noradrenaline systems (for a review,

GWAS – the end of the beginning?

Recent advances in high-throughput genotyping permit genome-wide association studies (GWAS), in which hundreds of thousands of DNA polymorphisms spread across the genome can be rapidly assayed in a large set of individuals for a realistic cost [44]. A suitably large number of common genetic polymorphisms can now be examined to provide a high level of association information across the whole genome 44, 45. This means that, in principle, a GWAS provides unbiased information about potential

Revisiting the bipolar phenotype

Although modern genetic tools are used in an attempt to understand the basis of psychiatric diseases, they are being applied using phenotype definitions that are rooted in the diagnostic concepts from the late 19^th century. The phenotype definitions are descriptive and were developed on the basis of having acceptable reliability rather than on the expectation that they will prove to be biologically valid entities. Although the definitions in current use define highly heritable clinical

Finding genes with small effect sizes – what is the point?

Consistent with findings in non-psychiatric disorders, the estimated effect sizes of polymorphisms implicated to date in bipolar disorder are small (odds ratios of ∼1.4 at ANK3 and ∼1.2 at CACNA1C). It is important to recognize that GWAS is a screening procedure to identify the location of pathogenically relevant variation. Follow up and detailed characterization of an association signal might result in identification of stronger signals. Nonetheless, when considered singly, polymorphisms with

The potential role of structural variation in bipolar disease

It has long been known that chromosomal abnormalities increase the risk of major psychiatric illness and there have been case and family reports of chromosome abnormalities in association with bipolar spectrum illness [55], including the velo-cardiofacial syndrome (VCFS) deletion on chromosome 22q11 [56] and the Prader-Willi syndrome maternal uniparental disomy on chromosome 15q11-q13 [57]. It has recently been recognized that structural genomic variants of small or modest size (100–500 000

Concluding remarks

Like other psychiatric illnesses, bipolar disorder is characterized by both phenotypic and genetic complexity. There are good grounds to believe that psychiatry, for the first time in its history, is moving towards developing an understanding of the biological underpinnings of the disorders that devastate the lives of patients.

Although approaches such as GWAS have a great deal to offer in this endeavour, it is but one (albeit currently one of the most important) component of the genetic

Acknowledgements

We are grateful to many members of the WTCCC and STEP–BD consortia for helpful discussions and would particularly like to thank Mark McCarthy for discussions about the differing uses of susceptibility alleles. We are indebted to all those who have participated in, and helped with, genetic studies of bipolar disorder.

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