A phenome-wide association study (PheWAS) in the Population Architecture using Genomics and Epidemiology (PAGE) study reveals potential pleiotropy in African Americans.
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...
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2019-01-01
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| author | 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 |
| author_facet | 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 |
| author_sort | Sarah A Pendergrass |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d1011295931b4e4fb3037f3c735bbbb4 |
| institution | DOAJ |
| issn | 1932-6203 |
| language | English |
| publishDate | 2019-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-d1011295931b4e4fb3037f3c735bbbb42025-08-20T02:55:16ZengPublic Library of Science (PLoS)PLoS ONE1932-62032019-01-011412e022677110.1371/journal.pone.0226771A phenome-wide association study (PheWAS) in the Population Architecture using Genomics and Epidemiology (PAGE) study reveals potential pleiotropy in African Americans.Sarah A PendergrassSteven BuyskeJanina M JeffAlex FraseScott DudekYuki BradfordJose-Luis AmbiteChristy L AveryPetra BuzkovaEwa DeelmanMegan D FesinmeyerChristopher HaimanGerardo HeissLucia A HindorffChun-Nan HsuRebecca D JacksonYi LinLoic Le MarchandTara C MatiseKristine R MonroeLarry MorelandKari E NorthSungshim L ParkAlex ReinerRobert WallaceLynne R WilkensCharles KooperbergMarylyn D RitchieDana C CrawfordWe 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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0226771&type=printable |
| spellingShingle | 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 A phenome-wide association study (PheWAS) in the Population Architecture using Genomics and Epidemiology (PAGE) study reveals potential pleiotropy in African Americans. PLoS ONE |
| title | A phenome-wide association study (PheWAS) in the Population Architecture using Genomics and Epidemiology (PAGE) study reveals potential pleiotropy in African Americans. |
| title_full | A phenome-wide association study (PheWAS) in the Population Architecture using Genomics and Epidemiology (PAGE) study reveals potential pleiotropy in African Americans. |
| title_fullStr | A phenome-wide association study (PheWAS) in the Population Architecture using Genomics and Epidemiology (PAGE) study reveals potential pleiotropy in African Americans. |
| title_full_unstemmed | A phenome-wide association study (PheWAS) in the Population Architecture using Genomics and Epidemiology (PAGE) study reveals potential pleiotropy in African Americans. |
| title_short | A phenome-wide association study (PheWAS) in the Population Architecture using Genomics and Epidemiology (PAGE) study reveals potential pleiotropy in African Americans. |
| title_sort | phenome wide association study phewas in the population architecture using genomics and epidemiology page study reveals potential pleiotropy in african americans |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0226771&type=printable |
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