caa a22 4500 445861843 CHVBK 20180317145446.0 cr unu---uuuuu 170323e20110501xx s 000 0 eng 10.1007/s00439-011-0956-2 doi (NATIONALLICENCE)springer-10.1007/s00439-011-0956-2 Genetic analysis of biological pathway data through genomic randomization [Elektronische Daten] [Brian Yaspan, William Bush, Eric Torstenson, Deqiong Ma, Margaret Pericak-Vance, Marylyn Ritchie, James Sutcliffe, Jonathan Haines] Genome Wide Association Studies (GWAS) are a standard approach for large-scale common variation characterization and for identification of single loci predisposing to disease. However, due to issues of moderate sample sizes and particularly multiple testing correction, many variants of smaller effect size are not detected within a single allele analysis framework. Thus, small main effects and potential epistatic effects are not consistently observed in GWAS using standard analytical approaches that consider only single SNP alleles. Here, we propose unique methodology that aggregates variants of interest (for example, genes in a biological pathway) using GWAS results. Multiple testing and type I error concerns are minimized using empirical genomic randomization to estimate significance. Randomization corrects for common pathway-based analysis biases, such as SNP coverage and density, linkage disequilibrium, gene size and pathway size. Pathway Analysis by Randomization Incorporating Structure (PARIS) applies this randomization and in doing so directly accounts for linkage disequilibrium effects. PARIS is independent of association analysis method and is thus applicable to GWAS datasets of all study designs. Using the KEGG database as an example, we apply PARIS to the publicly available Autism Genetic Resource Exchange GWAS dataset, revealing pathways with a significant enrichment of positive association results. Springer-Verlag, 2011 Yaspan Brian Center for Human Genetics Research, Vanderbilt University Medical Center, 37232, Nashville, TN, USA aut Bush William Center for Human Genetics Research, Vanderbilt University Medical Center, 37232, Nashville, TN, USA aut Torstenson Eric Center for Human Genetics Research, Vanderbilt University Medical Center, 37232, Nashville, TN, USA aut Ma Deqiong The John P. Hussman Institute for Human Genomics, University of Miami, 33101, Miami, FL, USA aut Pericak-Vance Margaret The John P. Hussman Institute for Human Genomics, University of Miami, 33101, Miami, FL, USA aut Ritchie Marylyn Center for Human Genetics Research, Vanderbilt University Medical Center, 37232, Nashville, TN, USA aut Sutcliffe James Center for Human Genetics Research, Vanderbilt University Medical Center, 37232, Nashville, TN, USA aut Haines Jonathan Center for Human Genetics Research, Vanderbilt University Medical Center, 37232, Nashville, TN, USA aut Human Genetics Springer-Verlag 129/5(2011-05-01), 563-571 0340-6717 129:5<563 2011 129 439 https://doi.org/10.1007/s00439-011-0956-2 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00439-011-0956-2 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Yaspan Brian Center for Human Genetics Research, Vanderbilt University Medical Center, 37232, Nashville, TN, USA aut NATIONALLICENCE 700 1- Bush William Center for Human Genetics Research, Vanderbilt University Medical Center, 37232, Nashville, TN, USA aut NATIONALLICENCE 700 1- Torstenson Eric Center for Human Genetics Research, Vanderbilt University Medical Center, 37232, Nashville, TN, USA aut NATIONALLICENCE 700 1- Ma Deqiong The John P. Hussman Institute for Human Genomics, University of Miami, 33101, Miami, FL, USA aut NATIONALLICENCE 700 1- Pericak-Vance Margaret The John P. Hussman Institute for Human Genomics, University of Miami, 33101, Miami, FL, USA aut NATIONALLICENCE 700 1- Ritchie Marylyn Center for Human Genetics Research, Vanderbilt University Medical Center, 37232, Nashville, TN, USA aut NATIONALLICENCE 700 1- Sutcliffe James Center for Human Genetics Research, Vanderbilt University Medical Center, 37232, Nashville, TN, USA aut NATIONALLICENCE 700 1- Haines Jonathan Center for Human Genetics Research, Vanderbilt University Medical Center, 37232, Nashville, TN, USA aut NATIONALLICENCE 773 0- Human Genetics Springer-Verlag 129/5(2011-05-01), 563-571 0340-6717 129:5<563 2011 129 439 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer