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A Phenome-Wide Association Study (Phewas) RESEARCH ARTICLE A phenome-wide association study (PheWAS) in the Population Architecture using Genomics and Epidemiology (PAGE) study reveals potential pleiotropy in African Americans 1 2,3 4 5 Sarah A. PendergrassID , Steven BuyskeID , Janina M. Jeff , Alex Frase , 5 5 6 7 8 a1111111111 Scott DudekID , Yuki Bradford , Jose-Luis AmbiteID , Christy L. Avery , Petra Buzkova , 6 9 10 7,11 a1111111111 Ewa Deelman , Megan D. Fesinmeyer , Christopher Haiman , Gerardo HeissID , Lucia 12 13 14 15 16 a1111111111 A. Hindorff , Chun-Nan HsuID , Rebecca D. Jackson , Yi Lin , Loic Le Marchand , 3 10 17 7,11 a1111111111 Tara C. MatiseID , Kristine R. Monroe , Larry Moreland , Kari E. North , Sungshim a1111111111 L. Park10, Alex Reiner18, Robert Wallace19, Lynne R. Wilkens16, Charles Kooperberg15, 5☯ 20,21☯ Marylyn D. Ritchie , Dana C. CrawfordID * 1 Genentech, Inc., South San Francisco, California, United States of America, 2 Department of Statistics, Rutgers University, Piscataway, New Jersey, United States of America, 3 Department of Genetics, Rutgers University, Piscataway, New Jersey, United States of America, 4 Illumina, Inc., San Diego, California, United OPEN ACCESS States of America, 5 Department of Genetics, Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America, 6 Information Citation: Pendergrass SA, Buyske S, Jeff JM, Frase Sciences Institute; University of Southern California, Marina del Rey, California, United States of America, A, Dudek S, Bradford Y, et al. (2019) A phenome- 7 Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, United States of wide association study (PheWAS) in the Population America, 8 Department of Biostatistics, University of Washington, Seattle, Washington, United States of Architecture using Genomics and Epidemiology America, 9 Amgen, Thousand Oaks, California, United States of America, 10 Department of Preventive (PAGE) study reveals potential pleiotropy in African Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Americans. PLoS ONE 14(12): e0226771. https:// Los Angeles, California, United States of America, 11 Carolina Center for Genome Sciences, University of doi.org/10.1371/journal.pone.0226771 North Carolina, Chapel Hill, North Carolina, United States of America, 12 National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America, 13 Center for Research Editor: Gregory P. Copenhaver, The University of in Biological Systems, Department of Neurosciences, University of California, San Diego, La Jolla, California, North Carolina at Chapel Hill, UNITED STATES United States of America, 14 The Ohio State University, Columbus, Ohio, United States of America, 15 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, Received: December 2, 2019 United States of America, 16 Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, United States of America, 17 University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America, Accepted: December 3, 2019 18 Department of Epidemiology, University of Washington, Seattle, Washington, United States of America, Published: December 31, 2019 19 Departments of Epidemiology and Internal Medicine, University of Iowa, Iowa City, Iowa, United States of America, 20 Cleveland Institute for Computational Biology, Cleveland, Ohio, United States of America, Copyright: This is an open access article, free of all 21 Departments of Population and Quantitative Health Sciences and Genetics and Genome Sciences, Case copyright, and may be freely reproduced, Western Reserve University, Cleveland, Ohio, United States of America distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. ☯ These authors contributed equally to this work. The work is made available under the Creative * [email protected] Commons CC0 public domain dedication. Data Availability Statement: The datasets generated as part of the PAGE study can be Abstract accessed through the dbGaP repository (http:// www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study. We performed a hypothesis-generating phenome-wide association study (PheWAS) to cgi?study_id=phs000356). identify and characterize cross-phenotype associations, where one SNP is associated with Funding: The Population Architecture Using two or more phenotypes, between thousands of genetic variants assayed on the Metabo- Genomics and Epidemiology (PAGE) program is chip and hundreds of phenotypes in 5,897 African Americans as part of the Population funded by the National Human Genome Research Architecture using Genomics and Epidemiology (PAGE) I study. The PAGE I study was a Institute (NHGRI), and this work was supported by U01HG004803 (CALiCo), U01HG004798 (EAGLE), National Human Genome Research Institute-funded collaboration of four study sites PLOS ONE | https://doi.org/10.1371/journal.pone.0226771 December 31, 2019 1 / 37 Pleiotropy in African Americans from PAGE U01HG004802 (MEC), U01HG004790 (WHI), and accessing diverse epidemiologic studies genotyped on the Metabochip, a custom genotyp- U01HG004801 (Coordinating Center), and their ing chip that has dense coverage of regions in the genome previously associated with car- respective NHGRI ARRA supplements. The contents of this paper are solely the responsibility dio-metabolic traits and outcomes in mostly European-descent populations. Here we focus of the authors and do not necessarily represent the on identifying novel phenome-genome relationships, where SNPs are associated with more official views of the NIH. The complete list of PAGE than one phenotype. To do this, we performed a PheWAS, testing each SNP on the Metabo- members can be found at http://www.pagestudy. chip for an association with up to 273 phenotypes in the participating PAGE I study sites. org. The data and materials included in this report result from a collaboration between the following We identified 133 putative pleiotropic variants, defined as SNPs associated at an empirically studies: The "Epidemiologic Architecture for Genes derived p-value threshold of p<0.01 in two or more PAGE study sites for two or more pheno- Linked to Environment (EAGLE)" is funded through type classes. We further annotated these PheWAS-identified variants using publicly avail- the NHGRI PAGE program (U01HG004798 and its able functional data and local genetic ancestry. Amongst our novel findings is SPARC NHGRI ARRA supplements). The Multiethnic Cohort study (MEC) characterization of rs4958487, associated with increased glucose levels and hypertension. SPARC has been epidemiological architecture is funded through the implicated in the pathogenesis of diabetes and is also known to have a potential role in fibro- NHGRI PAGE program (U01HG004802 and its sis, a common consequence of multiple conditions including hypertension. The SPARC NHGRI ARRA supplement). The MEC study is funded through the National Cancer Institute example and others highlight the potential that PheWAS approaches have in improving our (R37CA54281, R01 CA63, P01CA33619, understanding of complex disease architecture by identifying novel relationships between U01CA136792, and U01CA98758). Funding genetic variants and an array of common human phenotypes. support for the ªEpidemiology of putative genetic variants: The Women's Health Initiativeº study is provided through the NHGRI PAGE program (U01HG004790 and its NHGRI ARRA supplement). The WHI program is funded by the National Heart, Lung, and Blood Institute; NIH; and U.S. Department of Health and Human Services through Introduction contracts N01WH22110, 24152, 32100-2, 32105- Pleiotropy, however defined, has long been recognized as a feature of genomes with respect to 6, 32108-9, 32111-13, 32115, 32118-32119, their relationships to individual traits and outcomes that characterize phenomes [1±3]. Interest 32122, 42107-26, 42129-32, and 44221. The authors thank the WHI investigators and staff for in human pleiotropy has spiked in the last decade owing to the availability of large genotype- their dedication, and the study participants for phenotype datasets generated from genome-wide association studies (GWAS). The analysis making the program possible. A full listing of WHI and catalog collection of one phenotype versus many genotypes studies revealed that a sizable investigators can be found at: http://www. proportion of common genetic variants are associated with multiple related and independent whiscience.org/publications/WHI_investigators_ phenotypes [4, 5]. These observations have led to the development of more systematic shortlist.pdf. Funding support for the Genetic Epidemiology of Causal Variants Across the Life approaches to identify variant-level pleiotropy [6, 7], many of which have been applied to pop- Course (CALiCo) program was provided through ulations of mostly European-descent individuals ascertained in clinical settings (e.g., [8]). the NHGRI PAGE program (U01HG004803 and its Here, we describe a phenotype wide association study (PheWAS), a systematic approach to NHGRI ARRA supplement). The following study identify cross-phenotype associations, in the Population Architecture using Genomics and contributed to this manuscript and is funded by the Epidemiology (PAGE) I study. The PAGE I study was established by the National Human following agencies: The Atherosclerosis Risk in Genome Research
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