title: Nonlinear dimension reduction with Wright-Fisher kernel for genotype aggregation and association mapping.
abstract: BACKGROUND
  Association tests based on next-generation sequencing data are often under-powered due to the presence of rare variants and large amount of neutral or protective variants. A successful strategy is to aggregate genetic information within meaningful single-nucleotide polymorphism (SNP) sets, e.g. genes or pathways, and test association on SNP sets. Many existing methods for group-wise tests require specific assumptions about the direction of individual SNP effects and/or perform poorly in the presence of interactions.
  
  
  RESULTS
  We propose a joint association test strategy based on two key components: a nonlinear supervised dimension reduction approach for effective SNP information aggregation and a novel kernel specially designed for qualitative genotype data. The new test demonstrates superior performance in identifying causal genes over existing methods across a large variety of disease models simulated from sequence data of real genes. In general, the proposed method provides an association test strategy that can (i) detect both rare and common causal variants, (ii) deal with both additive and interaction effect, (iii) handle both quantitative traits and disease dichotomies and (iv) incorporate non-genetic covariates. In addition, the new kernel can potentially boost the power of the entire family of kernel-based methods for genetic data analysis.
  
  
  BACKGROUND
  The method is implemented in MATLAB. Source code is available upon request.
  
  
  BACKGROUND
  hongjie.zhu@duke.edu.
authors.affiliation: Department of Psychiatry and Behavior Science, Duke University, Durham, NC 27710, USA. hongjie.zhu@duke.edu
authors.forename: Hongjie
authors.initials: H
authors.lastname: Zhu
authors.forename: Lexin
authors.initials: L
authors.lastname: Li
authors.forename: Hua
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000465:Algorithms; D056726:Genetic Association Studies; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008390:Markov Chains; D020641:Polymorphism, Single Nucleotide