Multiple comparisons in genetic association studies: a hierarchical modeling approach

TitleMultiple comparisons in genetic association studies: a hierarchical modeling approach
Publication TypeJournal Article
Year of Publication2014
AuthorsYi N, Xu S, Lou X-Y, Mallick H
JournalStat Appl Genet Mol Biol
Volume13
Issue1
Pagination35-48
Date Published2014 Feb
ISSN1544-6115
KeywordsAdiponectin, Algorithms, Bayes Theorem, Case-Control Studies, Colorectal Neoplasms, Computer Simulation, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Heart Diseases, Humans, Linear Models, Linkage Disequilibrium, Models, Genetic, Polymorphism, Single Nucleotide, Risk, Software
Abstract

Multiple comparisons or multiple testing has been viewed as a thorny issue in genetic association studies aiming to detect disease-associated genetic variants from a large number of genotyped variants. We alleviate the problem of multiple comparisons by proposing a hierarchical modeling approach that is fundamentally different from the existing methods. The proposed hierarchical models simultaneously fit as many variables as possible and shrink unimportant effects towards zero. Thus, the hierarchical models yield more efficient estimates of parameters than the traditional methods that analyze genetic variants separately, and also coherently address the multiple comparisons problem due to largely reducing the effective number of genetic effects and the number of statistically "significant" effects. We develop a method for computing the effective number of genetic effects in hierarchical generalized linear models, and propose a new adjustment for multiple comparisons, the hierarchical Bonferroni correction, based on the effective number of genetic effects. Our approach not only increases the power to detect disease-associated variants but also controls the Type I error. We illustrate and evaluate our method with real and simulated data sets from genetic association studies. The method has been implemented in our freely available R package BhGLM (http://www.ssg.uab.edu/bhglm/).

DOI10.1515/sagmb-2012-0040
Alternate JournalStat Appl Genet Mol Biol
PubMed ID24259248
PubMed Central IDPMC5003626
Grant ListR01 DA025095 / DA / NIDA NIH HHS / United States
R01 GM069430 / GM / NIGMS NIH HHS / United States
5R01GM069430-08 / GM / NIGMS NIH HHS / United States
5R01DA025095 / DA / NIDA NIH HHS / United States