Examination of the clock gene Cryptochrome 1 in bipolar... : Psychiatric Genetics (original) (raw)

ORIGINAL ARTICLES

Examination of the clock gene Cryptochrome 1 in bipolar disorder: mutational analysis and absence of evidence for linkage or association

Nievergelt, Caroline M.a; Kripke, Daniel F.a; Remick, Ronald A.b; Sadovnick, A. Dessac; McElroy, Susan L.d; Keck, Paul E. Jr.d; Kelsoe, John R.a e

aDepartment of Psychiatry, University of California, San Diego, La Jolla, California, USA

bDepartment of Psychiatry, St Paul's Hospital, Vancouver, Canada

cDepartment of Medical Genetics, University of British Columbia, Vancouver, Canada

dBiological Psychiatry Program, Department of Psychiatry, University of Cincinnati, College of Medicine, Cincinnati, Ohio, USA

eDepartment of Psychiatry, San Diego VA Healthcare System, La Jolla, California, USA

Sponsorship: This work was supported by a grant from the Swiss National Science Foundation (823A-061200) to C.M.N. D.F.K. has been supported by AG15763, AG12364, and HL61280. J.R.K. was supported by NIMH (MH59567, MH47612), the Department of Veterans Affairs and by the UCSD General Clinical Research Center (M01 RR00827).

Correspondence and requests for reprints to John R. Kelsoe, M.D., Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093-0603, USA.

Tel: +1 858 534 5927; fax: +1 858 534 5527;

e-mail: [email protected]

Received 24 September 2003 Accepted 17 March 2004

Note: J.R.K. is a founder and holds equity in Psynomics, Inc.

Note: Data and biomaterials were collected in four projects that participated in the NIMH Bipolar Disorder Genetics Initiative. From 1991 to 1998, the Principal Investigators and Co-Investigators were: Indiana University (Indianapolis, Indiana, USA; UO1 MH46282), John Nurnberger, M.D., Ph.D., Marvin Miller, M.D., and Elizabeth Bowman, M.D.; Washington University (St Louis, Missouri, USA; UO1 MH46280), Theodore Reich, M.D., Allison Goate, Ph.D., and John Rice, Ph.D.; Johns Hopkins University (Baltimore, Maryland, USA; UO1 MH46274), J. Raymond DePaulo, Jr., M.D., Sylvia Simpson, M.D., MPH, and Colin Stine, Ph.D.; NIMH Intramural Research Program, Clinical Neurogenetics Branch (Bethesda, Maryland, USA), Elliot Gershon, M.D., Diane Kazuba, B.A., and Elizabeth Maxwell, M.S.W.

Abstract

Bipolar disorder is associated with malfunctions of the circadian system, which regulates individual circadian rhythms and which enables the adaptation to a daily 24-h cycle and seasonal change. One of the human circadian clock genes, cryptochrome 1 (Cry1) (located on 12q23-q24.1) was analyzed because of its close correspondence to a linkage hotspot for bipolar disorder.

We found no evidence for linkage of 52 bipolar families to two Cry1 flanking microsatellites under several parametric and non-parametric models. In order to employ association for a more sensitive test, 25 affected subjects selected from families with positive LOD scores were screened for mutations by sequencing 9.5% of the Cry1 gene. A total of 16 single nucleotide polymorphisms (SNPs) and a 3 base pair insertion were identified. However, no mutations with probable functional impact were found. These novel SNPs and data on allele frequency and linkage disequilibrium structure will be useful for future association analyses. Nine SNPs have been analyzed in a set of 159 parent proband triads. Linkage disequilibrium analyses using single SNPs and haplotypes showed no association to bipolar disease.

Additional, more powerful, studies involving Cry1 and other circadian clock genes need to be tested before an association of circadian abnormalities with bipolar disorder can be excluded.