Techniques will be developed for genetic analysis of complex diseases segregating in pedigrees of arbitrary size and structure. Cardiovascular, neurological and behavioral traits are among those having both environmental and genetic components. However, identification of genes contributing to increased risk of related disorders has been limited by both computational and statistical constraints. The development of Markov chain Monte Carlo (MCMC) methods has helped overcome these limitations, and the research now proposed concerns extension of these computational and statistical methods in several areas. Improved methods will be developed for the MCMC analysis of gene identity by descent (ibd) in general pedigrees, given data at a dense genome screen of markers, together with the use of this ibd in analyses of complex traits. The ibd inferred from dense genetic markers permits the combination of information within and among pedigrees, increasing the power and resolution of linkage analyses. The ibd framework also provides for far more computationally efficient trait analyses, enabling models for discrete and quantitative trait phenotypes to be extended to a variety of complex models. Additionally, use of the same MCMC-realized ibd patterns in the analysis of multiple trait models provide measures of trait model robustness, and of confidence and significance of linkage findings. With the availability of sparser genetic marker data on extended pedigrees, together with dense localized data on a subset of individuals, the problems of haplotyping, genotype imputation, and error detection, assume increasing importance. Again, MCMC-based realization of ibd at sparser locations provides new methods for imputation of genotypes and haplotypes at denser locations, incorporating linkage disequilibrium and models for next-generation sequence data into the analysis of trait data on pedigrees. Methods will be evaluated by analyses on several simulated and real data sets, including pedigrees segregating cardiovascular disease or behavioral disorders. These real data sets include several on which are available genome-wide marker screens, localized multigene haplotypes, and next-generation sequence data. Finally, software implementing these methods will be developed, documented and released.

Public Health Relevance

Complex traits including cardiovascular, neurological and behavioral phenotypes are related to human health disorders which carry a significant public health burden. Identification of genes contributing to increased disease risk has been limited by trait complexity. Development of methods for genetic analysis offers the potential for finding the genes contributing to risk, and for resolving the interaction of genes and environment.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM046255-23
Application #
8606854
Study Section
Special Emphasis Panel (NSS)
Program Officer
Krasnewich, Donna M
Project Start
1991-09-01
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
23
Fiscal Year
2014
Total Cost
$340,178
Indirect Cost
$115,178
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
Sverdlov, Serge; Thompson, Elizabeth (2016) Combinatorial Methods for Epistasis and Dominance. J Comput Biol :
Wijsman, Ellen M (2016) Family-based approaches: design, imputation, analysis, and beyond. BMC Genet 17 Suppl 2:9
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
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
Glazner, Chris; Thompson, Elizabeth (2015) Pedigree-Free Descent-Based Gene Mapping from Population Samples. Hum Hered 80:21-35
Nato Jr, Alejandro Q; Chapman, Nicola H; Sohi, Harkirat K et al. (2015) PBAP: a pipeline for file processing and quality control of pedigree data with dense genetic markers. Bioinformatics 31:3790-8
Blue, Elizabeth M; Sun, Lei; Tintle, Nathan L et al. (2014) Value of Mendelian laws of segregation in families: data quality control, imputation, and beyond. Genet Epidemiol 38 Suppl 1:S21-8
Cheung, Charles Y K; Thompson, Elizabeth A; Wijsman, Ellen M (2014) Detection of Mendelian consistent genotyping errors in pedigrees. Genet Epidemiol 38:291-9
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

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