Abstract

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 …

Date

December 31, 2019

Authors

Sarah A Pendergrass, Steven Buyske, Janina M Jeff, Alex Frase, Scott Dudek, Yuki Bradford, Jose-Luis Ambite, Christy L Avery, Petra Buzkova, Ewa Deelman, Megan D Fesinmeyer, Christopher Haiman, Gerardo Heiss, Lucia A Hindorff, Chun-Nan Hsu, Rebecca D Jackson, Yi Lin, Loic Le Marchand, Tara C Matise, Kristine R Monroe, Larry Moreland, Kari E North, Sungshim L Park, Alex Reiner, Robert Wallace, Lynne R Wilkens, Charles Kooperberg, Marylyn D Ritchie, Dana C Crawford

Journal

PLoS One

Volume

14

Issue

12

Pages

e0226771

Publisher

Public Library of Science