title: Integrative approaches for large-scale transcriptome-wide association studies.
abstract: Many genetic variants influence complex traits by modulating gene expression, thus altering the abundance of one or multiple proteins. Here we introduce a powerful strategy that integrates gene expression measurements with summary association statistics from large-scale genome-wide association studies (GWAS) to identify genes whose cis-regulated expression is associated with complex traits. We leverage expression imputation from genetic data to perform a transcriptome-wide association study (TWAS) to identify significant expression-trait associations. We applied our approaches to expression data from blood and adipose tissue measured in ∼ 3,000 individuals overall. We imputed gene expression into GWAS data from over 900,000 phenotype measurements to identify 69 new genes significantly associated with obesity-related traits (BMI, lipids and height). Many of these genes are associated with relevant phenotypes in the Hybrid Mouse Diversity Panel. Our results showcase the power of integrating genotype, gene expression and phenotype to gain insights into the genetic basis of complex traits.
authors: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.|Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
authors: Alexander
authors: A
authors: Gusev
authors: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.|Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California, USA.
authors: Arthur
authors: http://orcid.org/0000-0002-1523-7225
authors: A
authors: Ko
authors: Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, California, USA.
authors: Huwenbo
authors: H
authors: Shi
authors: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.|Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
authors: Gaurav
authors: G
authors: Bhatia
authors: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
authors: Wonil
authors: http://orcid.org/0000-0002-5766-6247
authors: W
authors: Chung
authors: Department of Psychiatry, VU University Medical Center, Amsterdam, the Netherlands.
authors: Brenda W J H
authors: BW
authors: Penninx
authors: Department of Psychiatry, VU University Medical Center, Amsterdam, the Netherlands.
authors: Rick
authors: http://orcid.org/0000-0002-3333-6737
authors: R
authors: Jansen
authors: Department of Biological Psychology, VU University, Amsterdam, the Netherlands.
authors: Eco J C
authors: http://orcid.org/0000-0001-6022-2666
authors: EJ
authors: de Geus
authors: Department of Biological Psychology, VU University, Amsterdam, the Netherlands.
authors: Dorret I
authors: DI
authors: Boomsma
authors: Bioinformatics Research Center, Department of Statistics, Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina, USA.
authors: Fred A
authors: FA
authors: Wright
authors: Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.|Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina, USA.|Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: Patrick F
authors: PF
authors: Sullivan
authors: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
authors: Elina
authors: E
authors: Nikkola
authors: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
authors: Marcus
authors: M
authors: Alvarez
authors: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
authors: Mete
authors: M
authors: Civelek
authors: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.|Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
authors: Aldons J
authors: AJ
authors: Lusis
authors: Department of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, Tampere, Finland.
authors: Terho
authors: T
authors: Lehtimäki
authors: Department of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, Tampere, Finland.
authors: Emma
authors: E
authors: Raitoharju
authors: Department of Clinical Physiology, Pirkanmaa Hospital District and University of Tampere School of Medicine, Tampere, Finland.
authors: Mika
authors: M
authors: Kähönen
authors: Department of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, Tampere, Finland.
authors: Ilkka
authors: I
authors: Seppälä
authors: Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.|Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
authors: Olli T
authors: OT
authors: Raitakari
authors: Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
authors: Johanna
authors: J
authors: Kuusisto
authors: Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
authors: Markku
authors: M
authors: Laakso
authors: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.|Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
authors: Alkes L
authors: AL
authors: Price
authors: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.|Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California, USA.
authors: Päivi
authors: P
authors: Pajukanta
authors: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.|Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, California, USA.|Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
authors: Bogdan
authors: B
authors: Pasaniuc
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D051379:Mice; D009765:Obesity / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D040641:Quantitative Trait Loci / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics*