Assessment of Positive Traits within the Bipolar Spectrum

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 DESCRIPTION (provided by applicant): Consistent with the rationale behind the NIMH Research Domain Criteria (RDoC), we propose a new and unexplored scientific initiative to evaluate bipolar disorder from a dimensional point of view via the interaction of `positive spectrum traits' (PSTs) related to creativity, temperament, personality, and cognitive flexibility.It has long been noted that positive traits or enhanced abilities occur in the unaffected relatives of bipolar patients, a view supported by numerous studies, yet no study has assessed a possible advantage of genetic loading for bipolar disorder. Accordingly, several investigators have suggested the balancing selection model for bipolar disorder, with adaptive advantages conferred by sub-threshold traits according to an `inverted-U' shaped curve, yet these theories have not been evaluated. We propose that what arose as beneficial mutations to increase the cognitive, creative, and social nature of developing humans eventually led to illness at the extreme. Recent genome-wide association results have suggested that common variation explains at least 25% of the genetic variance in bipolar disorder, 68% of which is shared with schizophrenia as a general risk for psychosis. This significant role of common variation in risk suggests that most susceptibility alleles exist in healthy individuals, raising the intriguing notin that the actual phenotypes being transmitted in the population may be positive traits that modulate behavior in healthy individuals, which are maintained through positive or balancing selection. Supporting this view are studies reporting evidence of positive selection for genes association with bipolar disorder, psychosis, and creativity in healthy individuals (e.g., NRG1). Most studies of dimensional phenotypes for bipolar disorder have focused on deficits in patients and their first-degree relatives compared with healthy individuals. Conversely, we aim to identify positive behavioral traits associated with the bipolar disorder spectrum that can be used to further explicate its underlying genetic architecture and evolutionary context. To achieve this goal, we will first investigate selected individual PSTs in bipolar patients, clinically unaffected siblings, and healthy controls with subsequent validation of composite PST phenotypes that can be used in future genetic studies of larger samples. Our approach is designed to evaluate dimensionality in terms of a continuum of PSTs in the general population, wherein bipolar disorder resides at the extreme. Furthermore, current practice in psychiatry is geared more towards controlling the symptoms of bipolar disorder, rather than understanding a patient's true needs and potential capabilities. Creative expression is a source of well-being, and bipolar patients often discontinue their medications due to subjective experiences of diminished creativity, among other unpleasant side effects. Studying the link between creativity and bipolar disorder will thus promote a deeper understanding of patients' needs and experiences and facilitate better treatment and compliance. We believe our findings will be one step toward advancing our understanding of bipolar disorder, from both etiological and population perspectives, and toward promoting better patient care.