A phenome-wide association study (PheWAS) in the Population Architecture using Genomics and Epidemiology (PAGE) study reveals potential pleiotropy in African Americans
Autoři:
Sarah A. Pendergrass aff001; Steven Buyske aff002; Janina M. Jeff aff004; Alex Frase aff005; Scott Dudek aff005; Yuki Bradford aff005; Jose-Luis Ambite aff006; Christy L. Avery aff007; Petra Buzkova aff008; Ewa Deelman aff006; Megan D. Fesinmeyer aff009; Christopher Haiman aff010; Gerardo Heiss aff007; Lucia A. Hindorff aff012; Chun-Nan Hsu aff013; Rebecca D. Jackson aff014; Yi Lin aff015; Loic Le Marchand aff016; Tara C. Matise aff003; Kristine R. Monroe aff010; Larry Moreland aff017; Kari E. North aff007; Sungshim L. Park aff010; Alex Reiner aff018; Robert Wallace aff019; Lynne R. Wilkens aff016; Charles Kooperberg aff015; Marylyn D. Ritchie aff005; Dana C. Crawford aff020
Působiště autorů:
Genentech, Inc., South San Francisco, California, United States of America
aff001; Department of Statistics, Rutgers University, Piscataway, New Jersey, United States of America
aff002; Department of Genetics, Rutgers University, Piscataway, New Jersey, United States of America
aff003; Illumina, Inc., San Diego, California, United States of America
aff004; Department of Genetics, Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
aff005; Information Sciences Institute; University of Southern California, Marina del Rey, California, United States of America
aff006; Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, United States of America
aff007; Department of Biostatistics, University of Washington, Seattle, Washington, United States of America
aff008; Amgen, Thousand Oaks, California, United States of America
aff009; Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California, United States of America
aff010; Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, North Carolina, United States of America
aff011; National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America
aff012; Center for Research in Biological Systems, Department of Neurosciences, University of California, San Diego, La Jolla, California, United States of America
aff013; The Ohio State University, Columbus, Ohio, United States of America
aff014; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
aff015; Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, United States of America
aff016; University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
aff017; Department of Epidemiology, University of Washington, Seattle, Washington, United states of America
aff018; Departments of Epidemiology and Internal Medicine, University of Iowa, Iowa City, Iowa, United States of America
aff019; Cleveland Institute for Computational Biology, Cleveland, Ohio, United States of America
aff020; Departments of Population and Quantitative Health Sciences and Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio, United States of America
aff021
Vyšlo v časopise:
PLoS ONE 14(12)
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pone.0226771
Souhrn
We performed a hypothesis-generating phenome-wide association study (PheWAS) to identify and characterize cross-phenotype associations, where one SNP is associated with two or more phenotypes, between thousands of genetic variants assayed on the Metabochip and hundreds of phenotypes in 5,897 African Americans as part of the Population Architecture using Genomics and Epidemiology (PAGE) I study. The PAGE I study was a National Human Genome Research Institute-funded collaboration of four study sites accessing diverse epidemiologic studies genotyped on the Metabochip, a custom genotyping chip that has dense coverage of regions in the genome previously associated with cardio-metabolic traits and outcomes in mostly European-descent populations. Here we focus on identifying novel phenome-genome relationships, where SNPs are associated with more than one phenotype. To do this, we performed a PheWAS, testing each SNP on the Metabochip for an association with up to 273 phenotypes in the participating PAGE I study sites. We identified 133 putative pleiotropic variants, defined as SNPs associated at an empirically derived p-value threshold of p<0.01 in two or more PAGE study sites for two or more phenotype classes. We further annotated these PheWAS-identified variants using publicly available functional data and local genetic ancestry. Amongst our novel findings is SPARC rs4958487, associated with increased glucose levels and hypertension. SPARC has been implicated in the pathogenesis of diabetes and is also known to have a potential role in fibrosis, a common consequence of multiple conditions including hypertension. The SPARC example and others highlight the potential that PheWAS approaches have in improving our understanding of complex disease architecture by identifying novel relationships between genetic variants and an array of common human phenotypes.
Klíčová slova:
African American people – Cell binding assay – Genome-wide association studies – Hematocrit – Hypertension – Insulin – Myocardial infarction – Smoking habits
Zdroje
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PLOS One
2019 Číslo 12
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