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PMID: 26258848 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

A gene-based association method for mapping traits using reference transcriptome data.

Nature genetics ·Vol. 47 ·No. 9 ·2015-09-00 ·Pages 1091-8

Gamazon ER, Wheeler HE, Shah KP, Mozaffari SV, Aquino-Michaels K, Carroll RJ, Eyler AE, Denny JC, GTEx Consortium, Nicolae DL, Cox NJ, Im HK

Abstract

Genome-wide association studies (GWAS) have identified thousands of variants robustly associated with complex traits. However, the biological mechanisms underlying these associations are, in general, not well understood. We propose a gene-based association method called PrediXcan that directly tests the molecular mechanisms through which genetic variation affects phenotype. The approach estimates the component of gene expression determined by an individual's genetic profile and correlates 'imputed' gene expression with the phenotype under investigation to identify genes involved in the etiology of the phenotype. Genetically regulated gene expression is estimated using whole-genome tissue-dependent prediction models trained with reference transcriptome data sets. PrediXcan enjoys the benefits of gene-based approaches such as reduced multiple-testing burden and a principled approach to the design of follow-up experiments. Our results demonstrate that PrediXcan can detect known and new genes associated with disease traits and provide insights into the mechanism of these associations.

MeSH Terms
Chromosome Mapping Gene Expression Profiling Genetic Predisposition to Disease Genome-Wide Association Study/methods Humans Phenotype Polymorphism, Single Nucleotide
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Gamazon Eric R ORCID
Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, USA. | Division of Genetic Medicine, Vanderbilt University, Nashville, Tennessee, USA.
Wheeler Heather E ORCID
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois, USA.
Shah Kaanan P
Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, USA.
Mozaffari Sahar V
Department of Human Genetics, University of Chicago, Chicago, Illinois, USA.
Aquino-Michaels Keston
Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, USA.
Carroll Robert J
Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee, USA.
Eyler Anne E
Rheumatology Center, NorthCrest Medical Center, Springfield, Tennessee, USA.
Denny Joshua C
Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee, USA.
GTEx Consortium
Nicolae Dan L
Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, USA. | Department of Human Genetics, University of Chicago, Chicago, Illinois, USA. | Department of Statistics, University of Chicago, Chicago, Illinois, USA.
Cox Nancy J
Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, USA. | Division of Genetic Medicine, Vanderbilt University, Nashville, Tennessee, USA. | Department of Human Genetics, University of Chicago, Chicago, Illinois, USA.
Im Hae Kyung ORCID
Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, USA.
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.3367
Published
2015-09-00
Epub
2015-00-10
Pages
1091-8
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC4552594
Subset
IM
Grants
NCATS NIH HHS · UL1 TR000430 · United States
NCI NIH HHS · F32 CA165823 · United States
NIGMS NIH HHS · U01 GM061393 · United States
NCI NIH HHS · K12 CA139160 · United States
NIMH NIH HHS · R01 MH107666 · United States
NHLBI NIH HHS · U19 HL065962 · United States
NIMH NIH HHS · P50 MH094267 · United States
NIDDK NIH HHS · P60 DK20595 · United States
NCI NIH HHS · T32 CA009594 · United States
NIGMS NIH HHS · U01 GM092691 · United States
NIGMS NIH HHS · U01 GM61393 · United States
NIMH NIH HHS · T32 MH020065 · United States
NIDDK NIH HHS · P30 DK20595 · United States
NIMH NIH HHS · R01 MH101820 · United States
NIGMS NIH HHS · T32 GM007197 · United States
NIDA NIH HHS · P50 DA037844 · United States
NIMH NIH HHS · R01 MH090937 · United States
NIDDK NIH HHS · P30 DK020595 · United States
NIDDK NIH HHS · P60 DK020595 · United States
External Links
PubMed source DOI: 10.1038/ng.3367 PMC Full Text View journal details
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