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.

The interactions between vitamin D and neurofilament light chain levels on cognitive domains in bipolar disorder

“…In addition, the age-modified interaction effect could contribute to evidence supporting the neuroimmune development of bipolar disorder, in which, at the onset of the illness, individuals experience an increased proinflammatory state in adolescence, an anti-inflammatory state during young adulthood and a nearly normalised immune state in later stages of the disease course. 35 The interaction plot revealed an antagonistic interaction effect of vitamin D and NfLs, indicating that in the early stages of bipolar disorder in younger patients, NfL level may serve as a marker for neuro-damage resulting from neuroinflammation, and cognition differed in patients with higher and lower NfL levels, particularly those with extremely low vitamin D levels. In older patients with bipolar disorder who have a longer disease course, neuroinflammatory processes become stable, and the positive effects of vitamin D become more prominent in patients with lower rather than higher NfL levels.…”

Oxidative DNA base damage and base excision repair abnormalities in siblings of individuals with bipolar disorder

“…Individuals who have a genetic predisposition to BD may display impairments in visual memory, verbal memory, processing speed, attention, and social cognition compared to HCs [46]. Structural and functional alterations in the prefrontal cortex [47][48][49] and white matter abnormalities in the body and splenium of the corpus callosum [50] have been observed in individuals with genetic predisposition to BD, as well as alterations in markers of neuroimmune dysregulation [51,52]. Our results suggest that the BER pathway may genes serve as candidate endophenotypes for BD.…”

Impaired Visuospatial Working Memory but Preserved Attentional Control in Bipolar Disorder

“…These have been linked to clinical severity (Swann, Lijffijt, Lane, Steinberg, & Moeller, 2009). Notably, sustained attention has also been implicated as an endophenotype for BD (Guglielmo, Miskowiak, & Hasler, 2021).…”