This is a revised application for competitive renewal of a grant aimed at identifying the genetic basis of severe bipolar disorder (BP-I), also termed manic depressive illness. The project aims to identify the full spectrum of genetic risk for BP-I in an isolated population that is exceptionally informative for genetic study, that of the Central Valley of Costa Rica (CVCR). The subjects include members of extended pedigrees, each with many individuals affected with BP-I. These pedigrees are hypothesized to segregate susceptibility alleles of relative high penetrance. Previous genome-wide linkage studies of two of these pedigrees have suggested localizations for such alleles on chromosomes 18q and 5q. In addition, a sample of BP-I probands, ascertained independently of each other, has been recruited from CVCR hospitals; this sample is most useful to identify susceptibility alleles of relatively low penetrance. Genome-wide linkage disequilibrium (LD) mapping studies of this sample have suggested several localizations of BP-I susceptibility alleles. In the renewal of this grant, further genotyping studies will be carried out. These studies will include both fine-scale mapping studies in genome regions suggested to contain BP-I genes by the prior genotyping studies in the CVCR, and independent genome-wide screens in newly ascertained pedigrees and population samples. The genotyping studies will delineate candidate regions for identifying BP-I genes.Much improvement is needed in the statistical and laboratory methodology for identifying genes for complex traits such as BP. Developing such improved methodology has been a major emphasis of this grant in the past and will still be a focus in the renewal; in particular, substantial effort is devoted to genetic mapping approaches that are specific to population isolates.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Study Section
Genome Study Section (GNM)
Program Officer
Moldin, Steven Owen
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Kerner, Berit; Jasinska, Anna J; DeYoung, Joseph et al. (2009) Polymorphisms in the GRIA1 gene region in psychotic bipolar disorder. Am J Med Genet B Neuropsychiatr Genet 150B:24-32
Jasinska, A J; Service, S; Jawaheer, D et al. (2009) A narrow and highly significant linkage signal for severe bipolar disorder in the chromosome 5q33 region in Latin American pedigrees. Am J Med Genet B Neuropsychiatr Genet 150B:998-1006
Wang, Sijia; Ray, Nicolas; Rojas, Winston et al. (2008) Geographic patterns of genome admixture in Latin American Mestizos. PLoS Genet 4:e1000037
Kerner, Berit; Brugman, Diana L; Freimer, Nelson B (2007) Evidence of linkage to psychosis on chromosome 5q33-34 in pedigrees ascertained for bipolar disorder. Am J Med Genet B Neuropsychiatr Genet 144B:74-8
Service, Susan; International Collaborative Group on Isolated Populations; Sabatti, Chiara et al. (2007) Tag SNPs chosen from HapMap perform well in several population isolates. Genet Epidemiol 31:189-94
Chen, Yuguo; Lin, Chia-Ho; Sabatti, Chiara (2006) Volume measures for linkage disequilibrium. BMC Genet 7:54
Wang, Hui; Lin, Chia-Ho; Service, Susan et al. (2006) Linkage disequilibrium and haplotype homozygosity in population samples genotyped at a high marker density. Hum Hered 62:175-89
Herzberg, Ibi; Jasinska, Anna; Garcia, Jenny et al. (2006) Convergent linkage evidence from two Latin-American population isolates supports the presence of a susceptibility locus for bipolar disorder in 5q31-34. Hum Mol Genet 15:3146-53
Bearden, Carrie E; Freimer, Nelson B (2006) Endophenotypes for psychiatric disorders: ready for primetime? Trends Genet 22:306-13
Service, Susan; Molina, Julio; Deyoung, Joseph et al. (2006) Results of a SNP genome screen in a large Costa Rican pedigree segregating for severe bipolar disorder. Am J Med Genet B Neuropsychiatr Genet 141B:367-73

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