Covariate-modulated local false discovery rate for genome-wide association studies.
BACKGROUND
Genome-wide association studies (GWAS) have largely failed to identify most of the genetic basis of highly heritable diseases and complex traits. Recent work has suggested this could be because many genetic variants, each with individually small effects, compose their genetic architecture, limiting the power of GWAS, given currently obtainable sample sizes. In this scenario, Bonferroni-derived thresholds are severely underpowered to detect the vast majority of associations. Local false discovery rate (fdr) methods provide more power to detect non-null associations, but implicit assumptions about the exchangeability of single nucleotide polymorphisms (SNPs) limit their ability to discover non-null loci.


METHODS
We propose a novel covariate-modulated local false discovery rate (cmfdr) that incorporates prior information about gene element-based functional annotations of SNPs, so that SNPs from categories enriched for non-null associations have a lower fdr for a given value of a test statistic than SNPs in unenriched categories. This readjustment of fdr based on functional annotations is achieved empirically by fitting a covariate-modulated parametric two-group mixture model. The proposed cmfdr methodology is applied to a large Crohn's disease GWAS.


RESULTS
Use of cmfdr dramatically improves power, e.g. increasing the number of loci declared significant at the 0.05 fdr level by a factor of 5.4. We also demonstrate that SNPs were declared significant using cmfdr compared with usual fdr replicate in much higher numbers, while maintaining similar replication rates for a given fdr cutoff in de novo samples, using the eight Crohn's disease substudies as independent training and test datasets. Availability an implementation: https://sites.google.com/site/covmodfdr/


BACKGROUND
: wes.stat@gmail.com


BACKGROUND
Supplementary data are available at Bioinformatics online.
Computational Science Research Center, San Diego State University, San Diego, CA 92182, USA, Cognitive Sciences Graduate Program, University of California at San Diego, La Jolla, CA 92093, USA, Department of Mathematics and Statistics, San Diego State University, San Diego, CA 92182, USA, Institute of Clinical Medicine, University of Oslo, Oslo, 0424, Norway, Multimodal Imaging Laboratory and Department of Psychiatry, University of California at San Diego, La Jolla, CA 92093, USA.
Rong W
RW
Zablocki
Computational Science Research Center, San Diego State University, San Diego, CA 92182, USA, Cognitive Sciences Graduate Program, University of California at San Diego, La Jolla, CA 92093, USA, Department of Mathematics and Statistics, San Diego State University, San Diego, CA 92182, USA, Institute of Clinical Medicine, University of Oslo, Oslo, 0424, Norway, Multimodal Imaging Laboratory and Department of Psychiatry, University of California at San Diego, La Jolla, CA 92093, USA.
Andrew J
AJ
Schork
Computational Science Research Center, San Diego State University, San Diego, CA 92182, USA, Cognitive Sciences Graduate Program, University of California at San Diego, La Jolla, CA 92093, USA, Department of Mathematics and Statistics, San Diego State University, San Diego, CA 92182, USA, Institute of Clinical Medicine, University of Oslo, Oslo, 0424, Norway, Multimodal Imaging Laboratory and Department of Psychiatry, University of California at San Diego, La Jolla, CA 92093, USA.
Richard A
RA
Levine
Computational Science Research Center, San Diego State University, San Diego, CA 92182, USA, Cognitive Sciences Graduate Program, University of California at San Diego, La Jolla, CA 92093, USA, Department of Mathematics and Statistics, San Diego State University, San Diego, CA 92182, USA, Institute of Clinical Medicine, University of Oslo, Oslo, 0424, Norway, Multimodal Imaging Laboratory and Department of Psychiatry, University of California at San Diego, La Jolla, CA 92093, USA.
Ole A
OA
Andreassen
Computational Science Research Center, San Diego State University, San Diego, CA 92182, USA, Cognitive Sciences Graduate Program, University of California at San Diego, La Jolla, CA 92093, USA, Department of Mathematics and Statistics, San Diego State University, San Diego, CA 92182, USA, Institute of Clinical Medicine, University of Oslo, Oslo, 0424, Norway, Multimodal Imaging Laboratory and Department of Psychiatry, University of California at San Diego, La Jolla, CA 92093, USAComputational Science Research Center, San Diego State University, San Diego, CA 92182, USA, Cognitive Sciences Graduate Program, University of California at San Diego, La Jolla, CA 92093, USA, Department of Mathematics and Statistics, San Diego State University, San Diego, CA 92182, USA, Institute of Clinical Medicine, University of Oslo, Oslo, 0424, Norway, Multimodal Imaging Laboratory and Department of Psychiatry, University of California at San Diego, La Jolla, CA 92093, USAComputational Science Research Center, San Diego State University, San Diego, CA 92182, USA, Cognitive Sciences Graduate Program, University of California at San Diego, La Jolla, CA 92093, USA, Department of Mathematics and Statistics, San Diego State University, San Diego, CA 92182, USA, Institute of Clinical Medicine, University of Oslo, Oslo, 0424, Norway, Multimodal Imaging Laboratory and Department of Psychiatry, University of California at San Diego, La Jolla, CA 92093, USA.
Anders M
AM
Dale
Computational Science Research Center, San Diego State University, San Diego, CA 92182, USA, Cognitive Sciences Graduate Program, University of California at San Diego, La Jolla, CA 92093, USA, Department of Mathematics and Statistics, San Diego State University, San Diego, CA 92182, USA, Institute of Clinical Medicine, University of Oslo, Oslo, 0424, Norway, Multimodal Imaging Laboratory and Department of Psychiatry, University of California at San Diego, La Jolla, CA 92093, USA.
Wesley K
WK
Thompson
D000704:Analysis of Variance; D001499:Bayes Theorem; D019295:Computational Biology / Q000379:methods*; D005189:False Positive Reactions; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D020641:Polymorphism, Single Nucleotide