Elsevier

The Lancet

Volume 381, Issue 9878, 11–17 May 2013, Pages 1654-1662
The Lancet

Series
Genetics of bipolar disorder

https://doi.org/10.1016/S0140-6736(13)60855-7Get rights and content

Summary

Studies of families and twins show the importance of genetic factors affecting susceptibility to bipolar disorder and suggest substantial genetic and phenotypic complexity. Robust and replicable genome-wide significant associations have recently been reported in genome-wide association studies at several common polymorphisms, including variants within the genes CACNA1C, ODZ4, and NCAN. Strong evidence exists for a polygenic contribution to risk (ie, many risk alleles of small effect). A notable finding is the overlap of susceptibility between bipolar disorder and schizophrenia for several individual risk alleles and for the polygenic risk. By contrast, genomic structural variation seems to play a smaller part in bipolar disorder than it does in schizophrenia. Together, these genetic findings suggest directions for future studies to delineate the aetiology and pathogenesis of bipolar disorder, indicate the need to re-evaluate our diagnostic classifications, and might eventually pave the way for major improvements in clinical management.

Section snippets

Bipolar disorder genetics: orientation

Bipolar disorder (also known as manic-depressive illness) is an episodic recurrent pathological mood disturbance that ranges from extreme elation or mania to severe depression, and is usually accompanied by disturbances in thinking and behaviour, and often by psychotic features (delusions and hallucinations; see other articles in this Series). Diagnostic tests do not yet exist and the bipolar disorder phenotype is defined solely according to clinical features. Several clinical subtypes are

Classical genetic epidemiology

Inherited factors are known to be important in bipolar disorder. In patients with established disease, a family history of mood or psychotic illness is common. Furthermore, a family history of bipolar disorder is an important clinical predictor of a likely bipolar course in a patient who presents with one or more episodes of depression even before their first personal episode of mood elevation. Consistent with these clinical observations, classical genetic epidemiological research with family,

Molecular genetic studies

The revolution in molecular biology has provided medicine with powerful methods to identify genetic variation that affects risk of illness.16, 17 The approaches used at any point have depended hugely on the available technologies, the resolution and cost profiles of which have improved dramatically in the past 25 years. Every research approach has its own strengths and limitations and is most suitable for the study of a particular part of the range of genetic variation. Initial research focused

Phenotypic issues

A major weakness of present research is that the clinical phenotype definitions remain rooted in diagnostic concepts from the late 19th century.61, 62 The definitions in use define highly heritable clinical entities, as measured in the family and twin studies discussed earlier, which allows the application of genetic methods. However, we can expect substantial overlaps of genetic susceptibility across, and substantial heterogeneity within, diagnostic categories. Many clinical phenotype

Clinical risk prediction?

No finding yet warrants clinical genetic testing for bipolar disorder but some results might do so in the near future. As an example, consider the susceptibility allele for bipolar disorder and other psychiatric phenotypes that has been robustly identified within CACNA1C. The allele is common in the general population (frequency 30%) and is associated with a small increase in risk of bipolar disorder; the risk is increased by about 18% in carriers. Clearly, most people with the risk allele do

The future

In the past decade, we have moved from knowing nothing about the types and number of genetic loci involved in mood and psychotic illness to the first robust steps towards an understanding of rare and common risk variants. The way forward is clear for further locus identification in the future. Many types of variants with weak effects will be involved and thus large samples will be necessary, irrespective of whether common or rare loci are sought. What has not advanced as rapidly is the

Conclusions

A range of genetic and non-genetic research approaches (panel 3) is needed to help us better understand the major biological, psychological, and social processes that contribute to bipolar disorder and other psychiatric illness. Together with these complementary research approaches, the ongoing major investments of time and money in molecular genetic studies of psychiatric disorders have the potential to identify pathways involved in illness and to help psychiatry move towards approaches to

Search strategy and selection criteria

We searched Medline (January, 1966 to January, 2013) with the search terms “bipolar disorder” or “mania” or “manic” in combination with the term “genetics”. We selected mainly articles published in the past 5 years, but did not exclude frequently referenced and highly regarded older publications. We also searched the reference lists of articles identified by this search strategy and selected those that we judged to be relevant. We also considered articles drawn to our attention by the referees.

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