All SNPs Are Not Created Equal: Genome-Wide Association Studies Reveal a Consistent Pattern of Enrichment among Functionally Annotated SNPs

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...

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Main Authors:	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, Schork, Nicholas J., Andreassen, Ole A., Dale, Anders M.
Format:	Online
Language:	English
Published:	Public Library of Science 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3636284/

id	pubmed-3636284
recordtype	oai_dc
spelling	pubmed-36362842013-05-01 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 Schork, Nicholas J. Andreassen, Ole A. Dale, Anders M. Research Article 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. Public Library of Science 2013-04-25 /pmc/articles/PMC3636284/ /pubmed/23637621 http://dx.doi.org/10.1371/journal.pgen.1003449 Text en © 2013 Schork et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
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 Schork, Nicholas J. Andreassen, Ole A. Dale, Anders M.
spellingShingle	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 Schork, Nicholas J. Andreassen, Ole A. Dale, Anders M. All SNPs Are Not Created Equal: Genome-Wide Association Studies Reveal a Consistent Pattern of Enrichment among Functionally Annotated SNPs
author_facet	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 Schork, Nicholas J. Andreassen, Ole A. Dale, Anders M.
author_sort	Schork, Andrew J.
title	All SNPs Are Not Created Equal: Genome-Wide Association Studies Reveal a Consistent Pattern of Enrichment among Functionally Annotated SNPs
title_short	All SNPs Are Not Created Equal: Genome-Wide Association Studies Reveal a Consistent Pattern of Enrichment among Functionally Annotated SNPs
title_full	All SNPs Are Not Created Equal: Genome-Wide Association Studies Reveal a Consistent Pattern of Enrichment among Functionally Annotated SNPs
title_fullStr	All SNPs Are Not Created Equal: Genome-Wide Association Studies Reveal a Consistent Pattern of Enrichment among Functionally Annotated SNPs
title_full_unstemmed	All SNPs Are Not Created Equal: Genome-Wide Association Studies Reveal a Consistent Pattern of Enrichment among Functionally Annotated SNPs
title_sort	all snps are not created equal: genome-wide association studies reveal a consistent pattern of enrichment among functionally annotated snps
description	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.
publisher	Public Library of Science
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3636284/
_version_	1611972732901130240

All SNPs Are Not Created Equal: Genome-Wide Association Studies Reveal a Consistent Pattern of Enrichment among Functionally Annotated SNPs

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