This article was prepared by a group consisting of both United States Government employees and non-United States Government employees, and as such is subject to 117 U.S.C. Sec. 105.
Endophenotypes in bipolar disorder†
Article first published online: 17 APR 2002
Published 2002 Wiley-Liss, Inc.
American Journal of Medical Genetics
Volume 114, Issue 4, pages 391–406, 8 May 2002
How to Cite
Lenox, R. H., Gould, T. D. and Manji, H. K. (2002), Endophenotypes in bipolar disorder. Am. J. Med. Genet., 114: 391–406. doi: 10.1002/ajmg.10360
- Issue published online: 23 OCT 2002
- Article first published online: 17 APR 2002
- Manuscript Accepted: 24 JAN 2002
- Manuscript Received: 9 OCT 2001
- National Institute of Mental Health. Grant Number: 5R01 MH59959
- National Institute of Mental Health, Intramural Research Program
- Theodore and Vada Stanley Foundation
- The National Alliance for Research on Schizophrenia and Depression (NARSAD)
- biological marker;
- subclinical trait;
- vulnerability marker;
- circadian rhythms;
The search for genes in bipolar disorder has provided numerous genetic loci that have been linked to susceptibility to developing the disorder. However, because of the genetic heterogeneity inherent in bipolar disorder, additional strategies may need to be employed to fully dissect the genetic underpinnings. One such strategy involves reducing complex behaviors into their component parts (endophenotypes). Abnormal neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, and neuropsychological findings are characteristics that often accompany psychiatric illness. It is possible that some of these may eventually be useful in subdefining complex genetic disorders, allowing for improvements in diagnostic assessment, genetic linkage studies, and development of animal models. Findings in patients with bipolar disorder that may eventually be useful as endophenotypes include abnormal regulation of circadian rhythms (the sleep/wake cycle, hormonal rhythms, etc.), response to sleep deprivation, P300 event-related potentials, behavioral responses to psychostimulants and other medications, response to cholinergics, increase in white matter hyperintensities (WHIs), and biochemical observations in peripheral mononuclear cells. Targeting circadian rhythm abnormalities may be a particularly useful strategy because circadian cycles appear to be an inherent evolutionarily conserved function in all organisms and have been implicated in the pathophysiology of bipolar disorder. Furthermore, lithium has been shown to regulate circadian cycles in diverse species, including humans, possibly through inhibition of glycogen synthase kinase 3-β (GSK-3β), a known target of lithium. Published 2002 Wiley-Liss, Inc.