title: Phenome-wide association studies demonstrating pleiotropy of genetic variants within FTO with and without adjustment for body mass index.
abstract: Phenome-wide association studies (PheWAS) have demonstrated utility in validating genetic associations derived from traditional genetic studies as well as identifying novel genetic associations. Here we used an electronic health record (EHR)-based PheWAS to explore pleiotropy of genetic variants in the fat mass and obesity associated gene (FTO), some of which have been previously associated with obesity and type 2 diabetes (T2D). We used a population of 10,487 individuals of European ancestry with genome-wide genotyping from the Electronic Medical Records and Genomics (eMERGE) Network and another population of 13,711 individuals of European ancestry from the BioVU DNA biobank at Vanderbilt genotyped using Illumina HumanExome BeadChip. A meta-analysis of the two study populations replicated the well-described associations between FTO variants and obesity (odds ratio [OR] = 1.25, 95% Confidence Interval = 1.11-1.24, p = 2.10 × 10(-9)) and FTO variants and T2D (OR = 1.14, 95% CI = 1.08-1.21, p = 2.34 × 10(-6)). The meta-analysis also demonstrated that FTO variant rs8050136 was significantly associated with sleep apnea (OR = 1.14, 95% CI = 1.07-1.22, p = 3.33 × 10(-5)); however, the association was attenuated after adjustment for body mass index (BMI). Novel phenotype associations with obesity-associated FTO variants included fibrocystic breast disease (rs9941349, OR = 0.81, 95% CI = 0.74-0.91, p = 5.41 × 10(-5)) and trends toward associations with non-alcoholic liver disease and gram-positive bacterial infections. FTO variants not associated with obesity demonstrated other potential disease associations including non-inflammatory disorders of the cervix and chronic periodontitis. These results suggest that genetic variants in FTO may have pleiotropic associations, some of which are not mediated by obesity.
authors.affiliation: Department of Medicine, Vanderbilt University Nashville, TN, USA ; Department of Biomedical Informatics, Vanderbilt University Nashville, TN, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Cronin
authors.affiliation: Office of Research, Vanderbilt University Nashville, TN, USA.
authors.forename: Julie R
authors.initials: JR
authors.lastname: Field
authors.affiliation: Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University Nashville, TN, USA.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Bradford
authors.affiliation: Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University Nashville, TN, USA.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Shaffer
authors.affiliation: Department of Medicine, Vanderbilt University Nashville, TN, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Carroll
authors.affiliation: Department of Medicine, Vanderbilt University Nashville, TN, USA ; Department of Pharmacology, Vanderbilt University Nashville, TN, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Mosley
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University Nashville, TN, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Bastarache
authors.affiliation: Vanderbilt Epidemiology Center, Vanderbilt University Nashville, TN, USA.
authors.forename: Todd L
authors.initials: TL
authors.lastname: Edwards
authors.affiliation: Center for Human Genetics, Marshfield Clinic Research Foundation Marshfield, WI, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Hebbring
authors.affiliation: Biomedical Informatics Research Center, Marshfield Clinic Research Foundation Marshfield, WI, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Lin
authors.affiliation: Division of Genomic Medicine, National Human Genome Research Institute Bethesda, MD, USA.
authors.forename: Lucia A
authors.initials: LA
authors.lastname: Hindorff
authors.affiliation: Department of Medicine, University of Washington Seattle, WA, USA.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Crane
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Systems Genomics, The Pennsylvania State University University Park, PA, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Pendergrass
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Systems Genomics, The Pennsylvania State University University Park, PA, USA.
authors.forename: Marylyn D
authors.initials: MD
authors.lastname: Ritchie
authors.affiliation: Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University Nashville, TN, USA.
authors.forename: Dana C
authors.initials: DC
authors.lastname: Crawford
authors.affiliation: Divisions of Biomedical Informatics and Statistics, Mayo Clinic Rochester, MN, USA.
authors.forename: Jyotishman
authors.initials: J
authors.lastname: Pathak
authors.affiliation: Division of Epidemiology, Mayo Clinic Rochester, MN, USA.
authors.forename: Suzette J
authors.initials: SJ
authors.lastname: Bielinski
authors.affiliation: Group Health Research Institute Seattle, WA, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Carrell
authors.affiliation: Department of Genome Sciences, University of Washington Seattle, WA, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Crosslin
authors.affiliation: Genomic Medicine Institute, Geisinger Health System Danville, PA, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Ledbetter
authors.affiliation: Weis Center for Research, Geisinger Health System Danville, PA, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Carey
authors.affiliation: Weis Center for Research, Geisinger Health System Danville, PA, USA.
authors.forename: Gerard
authors.initials: G
authors.lastname: Tromp
authors.affiliation: Genomic Medicine Institute, Geisinger Health System Danville, PA, USA.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Williams
authors.affiliation: Group Health Research Institute Seattle, WA, USA.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Larson
authors.affiliation: Department of Medicine, University of Washington Seattle, WA, USA ; Department of Genome Sciences, University of Washington Seattle, WA, USA.
authors.forename: Gail P
authors.initials: GP
authors.lastname: Jarvik
authors.affiliation: Biomedical Informatics Research Center, Marshfield Clinic Research Foundation Marshfield, WI, USA.
authors.forename: Peggy L
authors.initials: PL
authors.lastname: Peissig
authors.affiliation: Center for Human Genetics, Marshfield Clinic Research Foundation Marshfield, WI, USA.
authors.forename: Murray H
authors.initials: MH
authors.lastname: Brilliant
authors.affiliation: Essentia Institute of Rural Health Duluth, MN, USA.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: McCarty
authors.affiliation: Divisions of Biomedical Informatics and Statistics, Mayo Clinic Rochester, MN, USA.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Chute
authors.affiliation: Division of Cardiovascular Diseases, Mayo Clinic Rochester, MN, USA.
authors.forename: Iftikhar J
authors.initials: IJ
authors.lastname: Kullo
authors.affiliation: The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai New York, NY, USA.
authors.forename: Erwin
authors.initials: E
authors.lastname: Bottinger
authors.affiliation: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University Evanston, IL, USA.
authors.forename: Rex
authors.initials: R
authors.lastname: Chisholm
authors.affiliation: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University Evanston, IL, USA.
authors.forename: Maureen E
authors.initials: ME
authors.lastname: Smith
authors.affiliation: Department of Medicine, Vanderbilt University Nashville, TN, USA ; Department of Pharmacology, Vanderbilt University Nashville, TN, USA.
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.affiliation: Department of Medicine, Vanderbilt University Nashville, TN, USA ; Department of Biomedical Informatics, Vanderbilt University Nashville, TN, USA.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Denny
keywords: BMI; Exome chip; FTO; PheWAS; genetic association; pleiotropy