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Original Article
February 2010

Neurocognitive Endophenotypes for Bipolar Disorder Identified in Multiplex Multigenerational Families

Author Affiliations

Author Affiliations: Olin Neuropsychiatry Research Center, Institute of Living, Hartford, Connecticut (Dr Glahn); Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut (Dr Glahn); Departments of Psychiatry (Drs Glahn, Hare, Dassori, Contreras, and Escamilla and Ms Barguil) and Cellular and Structural Biology (Dr Escamilla), The University of Texas Health Science Center at San Antonio, and Department of Genetics, Southwest Foundation for Biomedical Research (Drs Almasy and Kent and Mr Peralta), San Antonio; Centro de Investigación en Biología Molecular y Celular, Universidad de Costa Rica, San José (Ms Barguil and Drs Contreras, Pacheco, and Raventós); and Grupo de Estudios Médicos y Familiares Carracci, Mexico City, Mexico (Ms Lanzagorta and Dr Nicolini).

Arch Gen Psychiatry. 2010;67(2):168-177. doi:10.1001/archgenpsychiatry.2009.184

Context  Although genetic influences on bipolar disorder are well established, localization of genes that predispose to the illness has proven difficult. Given that genes predisposing to bipolar disorder may be transmitted without expression of the categorical clinical phenotype, a strategy for identifying risk genes is to identify and map quantitative intermediate phenotypes or endophenotypes.

Objective  To adjudicate neurocognitive endophenotypes for bipolar disorder.

Design  All participants underwent diagnostic interviews and comprehensive neurocognitive evaluations. Neurocognitive measures found to be heritable were entered into analyses designed to determine which test results are impaired in affected individuals, are sensitive to the genetic liability for the illness, and are genetically correlated with affection status.

Setting  Central valley of Costa Rica; Mexico City, Mexico; and San Antonio, Texas.

Participants  Seven hundred nine Latino individuals participated in the study. Of these, 660 were members of extended pedigrees with at least 2 siblings diagnosed as having bipolar disorder (n = 230). The remaining subjects were community control subjects drawn from each site who did not have a personal or family history of bipolar disorder or schizophrenia.

Main Outcome Measure  Neurocognitive test performance.

Results  Two of the 22 neurocognitive variables were not significantly heritable and were excluded from subsequent analyses. Patients with bipolar disorder were impaired on 6 cognitive measures compared with nonrelated healthy controls. Nonbipolar first-degree relatives were impaired on 5 of these, and the following 3 tests were genetically correlated with affection status: Digit Symbol Coding Task, Object Delayed Response Task, and immediate facial memory.

Conclusion  This large-scale extended pedigree study of cognitive functioning in bipolar disorder identifies measures of processing speed, working memory, and declarative (facial) memory as candidate endophenotypes for bipolar disorder.