Techniques will be developed for genetic analysis of complex diseases segregating in extended pedigrees of arbitrary structure. Diseases such as hypertension and psychiatric illness have both environmental and genetic components. However, identification of genes contributing to increased risk of such diseases has been limited by both computational and statistical constraints. The development of Markov Chain Monte Carlo (MCMC) methods have helped to overcome these limitations, providing information for gene localization, trait model estimation, haplotype analysis, and genetic map analyses, using data on extended pedigrees. The research now proposed is concerned with the extension of MCMC methods in several areas. We will develop improved methods for the MCMC analysis of gene descent in extended pedigrees, given data at multiple markers, using also sequential imputation and importance sampling Monte Carlo methods. The current approach to efficient MCMC sampling on pedigrees will be extended to allow explicit models for complex phenotypes to be included within Bayesian and likelihood-based joint segregation and multilocus linkage analyses. Where marker and phenotypic data are available on members of an extended pedigree, current methods will be extended to handle additional trait measures such as multivariate and ordered categorical phenotypes, to incorporate more complex patterns of censoring, and to allow for missing covariate information. We will develop measures of haplotype identity by descent (ibd) computationally and statistically well suited to linkage detection using data on extended pedigrees. We will compare the computational efficiency and statistical power of ibd-based linkage-detection methods with those of Bayesian and likelihood-based joint segregation and linkage analysis. We will develop MCMC methods for analysis of genetic map heterogeneity, genetic interference, and pedigree and genotyping errors, and assess the impact of these on the localization of genes contributing to complex traits. Methods will be evaluated by analyses on several simulated and real data sets, including pedigrees segregating cardiovascular disease or psychiatric disorders. These real data sets include several on which are available genome-wide marker screens or more localized multigene haplotypes. Finally, software will be developed that implements these methods, and will be documented and released for use by practitioners.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM046255-14
Application #
6835205
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Krasnewich, Donna M
Project Start
1991-09-01
Project End
2007-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
14
Fiscal Year
2005
Total Cost
$358,622
Indirect Cost
Name
University of Washington
Department
Biostatistics & Other Math Sci
Type
Schools of Arts and Sciences
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Blue, Elizabeth M; Brown, Lisa A; Conomos, Matthew P et al. (2016) Estimating relationships between phenotypes and subjects drawn from admixed families. BMC Proc 10:357-362
Saad, Mohamad; Nato Jr, Alejandro Q; Grimson, Fiona L et al. (2016) Identity-by-descent estimation with population- and pedigree-based imputation in admixed family data. BMC Proc 10:295-301
Raffa, Jesse D; Thompson, Elizabeth A (2016) Power and Effective Study Size in Heritability Studies. Stat Biosci 8:264-283
Kim, Sulgi; Saad, Mohamad; Tsuang, Debby W et al. (2014) Visualization of haplotype sharing patterns in pedigree samples. Hum Hered 78:1-8
Zheng, Chaozhi; Kuhner, Mary K; Thompson, Elizabeth A (2014) Joint inference of identity by descent along multiple chromosomes from population samples. J Comput Biol 21:185-200
Zheng, Chaozhi; Kuhner, Mary K; Thompson, Elizabeth A (2014) Bayesian inference of local trees along chromosomes by the sequential Markov coalescent. J Mol Evol 78:279-92
Ryman, Davis C; Acosta-Baena, Natalia; Aisen, Paul S et al. (2014) Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology 83:253-60
Thompson, Elizabeth A (2013) Identity by descent: variation in meiosis, across genomes, and in populations. Genetics 194:301-26
Koepke, Hoyt; Thompson, Elizabeth (2013) Efficient identification of equivalences in dynamic graphs and pedigree structures. J Comput Biol 20:551-70
Sverdlov, Serge; Thompson, Elizabeth A (2013) Correlation between relatives given complete genotypes: from identity by descent to identity by function. Theor Popul Biol 88:57-67

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