Despite the demonstrated high heritability of bipolar disorder, few susceptibility genes have been identified and linkage and/or association studies have produced conflicting results. This lack of replication has been accounted for by the use of invalid phenotypes, sample heterogeneity, unknown genetic parameters, and the underexploration of environmental aspects of the disease, which remain poorly understood.

This presentation will give examples of complementary approaches proposed to facilitate the identification of susceptibility genes in bipolar disorder. The first approach involves the identification of "candidate symptoms," rendering diagnostic entities presumably more likely to have a similar and simpler genetic basis. The candidate symptom approach has led to the identification of early-onset bipolar disorder (Leboyer et al, 2005) resulting in the identification of two genes involved in the phosphoinositide signalling pathway through a genome-wide-association study (GWAs) (Jamain et al, subm).

The second approach relies on the genetic exploration of the severely disrupted circadian rhythms observed among bipolar patients. Exploration of candidate biological system, such as melatonergic pathway revealed mutations correlated with a decreased activity of the protein encoded by the gene acetylserotonin methyltransferase (ASMT) which is the last enzyme of the melatonin synthesis. Haplotype analysis of the gene showed a significant association with bipolar disorder (Etain et al, 2009).
The third approach involves the use of quantitative intermediate phenotype such as the measure of abnormal emotional reactivity in a GWAs analysis. Preliminary results showed that lability and intensity of emotions measured by two self rating scales might be influenced by genetic factors located on 13q31 and 18q21 (Etain et al, submitted).
However, narrowing down the phenotype into more homogeneous subtypes is insufficient to unravel the genetic background of bipolar disorder, and incorporation of environmental factors is probably needed to account for the multifactorial origin of bipolar. In particular, growing evidence suggests that early childhood trauma are frequent in bipolar disorder, impacts the clinical expression of the disease in terms of suicidal behaviour and age at onset, and may interact with genetic susceptibility factors underlying hyper-emotional reactivity. Further exploration of this environmental factor and of its interaction with susceptibility genes will be proposed (Etain et al, 2008).


Leboyer M, Henry C, Paillere-Martinot ML, Bellivier F. Age at onset in bipolar affective disorders: a review. Bipolar Disorder, 2005; 7(2): 111-118.

Etain B, Dumaine A, Mathieu F, Chevalier F, Henry C, Kahn JP, Deshommes J Bellivier F, Leboyer M, Jamain S. A SNAP-25 promoter variant is associated with early-onset bipolar disorder and a high expression in the brain, Molecular Psychiatry, January 2009

Etain B, Henry C, Bellivier F, Mathieu F, Leboyer M Beyond genetics: childhood affective trauma in bipolar disorder. Bipolar Disord. 2008 Dec;10(8):867-7