A phenome-wide association study (PheWAS) in the Population Architecture using Genomics and Epidemiology (PAGE) study reveals potential pleiotropy in African Americans. Pendergrass, S. A., Buyske, S., Jeff, J. M., Frase, A., Dudek, S., Bradford, Y., Ambite, J., Avery, C. L., Buzkova, P., Deelman, E., Fesinmeyer, M. D., Haiman, C., Heiss, G., Hindorff, L. A., Hsu, C., Jackson, R. D., Lin, Y., Le Marchand, L., Matise, T. C., Monroe, K. R., Moreland, L., North, K. E., Park, S. L., Reiner, A., Wallace, R., Wilkens, L. R., Kooperberg, C., Ritchie, M. D., & Crawford, D. C. PloS one, 14:e0226771, 2019.
A phenome-wide association study (PheWAS) in the Population Architecture using Genomics and Epidemiology (PAGE) study reveals potential pleiotropy in African Americans. [link]Paper  doi  abstract   bibtex   3 downloads  
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.
@article{PendergrassBuyskeJeffEtAl2019,
	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.},
	author = {Pendergrass, Sarah A. and Buyske, Steven and Jeff, Janina M. and Frase, Alex and Dudek, Scott and Bradford, Yuki and Ambite, Jose-Luis and Avery, Christy L. and Buzkova, Petra and Deelman, Ewa and Fesinmeyer, Megan D. and Haiman, Christopher and Heiss, Gerardo and Hindorff, Lucia A. and Hsu, Chun-Nan and Jackson, Rebecca D. and Lin, Yi and Le Marchand, Loic and Matise, Tara C. and Monroe, Kristine R. and Moreland, Larry and North, Kari E. and Park, Sungshim L. and Reiner, Alex and Wallace, Robert and Wilkens, Lynne R. and Kooperberg, Charles and Ritchie, Marylyn D. and Crawford, Dana C.},
	citation-subset = {IM},
	completed = {2020-04-06},
	country = {United States},
	doi = {10.1371/journal.pone.0226771},
	issn = {1932-6203},
	issn-linking = {1932-6203},
	issue = {12},
	journal = {PloS one},
	keywords = {African Americans, genetics; Aged; Atherosclerosis, genetics; Epidemiologic Studies; Female; Genetic Pleiotropy; Genome-Wide Association Study; Humans; Male; Metagenomics; Middle Aged; Phenomics; Polymorphism, Single Nucleotide},
	nlm-id = {101285081},
	owner = {NLM},
	pages = {e0226771},
	pii = {PONE-D-19-33442},
	pmc = {PMC6938343},
	pmid = {31891604},
	url = {https://pubmed.ncbi.nlm.nih.gov/31891604/},

	pubmodel = {Electronic-eCollection},
	pubstate = {epublish},
	revised = {2020-04-30},
	title = {A phenome-wide association study ({PheWAS}) in the {Population Architecture using Genomics and Epidemiology} ({PAGE}) study reveals potential pleiotropy in {African Americans}.},
	volume = {14},
	year = {2019},
	bdsk-url-1 = {https://pubmed.ncbi.nlm.nih.gov/31891604/},
	bdsk-url-2 = {https://doi.org/10.1371/journal.pone.0226771}}
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