AUTHOR=Cronin Robert M. , Field Julie R. , Bradford Yuki , Shaffer Christian M. , Carroll Robert J. , Mosley Jonathan D. , Bastarache Lisa , Edwards Todd L. , Hebbring Scott J. , Lin Simon , Hindorff Lucia A. , Crane Paul K. , Pendergrass Sarah A. , Ritchie Marylyn D. , Crawford Dana C. , Pathak Jyotishman , Bielinski Suzette J. , Carrell David S. , Crosslin David R. , Ledbetter David H. , Carey David J. , Tromp Gerard , Williams Marc S. , Larson Eric B. , Jarvik Gail P. , Peissig Peggy L. , Brilliant Murray H. , McCarty Catherine A. , Chute Christopher G. , Kullo Iftikhar J. , Bottinger Erwin , Chisholm Rex , Smith Maureen E. , Roden Dan M. , Denny Joshua C. 

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

JOURNAL=Frontiers in Genetics

VOLUME=5

YEAR=2014

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2014.00250

DOI=10.3389/fgene.2014.00250

ISSN=1664-8021

ABSTRACT=<p>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 (<italic>FTO</italic>), 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 <italic>FTO</italic> variants and obesity (odds ratio [OR] = 1.25, 95% Confidence Interval = 1.11–1.24, <italic>p</italic> = 2.10 × 10<sup>−9</sup>) and <italic>FTO</italic> variants and T2D (<italic>OR</italic> = 1.14, 95% <italic>CI</italic> = 1.08–1.21, <italic>p</italic> = 2.34 × 10<sup>−6</sup>). The meta-analysis also demonstrated that <italic>FTO</italic> variant rs8050136 was significantly associated with sleep apnea (<italic>OR</italic> = 1.14, 95% <italic>CI</italic> = 1.07–1.22, <italic>p</italic> = 3.33 × 10<sup>−5</sup>); however, the association was attenuated after adjustment for body mass index (BMI). Novel phenotype associations with obesity-associated <italic>FTO</italic> variants included fibrocystic breast disease (rs9941349, <italic>OR</italic> = 0.81, 95% <italic>CI</italic> = 0.74–0.91, <italic>p</italic> = 5.41 × 10<sup>−5</sup>) and trends toward associations with non-alcoholic liver disease and gram-positive bacterial infections. <italic>FTO</italic> 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 <italic>FTO</italic> may have pleiotropic associations, some of which are not mediated by obesity.</p>