The goal of the proposed research is to identify mutations that promote susceptibility to bipolar disorder (BP); genomic mapping approaches will be used to attain this goal. Specifically, a number of established and newly developed methods will be used to pinpoint a putative BP mutation on the X chromosome, through analyses of DNA from members of three Israeli pedigrees. This locus was pinpointed to the distal long arm of X by linkage analysis; more precise localization has resulted from further genetic analyses using multiple DNA markers. The proposed studies will progressively narrow the region that could contain a BP mutation. First, markers in the region will be precisely ordered and new markers generated through construction of radiation hybrids. Next, maximal genetic localization of BP will be accomplished using several methods to detect polymorphisms at new and previously described loci. Focused studies of sub-chromosomal regions of greatest interest will be accomplished using cloning vectors capable of accommodating large inserts of human genomic DNA. A number of complementary methods will then be used to identify and characterize coding sequences from these regions. To increase the genetic power of the study, attempts will be made to identify and investigate additional families in which BP segregates in a manner consistent with X-linkage. Characterizing a BP locus on the X chromosome will enable greater understanding of the pathogenesis of BP and will likely lead to advances in diagnosis and treatment of this disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Scientist Development Award (K21)
Project #
5K21MH000916-02
Application #
3089065
Study Section
Research Scientist Development Review Committee (MHK)
Project Start
1991-02-01
Project End
1996-01-31
Budget Start
1992-02-01
Budget End
1993-01-31
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Hong, Kyung Sue; McInnes, L Alison; Service, Susan K et al. (2004) Genetic mapping using haplotype and model-free linkage analysis supports previous evidence for a locus predisposing to severe bipolar disorder at 5q31-33. Am J Med Genet B Neuropsychiatr Genet 125B:83-6
Escamilla, Michael A; Batki, Steven; Reus, Victor I et al. (2002) Comorbidity of bipolar disorder and substance abuse in Costa Rica: pedigree- and population-based studies. J Affect Disord 71:71-83
Garner, C; McInnes, L A; Service, S K et al. (2001) Linkage analysis of a complex pedigree with severe bipolar disorder, using a Markov chain Monte Carlo method. Am J Hum Genet 68:1061-4
McInnes, L A; Service, S K; Reus, V I et al. (2001) Fine-scale mapping of a locus for severe bipolar mood disorder on chromosome 18p11.3 in the Costa Rican population. Proc Natl Acad Sci U S A 98:11485-90
Escamilla, M A; McInnes, L A; Spesny, M et al. (1999) Assessing the feasibility of linkage disequilibrium methods for mapping complex traits: an initial screen for bipolar disorder loci on chromosome 18. Am J Hum Genet 64:1670-8
McInnes, L A; Reus, V I; Freimer, N B (1998) Mapping genes for psychiatric disorders and behavioral traits. Curr Opin Genet Dev 8:287-92
Bull, L N; Carlton, V E; Stricker, N L et al. (1997) Genetic and morphological findings in progressive familial intrahepatic cholestasis (Byler disease [PFIC-1] and Byler syndrome): evidence for heterogeneity. Hepatology 26:155-64
Smith, L B; Sapers, B; Reus, V I et al. (1996) Attitudes towards bipolar disorder and predictive genetic testing among patients and providers. J Med Genet 33:544-9
Escamilla, M A; Spesny, M; Reus, V I et al. (1996) Use of linkage disequilibrium approaches to map genes for bipolar disorder in the Costa Rican population. Am J Med Genet 67:244-53
Freimer, N B; Reus, V I; Escamilla, M et al. (1996) An approach to investigating linkage for bipolar disorder using large Costa Rican pedigrees. Am J Med Genet 67:254-63

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