Schizophrenia unquestionably has a significant genetic component but the nature of that genetic component remains unresolved. Genetic linkage is a powerful research paradigm for identifying major loci that might exist as causes of some cases of schizophrenia. Two major problems have complicated previous genetic linkage studies of schizophrenia: The inability to infer precisely the inheritance pattern of the putative major segregating in high density families and the difficulty in inferring precisely the segregation of marker loci in sparse, complex, and disjointed pedigrees. We propose genetic linkage studies that will address both of those issues. The improved inference of the major locus will be possible because of the use of additional diagnostic as well as psychophysiological evaluations of all family members. This approach, motivated by a latent trait model, is already underway as part of a funded research project. This present application is to fund a more exhaustive and detailed evaluation of how genetic material has in fact been transmitted within these large high density families using new technologies to evaluate, in an efficient and accurate way, the class of DNA polymorphisms known as short tandem repeats. These polymorphisms are present every 10 or so kilobases throughout the genome, have heterozygosities generally greater than 70%, and have discrete allelic states easy to classify with semi-automated methodologies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH050390-01
Application #
3389569
Study Section
Epidemiology and Genetics Review Committee (EPI)
Project Start
1993-01-01
Project End
1997-12-31
Budget Start
1993-01-01
Budget End
1993-12-31
Support Year
1
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Calafell, F; Shuster, A; Speed, W C et al. (1999) Genealogy reconstruction from short tandem repeat genotypes in an Amazonian population. Am J Phys Anthropol 108:137-46
Tishkoff, S A; Goldman, A; Calafell, F et al. (1998) A global haplotype analysis of the myotonic dystrophy locus: implications for the evolution of modern humans and for the origin of myotonic dystrophy mutations. Am J Hum Genet 62:1389-402
Sirugo, G; Kidd, K K (1998) Repeat expansion-detection analysis of telomeric uninterrupted (TTAGGG)n arrays. Am J Hum Genet 63:648-51
Calafell, F; Shuster, A; Speed, W C et al. (1998) Short tandem repeat polymorphism evolution in humans. Eur J Hum Genet 6:38-49
Sirugo, G; Pakstis, A J; Kidd, K K et al. (1997) Detection of a large CTG/CAG trinucleotide repeat expansion in a Danish schizophrenia kindred. Am J Med Genet 74:546-8
Sirugo, G; Deinard, A S; Kidd, J R et al. (1997) Survey of maximum CTG/CAG repeat lengths in humans and non-human primates: total genome scan in populations using the Repeat Expansion Detection method. Hum Mol Genet 6:403-8
Kidd, K K (1997) Can we find genes for schizophrenia? Am J Med Genet 74:104-11
Haaf, T; Sirugo, G; Kidd, K K et al. (1996) Chromosomal localization of long trinucleotide repeats in the human genome by fluorescence in situ hybridization. Nat Genet 12:183-5