Evaluating endophenotypes for bipolar disorder

Abstract

Background: Phenotypic heterogeneity is a major impediment to the elucidation of the neurobiology and genetics of bipolar disorder. Endophenotype could help in reducing heterogeneity by defining biological traits that are more direct expressions of gene effects. The aim of this review is to examine the recent literature on clinical, epidemiological, neurobiological, and genetic findings and to select and evaluate candidate endophenotypes for bipolar disorder. Evaluating putative endophenotype could be helpful in better understanding the neurobiology of bipolar disorder by improving the definition of bipolar-related phenotypes in genetic studies. In this manner, research on endophenotypes could be useful to improve psychopathological diagnostics in the long-run by dissecting psychiatric macro phenotypes into biologically valid components.

Main body: The associations among the psychopathological and biological endophenotypes are discussed with respect to specificity, temporal stability, heritability, familiarity, and clinical and biological plausibility. Numerous findings regarding brain function, brain structure, neuropsychology and altered neurochemical pathways in patients with bipolar disorder and their relatives deserve further investigation. Overall, major findings suggest a developmental origin of this disorder as all the candidate endophenotypes that we have been able to select are present both in the early stages of the disorder as well as in subjects at risk.

Conclusions: Among the stronger candidate endophenotypes, we suggest circadian rhythm instability, dysmodulation of emotion and reward, altered neuroimmune state, attention and executive dysfunctions, anterior cingulate cortex thickness and early white matter abnormalities. In particular, early white matter abnormalities could be the result of a vulnerable brain on which new stressors are added in young adulthood which favours the onset of the disorder. Possible pathways that lead to a vulnerable brain are discussed starting from the data about molecular and imaging endophenotypes of bipolar disorder.

Keywords: Bipolar disorder; Cognition; Endophenotype; Neuroimaging; Neuroinflammation.

Fig. 1

Putative endophenotypes for bipolar disorder. Heuristic model to link the putative endophenotypes (molecular, imaging and cognitive) to distal phenotypes like BD symptoms. Major findings in endophenotype research suggest a developmental origin of BD. This figure shows as the interplay between environmental risk factors like stress and infections, and the genetic susceptibility of different systems like immune, circadian and glutamatergic systems could shape a vulnerable brain on which new stressors are added in young adulthood which favours the onset and the progression of the disorder. ACC anterior cingulate cortex, ACNA1 Calcium Voltage-Gated Channel Subunit Alpha1, ANK3 Ankyrin 3, AMY amygdala, BDNF Brain Derived Neurotrophic Factor, CACNA1 Calcium Voltage-Gated Channel Subunit Alpha1, CCL11 C-C Motif Chemokine Ligand 11, CCL24 C-C Motif Chemokine Ligand 24, CXCL10 C-X-C Motif Chemokine Ligand 10, CRP C-Reactive Protein, CREB CREB Binding Protein, GRM1 Glutamate Metabotropic Receptor 1, GRM7 Glutamate Metabotropic Receptor 7, GNG2 G Protein Subunit Gamma 2, HPC hippocampus, HYP hypothalamus, IL6 Interleukin 6, IL10 Interleukin 10, OPG Osteoprotegerin, PFC prefrontal cortex, TNF Tumor Necrosis Factor, ZNF804A Zinc Finger Protein 804A