Methods for the Genetic Epidemiology of Complex Traits (GM-46255-17) Techniques will be developed for genetic analysis of complex diseases segregating in extended pedigrees of arbitrary 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 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. Improved methods will be developed for the MCMC analysis of gene descent in extended pedigrees, given data at a dense genome screen of markers, together with the use of these gene descent patterns in joint multilocus linkage and segregation analysis of complex traits. Models for discrete and quantitative trait phenotypes in these analyses will be extended to include epistasis and pleiotropy. MCMC-based likelihood-ratio methods for assessment of trait-model robustness will be incorporated into our toolkit. Further, methods will be developed for assessment of the statistical significance of linkage findings, including correction for multiple testing at linked genome locations. Conditional on marker data, trait-data resimulation and permutation will be used to develop measures of significance. Also, the conditional distributions of gene descent at marker locations will be used to provide both measures of significance and confidence sets for trait-locus locations. Methods will also be developed for the use of patterns of gene descent realized conditional on marker data in the analysis of genetic maps and marker models, including multi-SNP haplotypes and copy-number variants in these analyses. The impact of marker map and model uncertainty on linkage findings will be investigated. In using multiple dense SNPs as markers, methods for incorporating linkage disequilibrium (LD) into the analysis of family data will be developed. The impact of LD on MCMC-based methods of haplotype inference, estimation of identity by descent (ibd) over regions, and lod score analyses will be investigated. 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 or more localized multigene haplotypes. Finally, software will be developed that implements these methods, and will be documented and released for use by practitioners.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Method to Extend Research in Time (MERIT) Award (R37)
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Biostatistical Methods and Research Design Study Section (BMRD)
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Krasnewich, Donna M
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University of Washington
Biostatistics & Other Math Sci
Schools of Arts and Sciences
United States
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Saad, Mohamad; Wijsman, Ellen M (2014) Combining family- and population-based imputation data for association analysis of rare and common variants in large pedigrees. Genet Epidemiol 38:579-90
Saad, Mohamad; Wijsman, Ellen M (2014) Power of family-based association designs to detect rare variants in large pedigrees using imputed genotypes. Genet Epidemiol 38:1-9
Cheung, Charles Y K; Marchani Blue, Elizabeth; Wijsman, Ellen M (2014) A statistical framework to guide sequencing choices in pedigrees. Am J Hum Genet 94:257-67
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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
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
Kim, Sulgi; Saad, Mohamad; Tsuang, Debby W et al. (2014) Visualization of haplotype sharing patterns in pedigree samples. Hum Hered 78:1-8
Koepke, Hoyt; Thompson, Elizabeth (2013) Efficient identification of equivalences in dynamic graphs and pedigree structures. J Comput Biol 20:551-70

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