An investigation of the genetic and environmental architecture of complex phenotypes, through an evaluation of a series of hypotheses pertaining to the interrelationships among the variables, constitutes the long-term goal of this (re-revised) proposal. This involves the development and evaluation of novel methods for evaluating the underlying hypotheses. Towards this end, the specific aims cover methodological issues in linkage and association analysis, dense SNP scans and haplotype methods, novel methods for taking advantage of gene-gene (GxG) and gene-environment (GxE) interactions, and novel sequential methods for bypassing the issue of multiple comparisons. Summer workshops will be held which include presentations on the methods and """"""""products"""""""" we develop(ed), hands-on computer lab sessions on the use of the products, and brain-storming sessions on the merits and pitfalls of these and other methods/products. All software developed will be freely distributed. The proposed research includes the development and evaluation of statistical methods for the analysis of phenotypic and genotypic data: timely and promising extensions of the variance components linkage models in SEGPATH to incorporate temporal trends in linkage analysis (to capture age-dependent genetic effects), parent-of-origin and imprinting effects, and LD and TDT-like methods; an assessment of the promise of dense SNP scans in candidate genes along with the analysts issues associated with them, theoretical challenges posed by the construction of haplotype maps, ambiguity of block boundaries arising on account of the ambiguity about the makeup of haplotype blocks, and the role of HapMap in mapping complex disease genes; novel methods for finding genes in the presence of GxG and GxE interactions in terms of """"""""tree linkage""""""""; and novel sequential methods for analysis of genome-wide linkage scans and association scans, with particular emphasis on tight control of false positives. Our direct access to several large collaborative family data sets, which have been phenotypically and genotypically well characterized, offers ample opportunity for testing the real utility of these methods. We believe that the proposed research will make a significant contribution to genetic epidemiology.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM028719-24A2
Application #
6923264
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Anderson, Richard A
Project Start
1980-06-01
Project End
2009-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
24
Fiscal Year
2005
Total Cost
$275,400
Indirect Cost
Name
Washington University
Department
Biostatistics & Other Math Sci
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Simino, Jeannette; Shi, Gang; Weder, Alan et al. (2014) Body mass index modulates blood pressure heritability: the Family Blood Pressure Program. Am J Hypertens 27:610-9
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Rice, Treva K; Sarzynski, Mark A; Sung, Yun Ju et al. (2012) Fine mapping of a QTL on chromosome 13 for submaximal exercise capacity training response: the HERITAGE Family Study. Eur J Appl Physiol 112:2969-78
Sun, Yan V; Sung, Yun Ju; Tintle, Nathan et al. (2011) Identification of genetic association of multiple rare variants using collapsing methods. Genet Epidemiol 35 Suppl 1:S101-6
Shi, Gang; Boerwinkle, Eric; Morrison, Alanna C et al. (2011) Mining gold dust under the genome wide significance level: a two-stage approach to analysis of GWAS. Genet Epidemiol 35:111-8
Shi, Gang; Gu, Chi C; Kraja, Aldi T et al. (2009) Genetic effect on blood pressure is modulated by age: the Hypertension Genetic Epidemiology Network Study. Hypertension 53:35-41
Neuman, Rosalind J; Sung, Yun Ju (2009) Multistage analysis strategies for genome-wide association studies: summary of group 3 contributions to Genetic Analysis Workshop 16. Genet Epidemiol 33 Suppl 1:S19-23
Rice, Treva K (2008) Familial resemblance and heritability. Adv Genet 60:35-49

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