Nature Genetics
12, 436 - 441 (1996)
doi:10.1038/ng0496-436
Genetic mapping using haplotype, association and linkage methods suggests a locus for severe bipolar disorder (BPI) at 18q22-q23Nelson B. Freimer1, 2, 3, 9, Victor I. Reus2, Michael A. Escamilla1, 2, L. Alison Mclnnes3, Mitzi Spesny4, Pedro Leon4, Susan K. Service1, 2, Lauren B. Smith1, Sandra Silva4, Eugenia Rojas4, Alvaro Gallegos5, 2, Luis Meza5, Eduardo Fournier4, Siamak Baharloo1, Kathleen Blankenship1, David J. Tyler1, Steven Batki6, 2, Sophia Vinogradov2, Jean Weissenbach7, Samuel H. Barondes2
& Lodewijk A. Sandkuijl8
1Neurogenetics Laboratory, University of California San Francisco, San Francisco California 94143, USA.
2Center for Neurobiology and Psychiatry, Department of Psychiatry, University of California San Francisco, San Francisco California 94143, USA.
3Programs in Genetics and Biomedical Sciences, University of California, San Francisco, San Francisco, California 94143.
4Cell and Molecular Biology Research Center and Escuela de Medicina (P.L) Universidad de Costa Rica, San Jose, Costa Rica.
5Hospital Calderon Guardia, San Jose Costa Rica.
6Department of Psychiatry, University of California San Francisco, San Francisco General Hospital, San Francisco California 94110, USA.
7Généthon 1 rue de l'Internationale, 91000 Evry, France and Unité de Génétique Moléculaire Humaine, CNRS URA 1445, Institut Pasteur, 75724 Paris Cédex, France.
8Department of Clinical Genetics, Erasmus University, Rotterdam, Department of Human Genetics, Leiden University, Department of Medical Genetics, Groningen University, The Netherlands.
9Correspondence should be addressed to N.B.F. at U.C.S.F. email:nbfr@itsa.ucsf.edu. Manic-depressive illness, or bipolar disorder (BP), is characterized by episodes of elevated mood (mania) and depression1. We designed a multistage study in the genetically isolated population of the Central Valley of Costa Rica2,3 to identify genes that promote susceptibility to severe BP (termed BPI), and screened the genome of two Costa Rican BPI pedigrees (Mclnnes et al., submitted). We considered only individuals who full-filled very stringent diagnostic criteria for BPI to be affected. The strongest evidence for a BPI locus was observed in 18q22-q23. We tested 16 additional markers in this region and seven yielded peak lod scores over 1.0. These suggestive lod scores were obtained over a far greater chromosomal length (about 40 cM) than in any other genome region. This localization is supported by marker haplotypes shared by 23 of 26 BPI affected individuals studied. Additionally, marker allele frequencies over portions of this region are significantly different in the patient sample from those of the general Costa Rican population. Finally, we performed an analysis which made use of both the evidence for linkage and for association in 18q23, and we observed significant lod scores for two markers in this region.
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