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Front Genet. 2014 Aug 5;5:250. doi: 10.3389/fgene.2014.00250. eCollection 2014.

Phenome-wide association studies demonstrating pleiotropy of genetic variants within FTO with and without adjustment for body mass index.

Author information

1
Department of Medicine, Vanderbilt University Nashville, TN, USA ; Department of Biomedical Informatics, Vanderbilt University Nashville, TN, USA.
2
Office of Research, Vanderbilt University Nashville, TN, USA.
3
Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University Nashville, TN, USA.
4
Department of Medicine, Vanderbilt University Nashville, TN, USA.
5
Department of Medicine, Vanderbilt University Nashville, TN, USA ; Department of Pharmacology, Vanderbilt University Nashville, TN, USA.
6
Department of Biomedical Informatics, Vanderbilt University Nashville, TN, USA.
7
Vanderbilt Epidemiology Center, Vanderbilt University Nashville, TN, USA.
8
Center for Human Genetics, Marshfield Clinic Research Foundation Marshfield, WI, USA.
9
Biomedical Informatics Research Center, Marshfield Clinic Research Foundation Marshfield, WI, USA.
10
Division of Genomic Medicine, National Human Genome Research Institute Bethesda, MD, USA.
11
Department of Medicine, University of Washington Seattle, WA, USA.
12
Department of Biochemistry and Molecular Biology, Center for Systems Genomics, The Pennsylvania State University University Park, PA, USA.
13
Divisions of Biomedical Informatics and Statistics, Mayo Clinic Rochester, MN, USA.
14
Division of Epidemiology, Mayo Clinic Rochester, MN, USA.
15
Group Health Research Institute Seattle, WA, USA.
16
Department of Genome Sciences, University of Washington Seattle, WA, USA.
17
Genomic Medicine Institute, Geisinger Health System Danville, PA, USA.
18
Weis Center for Research, Geisinger Health System Danville, PA, USA.
19
Department of Medicine, University of Washington Seattle, WA, USA ; Department of Genome Sciences, University of Washington Seattle, WA, USA.
20
Essentia Institute of Rural Health Duluth, MN, USA.
21
Division of Cardiovascular Diseases, Mayo Clinic Rochester, MN, USA.
22
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai New York, NY, USA.
23
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University Evanston, IL, USA.

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.

KEYWORDS:

BMI; Exome chip; FTO; PheWAS; genetic association; pleiotropy

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