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PMID: 24270849 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data.

Nature biotechnology ·Vol. 31 ·No. 12 ·2013-12-00 ·Pages 1102-10

Denny JC, Bastarache L, Ritchie MD, Carroll RJ, Zink R, Mosley JD, Field JR, Pulley JM, Ramirez AH, Bowton E, Basford MA, Carrell DS, Peissig PL, Kho AN, Pacheco JA, Rasmussen LV, Crosslin DR, Crane PK, Pathak J, Bielinski SJ, Pendergrass SA, Xu H, Hindorff LA, Li R, Manolio TA, Chute CG, Chisholm RL, Larson EB, Jarvik GP, Brilliant MH, McCarty CA, Kullo IJ, Haines JL, Crawford DC, Masys DR, Roden DM

Abstract

Candidate gene and genome-wide association studies (GWAS) have identified genetic variants that modulate risk for human disease; many of these associations require further study to replicate the results. Here we report the first large-scale application of the phenome-wide association study (PheWAS) paradigm within electronic medical records (EMRs), an unbiased approach to replication and discovery that interrogates relationships between targeted genotypes and multiple phenotypes. We scanned for associations between 3,144 single-nucleotide polymorphisms (previously implicated by GWAS as mediators of human traits) and 1,358 EMR-derived phenotypes in 13,835 individuals of European ancestry. This PheWAS replicated 66% (51/77) of sufficiently powered prior GWAS associations and revealed 63 potentially pleiotropic associations with P < 4.6 × 10⁻⁶ (false discovery rate < 0.1); the strongest of these novel associations were replicated in an independent cohort (n = 7,406). These findings validate PheWAS as a tool to allow unbiased interrogation across multiple phenotypes in EMR-based cohorts and to enhance analysis of the genomic basis of human disease.

MeSH Terms
Chromosome Mapping/methods Data Mining/methods Electronic Health Records/statistics & numerical data Genetic Predisposition to Disease/epidemiology,genetics Genome-Wide Association Study/methods,statistics & numerical data Humans Medical Record Linkage/methods Phenotype Polymorphism, Single Nucleotide/genetics
Authors & Affiliations
36 authors, click to expand affiliations / ORCID
Denny Joshua C
Bastarache Lisa
Ritchie Marylyn D
Carroll Robert J
Zink Raquel
Mosley Jonathan D
Field Julie R
Pulley Jill M
Ramirez Andrea H
Bowton Erica
Basford Melissa A
Carrell David S
Peissig Peggy L
Kho Abel N
Pacheco Jennifer A
Rasmussen Luke V
Crosslin David R
Crane Paul K
Pathak Jyotishman
Bielinski Suzette J
Pendergrass Sarah A
Xu Hua
Hindorff Lucia A
Li Rongling
Manolio Teri A
Chute Christopher G
Chisholm Rex L
Larson Eric B
Jarvik Gail P
Brilliant Murray H
McCarty Catherine A
Kullo Iftikhar J
Haines Jonathan L
Crawford Dana C
Masys Daniel R
Roden Dan M
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Article Info
Journal
Nature biotechnology
Abbr.
Nat Biotechnol
ISSN
1546-1696
DOI
10.1038/nbt.2749
Published
2013-12-00
Pages
1102-10
Language
English
Region
United States
NLM ID
9604648
PMCID
PMC3969265
Subset
IM
Grants
NHGRI NIH HHS · U01-HG004424 · United States
NHGRI NIH HHS · U01-HG004610 · United States
NHGRI NIH HHS · U01-HG006389 · United States
NHGRI NIH HHS · U01-HG006385 · United States
NHGRI NIH HHS · U01 HG004603 · United States
NHGRI NIH HHS · U01 HG004424 · United States
NIGMS NIH HHS · RC2-GM092318 · United States
NHGRI NIH HHS · U01 HG004608 · United States
NHGRI NIH HHS · U01-HG004603 · United States
NHGRI NIH HHS · U01-HG004599 · United States
NHGRI NIH HHS · U01 HG006385 · United States
NCATS NIH HHS · UL1 TR000445 · United States
NHGRI NIH HHS · U01-HG006379 · United States
NHGRI NIH HHS · U01 HG006375 · United States
NHGRI NIH HHS · U01 HG004438 · United States
NCATS NIH HHS · UL1 TR000150 · United States
NHGRI NIH HHS · U01-HG006388 · United States
NCATS NIH HHS · UL1 TR000427 · United States
NHGRI NIH HHS · U01-HG006375 · United States
NIGMS NIH HHS · T32 GM007569 · United States
NHGRI NIH HHS · U01-HG004608 · United States
NLM NIH HHS · T15 LM007450 · United States
NLM NIH HHS · R01-LM010685 · United States
NCATS NIH HHS · 2 UL1 TR000445 · United States
NLM NIH HHS · R01 LM010685 · United States
NHGRI NIH HHS · U01 HG004609 · United States
NHGRI NIH HHS · U01 HG006389 · United States
NHGRI NIH HHS · U01 HG004599 · United States
American Heart Association-American Stroke Association · 16FTF30130005 · United States
NCI NIH HHS · P30 CA060553 · United States
NCATS NIH HHS · UL1TR000427 · United States
NHGRI NIH HHS · U01 HG006388 · United States
NHGRI NIH HHS · U01-HG006378 · United States
NHGRI NIH HHS · U01 HG006378 · United States
NHGRI NIH HHS · U01-HG004609 · United States
NIGMS NIH HHS · R01 GM105688 · United States
NHGRI NIH HHS · U01 HG004610 · United States
NCRR NIH HHS · UL1 RR024975 · United States
NHGRI NIH HHS · U01 HG006379 · United States
NHGRI NIH HHS · U01-HG004438 · United States
Databases
dbGaP
PHS000360
Corrections
CommentIn
PMID: 24316646
CommentIn
PMID: 24322724
CommentIn
PMID: 25850054
External Links
PubMed source DOI: 10.1038/nbt.2749 PMC Full Text View journal details
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