Genome-wide association studies (GWAS) have mapped thousands of common trait-influencing variants yet the overwhelming majority of trait loci have yet to be discovered. The goal of this proposal is to develop and apply statistical approaches that move beyond the standard GWAS paradigm to map additional trait-influencing variation within the human genome. Most of our proposed tools are based on a flexible high-dimensional framework called kernel machine regression, which we have had past success employing for powerful gene mapping of complex traits in GWAS and next-generation sequencing (NGS) studies. We believe the inherent flexibility of the kernel framework makes it ideal for exploring new paradigms in gene mapping of complex human traits.
Aim 1 proposes novel kernel methods for integrated analysis of both single-nucleotide variation data (derived from GWAS and/or NGS) and genomic data (such as gene-expression and methylation patterns) that we believe will provide improved power for trait mapping.
Aim 2 proposes novel kernel methods for large scale gene-gene interaction analysis across the genome, as well as a computational approach that enables efficient adjustment for multiple testing when applying such exhaustive testing procedures.
Aim 3 establishes novel kernel methods for association mapping of SNVs on the X chromosome. The flexible nature of kernel machines makes it ideal for modeling potential sex-specific effects on this chromosome and the methods further can accommodate random X inactivation.
Aim 4 proposes novel kernel approach for robust analysis of rare trait-influencing variation within families;such family-based designs are generally not considered in current rare-variant procedures. We will evaluate these methods on large-scale datasets that we are actively involved in and will implement the methods in user-friendly software for public distribution (Aim 5).

Public Health Relevance

The goal of this project is to develop novel and powerful statistical tools for identifying genetic loci acting independently or in conjunction with other genetic/environmental factors to influence complex human diseases or disease-related quantitative traits. Application of the proposed methods to applied datasets should improve our understanding of the genetic origins of complex traits and enhance existing risk-prediction models of complex disease.

National Institute of Health (NIH)
National Human Genome Research Institute (NHGRI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Brooks, Lisa
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Emory University
Schools of Medicine
United States
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Zhan, Xiang; Girirajan, Santhosh; Zhao, Ni et al. (2016) A novel copy number variants kernel association test with application to autism spectrum disorders studies. Bioinformatics 32:3603-3610
Broadaway, K Alaine; Cutler, David J; Duncan, Richard et al. (2016) A Statistical Approach for Testing Cross-Phenotype Effects of Rare Variants. Am J Hum Genet 98:525-40
He, Qianchuan; Cai, Tianxi; Liu, Yang et al. (2016) Prioritizing individual genetic variants after kernel machine testing using variable selection. Genet Epidemiol 40:722-731
Broadaway, K Alaine; Duncan, Richard; Conneely, Karen N et al. (2015) Kernel Approach for Modeling Interaction Effects in Genetic Association Studies of Complex Quantitative Traits. Genet Epidemiol 39:366-75
Urrutia, Eugene; Lee, Seunggeun; Maity, Arnab et al. (2015) Rare variant testing across methods and thresholds using the multi-kernel sequence kernel association test (MK-SKAT). Stat Interface 8:495-505
Epstein, Michael P; Duncan, Richard; Ware, Erin B et al. (2015) A statistical approach for rare-variant association testing in affected sibships. Am J Hum Genet 96:543-54
Zhao, Ni; Chen, Jun; Carroll, Ian M et al. (2015) Testing in Microbiome-Profiling Studies with MiRKAT, the Microbiome Regression-Based Kernel Association Test. Am J Hum Genet 96:797-807
Jiang, Yu; Satten, Glen A; Han, Yujun et al. (2014) Utilizing population controls in rare-variant case-parent association tests. Am J Hum Genet 94:845-53
Wang, Xin; Epstein, Michael P; Tzeng, Jung-Ying (2014) Analysis of gene-gene interactions using gene-trait similarity regression. Hum Hered 78:17-26
Jiang, Yunxuan; Conneely, Karen N; Epstein, Michael P (2014) Flexible and robust methods for rare-variant testing of quantitative traits in trios and nuclear families. Genet Epidemiol 38:542-51

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