Genetics of bipolar disorder – update

Unraveling the genetics of bipolar disorder has been a much more complicated task than anyone thought.

Although the best estimates suggest that genetic factors account for the very high percentage of the risk of developing bipolar, with an estimated an estimated 0.7 to 0.8 heritability (Sullivan), it has been remarkably difficult to find genes with significant individual effects that are replicated in several studies.

Initial efforts to identify the genetic basis for a number of neuropsychiatric disorders involved careful analysis of a small number of genes in families where it was possible to collect genetic samples from a large number of family members, and a large number of family members were affected by a given condition (family studies). These efforts were successful in identifying genes for some forms of Parkinson’s and Alzheimer’s disease, but have not been very helpful in identifying genes for people with most psychiatric conditions.

For this reason the focus of genetic research shifted to collecting samples from large groups of unrelated people, both with and without a given condition (case-control studies). By and large the result of these studies was to collect a tantalizing set of hints (genes associated with the condition in one study which were then not duplicated in a follow-up study) suggesting that bipolar disorder and many other psychiatric disorders was caused by the presence of a large number of genes, each of which conferred a small increased risk of developing the condition.

An article in the April 2016 issue of JAMA Psychiatry suggests that it may be time to return to family studies, but use the whole genome technology that was developed in case-control studies.

The image below shows the family trees of eight families that were studied with a high number of bipolar, major depression, or schizoaffective disorder diagnoses. 

The researchers (Goes) first identified rare genes that were significantly associated with a bipolar spectrum in individual families. They then tested these possibilities in much larger samples.

What they found was a set of genes that seemed to be risk factors for bipolar, but in the larger sample, they found that these genes were associated with much more than just bipolar, they were a risk for autism and schizophrenia as well.

In an accompanying editorial, Kemper summarizes the conclusions from this study, that summary could also be a good explanation for the failure so far to satisfactorily untangle the genetics of bipolar –

1. Many genes are involved (no one gene is enough to cause bipolar).
2. The groups of risks may be different in different families (there may be groups of genes that are associated with bipolar, but finding the groups will be hard without family studies).
3. The genes are not likely to be clearly linked to brain function (most of the 82 genes identified in this study were not clearly linked to neurons or neuron growth).
4. The genes are likely to be associated with multiple medical and psychiatric conditions.

References

Sullivan  PF, Daly  MJ, O’Donovan  M.  Genetic architectures of psychiatric disorders: the emerging picture and its implications. Nat Rev Genet. 2012;13(8):537-551.

Goes  FS, Pirooznia  M, Parla  JS,  et al.  Exome sequencing of familial bipolar disorder [published online April 27, 2016]. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2016.0251.

Kember RL, Bućan M. Promising 2-Pronged Approach to Genetic Basis of Bipolar Disorder. JAMA Psychiatry. Published online April 27, 2016. doi:10.1001/jamapsychiatry.2016.0298.

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