All SNPs are not created equal: genome-wide association studies reveal a consistent pattern of enrichment among functionally annotated SNPs

Schork, Andrew J., Thompson, Wesley K., Pham, Phillip, Torkamani, Ali, Roddey, J. Cooper, Sullivan, Patrick F., Kelsoe, John R., O'Donovan, Michael C., Furberg, Helena, The Tobacco and Genetics Consortium, The Bipolar Disorder Psychiatric Genomics Consortium, The Schizophrenia Psychiatric Genomics Consortium, Schork, Nicholas J., Andreassen, Ole A., Dale, Anders M., McGrath, John J., Mowry, Bryan and Visscher, Peter (2013) All SNPs are not created equal: genome-wide association studies reveal a consistent pattern of enrichment among functionally annotated SNPs. PloS Genetics, 9 4: . doi:10.1371/journal.pgen.1003449

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Author Schork, Andrew J.
Thompson, Wesley K.
Pham, Phillip
Torkamani, Ali
Roddey, J. Cooper
Sullivan, Patrick F.
Kelsoe, John R.
O'Donovan, Michael C.
Furberg, Helena
The Tobacco and Genetics Consortium
The Bipolar Disorder Psychiatric Genomics Consortium
The Schizophrenia Psychiatric Genomics Consortium
Schork, Nicholas J.
Andreassen, Ole A.
Dale, Anders M.
McGrath, John J.
Mowry, Bryan
Visscher, Peter
Total Author Count Override 392
Title All SNPs are not created equal: genome-wide association studies reveal a consistent pattern of enrichment among functionally annotated SNPs
Journal name PloS Genetics   Check publisher's open access policy
ISSN 1553-7404
Publication date 2013-04-25
Year available 2013
Sub-type Article (original research)
DOI 10.1371/journal.pgen.1003449
Open Access Status DOI
Volume 9
Issue 4
Total pages 13
Place of publication San Francisco, United States
Publisher Public Library of Science
Collection year 2014
Language eng
Abstract Recent results indicate that genome-wide association studies (GWAS) have the potential to explain much of the heritability of common complex phenotypes, but methods are lacking to reliably identify the remaining associated single nucleotide polymorphisms (SNPs). We applied stratified False Discovery Rate (sFDR) methods to leverage genic enrichment in GWAS summary statistics data to uncover new loci likely to replicate in independent samples. Specifically, we use linkage disequilibrium-weighted annotations for each SNP in combination with nominal p-values to estimate the True Discovery Rate (TDR = 1−FDR) for strata determined by different genic categories. We show a consistent pattern of enrichment of polygenic effects in specific annotation categories across diverse phenotypes, with the greatest enrichment for SNPs tagging regulatory and coding genic elements, little enrichment in introns, and negative enrichment for intergenic SNPs. Stratified enrichment directly leads to increased TDR for a given p-value, mirrored by increased replication rates in independent samples. We show this in independent Crohn's disease GWAS, where we find a hundredfold variation in replication rate across genic categories. Applying a well-established sFDR methodology we demonstrate the utility of stratification for improving power of GWAS in complex phenotypes, with increased rejection rates from 20% in height to 300% in schizophrenia with traditional FDR and sFDR both fixed at 0.05. Our analyses demonstrate an inherent stratification among GWAS SNPs with important conceptual implications that can be leveraged by statistical methods to improve the discovery of loci.
Keyword False discovery rate
Complex traits
Genetic-variants
Common Snps
Loci
Diseases
Susceptibility
Heritability
Architecture
Individuals
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Faculty of Health and Behavioural Sciences -- Publications
Queensland Brain Institute Publications
Official 2014 Collection
 
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Citation counts: TR Web of Science Citation Count  Cited 70 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 76 times in Scopus Article | Citations
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