Format

Send to

Choose Destination
PLoS One. 2019 Dec 31;14(12):e0226771. doi: 10.1371/journal.pone.0226771. eCollection 2019.

A phenome-wide association study (PheWAS) in the Population Architecture using Genomics and Epidemiology (PAGE) study reveals potential pleiotropy in African Americans.

Author information

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 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 Sciences Institute; University of Southern California, Marina del Rey, California, United States of America.
7
Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, United States of America.
8
Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.
9
Amgen, Thousand Oaks, California, United States of America.
10
Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California, United States of America.
11
Carolina Center for Genome Sciences, University of 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 in Biological Systems, Department of Neurosciences, University of California, San Diego, La Jolla, California, 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, 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.
18
Department of Epidemiology, University of Washington, Seattle, Washington, United States of America.
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.
21
Departments of Population and Quantitative Health Sciences and Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio, United States of America.

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 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.

Conflict of interest statement

SAP is employed by and receives salary from Genentech Inc, and JMJ is employed by and receives salary from Illumina, Inc. This does not alter our adherence with PLOS ONE policies on sharing data and materials. DCC is an academic editor of PLOS ONE. DCC is not involved in the review of this manuscript per journal policy.

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center