The Restricted Partition Method

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Abstract

For many complex traits, the bulk of the phenotypic variation attributable to genetic factors remains unexplained, even after well-powered genome-wide association studies. Among the multiple possible explanations for the "missing" variance, joint effects of multiple genetic variants are a particularly appealing target for investigation: they are well documented in biology and can often be evaluated using existing data. The first two sections of this chapter discusses these and other concerns that led to the development of the Restricted Partition Method (RPM).The RPM is an exploratory tool designed to investigate, in a model agnostic manner, joint effects of genetic and environmental factors contributing to quantitative or dichotomous phenotypes. The method partitions multilocus genotypes (or genotype-environmental exposure classes) into statistically distinct "risk" groups, then evaluates the resulting model for phenotypic variance explained. It is sensitive to factors whose effects are apparent only in a joint analysis, and which would therefore be missed by many other methods. The third section of the chapter provides details of the RPM algorithm and walks the reader through an example.The final sections of the chapter discuss practical issues related to the use of the method. Because exhaustive pairwise or higher order analyses of many SNPs are computationally burdensome, much of the discussion focuses on computational issues. The RPM proved to be practical for a large candidate gene analysis, consisting of over 40,000 SNPs, using a desktop computer. Because the algorithm and software lend themselves to distributed processing, larger analyses can easily be split among multiple computers.

Original languageEnglish
Pages (from-to)117-139
Number of pages23
JournalAdvances in Genetics
Volume72
Issue numberC
DOIs
StatePublished - 2010

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