The aims in this study will (1) develop candidate neurocognitive and neuroimaging endophenotypes for bipolar I disorder (BPI), (2) examine the association of history of psychosis and these brain-behavior markers in BPI patients, and (3) determine if markers are sensitive to liability for psychosis. Thus, the project has two overlapping goals: the development of candidate endophenotypes for BPI broadly and the identification of candidate endophenotypes for psychosis. The ultimate promise of this research is to develop markers that will characterize the biological mechanisms of BPI and facilitate the discovery of genes that predispose the illness. We believe that a comprehensive assessment of neuropsychological functioning and brain structure and function in sibling pairs discordant for bipolar disorder and stratified for psychosis history is a strategically strong first step towards reaching these goals. To this end, we will perform anatomic and functional neuroimaging and conduct neuropsychological examinations on 130 euthymic patients with BPI (65 with history of psychosis), 130 of their unaffected same-sex siblings and 65 unrelated comparison subjects. Markers found to be aberrant in both affected individuals (regardless of history of psychosis) and in their unaffected relatives will be considered candidate endophenotypes for BPI (Aim 1). Neuropsychological and neuroimaging measures that distinguish between BPI patients with and without history of psychosis (Aim 2) and their siblings (Aim 3) will be considered potential endophenotypes for psychosis. Bipolar I disorder represents a significant economic burden and is associated with substantial morbidity and mortality rates. Although it is well established that BPI is substantially heritable, the molecular genetic basis for this illness remains elusive, potentially because of illness complexity, heterogeneity of disease expression, and comorbidity with other disorders that may distort clinical presentation. In the face of evidence that genes predisposing to BPI may be transmitted without expression of the clinical phenotype, interest has arisen in developing endophenotypes for the illness, indicators of processes mediating between genotype and phenotype. Given the high rates of psychosis in BPI and that history of psychosis may alter brain structure and function, we believe that elucidating neurocognitive and neuroimaging endophenotypes for the disorder must account for the potential impact of hallucinations and delusions on these markers. This research will established biomarkers that could improve the identification and treatment of BPI patients and, potentially, patients with psychotic disorders, independent of their formal diagnosis.

Public Health Relevance

Bipolar I disorder is a major public health burden whose biology is still largely unknown. Through the development of brain-behavior markers sensitive to genetic liability for bipolar disorder, the proposed research should significantly aid the discovery of genes that predispose the illness and facilitate the identification of the biological determinants of bipolar disorder. This, in turn, should lead to improved characterization and treatment of bipolar disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH080912-05
Application #
8241065
Study Section
Behavioral Genetics and Epidemiology Study Section (BGES)
Program Officer
Chavez, Mark
Project Start
2008-05-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
5
Fiscal Year
2012
Total Cost
$420,577
Indirect Cost
$99,912
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Carmiol, N; Peralta, J M; Almasy, L et al. (2014) Shared genetic factors influence risk for bipolar disorder and alcohol use disorders. Eur Psychiatry 29:282-7
Glahn, David C; Knowles, Emma E M; McKay, D Reese et al. (2014) Arguments for the sake of endophenotypes: examining common misconceptions about the use of endophenotypes in psychiatric genetics. Am J Med Genet B Neuropsychiatr Genet 165B:122-30
Lencz, T; Knowles, E; Davies, G et al. (2014) Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT). Mol Psychiatry 19:168-74
Yang, Genevieve J; Murray, John D; Repovs, Grega et al. (2014) Altered global brain signal in schizophrenia. Proc Natl Acad Sci U S A 111:7438-43
Anticevic, Alan; Yang, Genevieve; Savic, Aleksandar et al. (2014) Mediodorsal and visual thalamic connectivity differ in schizophrenia and bipolar disorder with and without psychosis history. Schizophr Bull 40:1227-43
Thompson, Paul M; Ge, Tian; Glahn, David C et al. (2013) Genetics of the connectome. Neuroimage 80:475-88
Sprooten, Emma; Brumbaugh, Margaret S; Knowles, Emma E M et al. (2013) Reduced white matter integrity in sibling pairs discordant for bipolar disorder. Am J Psychiatry 170:1317-25
Anticevic, Alan; Brumbaugh, Margaret S; Winkler, Anderson M et al. (2013) Global prefrontal and fronto-amygdala dysconnectivity in bipolar I disorder with psychosis history. Biol Psychiatry 73:565-73
Karlsgodt, Katherine H; Bachman, Peter; Winkler, Anderson M et al. (2011) Genetic influence on the working memory circuitry: behavior, structure, function and extensions to illness. Behav Brain Res 225:610-22
Glahn, David C; Almasy, Laura; Barguil, Marcela et al. (2010) Neurocognitive endophenotypes for bipolar disorder identified in multiplex multigenerational families. Arch Gen Psychiatry 67:168-77

Showing the most recent 10 out of 12 publications