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Detection of pleiotropy through a Phenome-wide association study (PheWAS) of epidemiologic data as part of the Environmental Architecture for Genes Linked to Environment (EAGLE) study.

Hall MA, Verma A, Brown-Gentry KD, Goodloe R, Boston J, Wilson S, McClellan B, Sutcliffe C, Dilks HH, Gillani NB, Jin H, Mayo P, Allen M, Schnetz-Boutaud N, Crawford DC, Ritchie MD, Pendergrass SA - PLoS Genet. (2014)

Bottom Line: We further explored results with gene-based biological networks, contrasting the direction of effect for pleiotropic associations across phenotypes.One PheWAS result was ABCG2 missense SNP rs2231142, associated with uric acid levels in both non-Hispanic whites and Mexican Americans, protoporphyrin levels in non-Hispanic whites and Mexican Americans, and blood pressure levels in Mexican Americans.Another example was SNP rs1800588 near LIPC, significantly associated with the novel phenotypes of folate levels (Mexican Americans), vitamin E levels (non-Hispanic whites) and triglyceride levels (non-Hispanic whites), and replication for cholesterol levels.

View Article: PubMed Central - PubMed

Affiliation: Center for Systems Genomics, Department of Biochemistry and Molecular Biology, The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania, United States of America.

ABSTRACT
We performed a Phenome-wide association study (PheWAS) utilizing diverse genotypic and phenotypic data existing across multiple populations in the National Health and Nutrition Examination Surveys (NHANES), conducted by the Centers for Disease Control and Prevention (CDC), and accessed by the Epidemiological Architecture for Genes Linked to Environment (EAGLE) study. We calculated comprehensive tests of association in Genetic NHANES using 80 SNPs and 1,008 phenotypes (grouped into 184 phenotype classes), stratified by race-ethnicity. Genetic NHANES includes three surveys (NHANES III, 1999-2000, and 2001-2002) and three race-ethnicities: non-Hispanic whites (n = 6,634), non-Hispanic blacks (n = 3,458), and Mexican Americans (n = 3,950). We identified 69 PheWAS associations replicating across surveys for the same SNP, phenotype-class, direction of effect, and race-ethnicity at p<0.01, allele frequency >0.01, and sample size >200. Of these 69 PheWAS associations, 39 replicated previously reported SNP-phenotype associations, 9 were related to previously reported associations, and 21 were novel associations. Fourteen results had the same direction of effect across more than one race-ethnicity: one result was novel, 11 replicated previously reported associations, and two were related to previously reported results. Thirteen SNPs showed evidence of pleiotropy. We further explored results with gene-based biological networks, contrasting the direction of effect for pleiotropic associations across phenotypes. One PheWAS result was ABCG2 missense SNP rs2231142, associated with uric acid levels in both non-Hispanic whites and Mexican Americans, protoporphyrin levels in non-Hispanic whites and Mexican Americans, and blood pressure levels in Mexican Americans. Another example was SNP rs1800588 near LIPC, significantly associated with the novel phenotypes of folate levels (Mexican Americans), vitamin E levels (non-Hispanic whites) and triglyceride levels (non-Hispanic whites), and replication for cholesterol levels. The results of this PheWAS show the utility of this approach for exposing more of the complex genetic architecture underlying multiple traits, through generating novel hypotheses for future research.

No MeSH data available.


Using PheWAS results, Biofilter, and Cytoscape to explore gene-gene connections with KEGG connections.The LIPC SNP rs1800588 was associated with folate levels, the LPL SNP rs328 was associated with HDL cholesterol, and both of these genes are in the glycerolipid metabolism KEGG pathway in Mexican Americans. The APOA5 SNP rs135506, associated with triglyceride levels in our study, shares the PPAR signaling pathway along with LPL.
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pgen-1004678-g010: Using PheWAS results, Biofilter, and Cytoscape to explore gene-gene connections with KEGG connections.The LIPC SNP rs1800588 was associated with folate levels, the LPL SNP rs328 was associated with HDL cholesterol, and both of these genes are in the glycerolipid metabolism KEGG pathway in Mexican Americans. The APOA5 SNP rs135506, associated with triglyceride levels in our study, shares the PPAR signaling pathway along with LPL.

Mentions: Fig. 10 displays an example using KEGG and the Mexican American PheWAS results. LPL and LIPC both are involved in the KEGG biological process “glycerolipid metabolism”. LPL SNP rs328 was associated in this study with HDL-C, while LIPC SNP rs1800588 was associated with folate levels. LPL was also involved in the KEGG pathway “Peroxisome Proliferator-Activated Receptor (PPAR) signaling pathway”, along with APOA5, which was associated with triglyceride levels through its SNP rs3135506. PPARs are transcription factors activated by lipids.


Detection of pleiotropy through a Phenome-wide association study (PheWAS) of epidemiologic data as part of the Environmental Architecture for Genes Linked to Environment (EAGLE) study.

Hall MA, Verma A, Brown-Gentry KD, Goodloe R, Boston J, Wilson S, McClellan B, Sutcliffe C, Dilks HH, Gillani NB, Jin H, Mayo P, Allen M, Schnetz-Boutaud N, Crawford DC, Ritchie MD, Pendergrass SA - PLoS Genet. (2014)

Using PheWAS results, Biofilter, and Cytoscape to explore gene-gene connections with KEGG connections.The LIPC SNP rs1800588 was associated with folate levels, the LPL SNP rs328 was associated with HDL cholesterol, and both of these genes are in the glycerolipid metabolism KEGG pathway in Mexican Americans. The APOA5 SNP rs135506, associated with triglyceride levels in our study, shares the PPAR signaling pathway along with LPL.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4256091&req=5

pgen-1004678-g010: Using PheWAS results, Biofilter, and Cytoscape to explore gene-gene connections with KEGG connections.The LIPC SNP rs1800588 was associated with folate levels, the LPL SNP rs328 was associated with HDL cholesterol, and both of these genes are in the glycerolipid metabolism KEGG pathway in Mexican Americans. The APOA5 SNP rs135506, associated with triglyceride levels in our study, shares the PPAR signaling pathway along with LPL.
Mentions: Fig. 10 displays an example using KEGG and the Mexican American PheWAS results. LPL and LIPC both are involved in the KEGG biological process “glycerolipid metabolism”. LPL SNP rs328 was associated in this study with HDL-C, while LIPC SNP rs1800588 was associated with folate levels. LPL was also involved in the KEGG pathway “Peroxisome Proliferator-Activated Receptor (PPAR) signaling pathway”, along with APOA5, which was associated with triglyceride levels through its SNP rs3135506. PPARs are transcription factors activated by lipids.

Bottom Line: We further explored results with gene-based biological networks, contrasting the direction of effect for pleiotropic associations across phenotypes.One PheWAS result was ABCG2 missense SNP rs2231142, associated with uric acid levels in both non-Hispanic whites and Mexican Americans, protoporphyrin levels in non-Hispanic whites and Mexican Americans, and blood pressure levels in Mexican Americans.Another example was SNP rs1800588 near LIPC, significantly associated with the novel phenotypes of folate levels (Mexican Americans), vitamin E levels (non-Hispanic whites) and triglyceride levels (non-Hispanic whites), and replication for cholesterol levels.

View Article: PubMed Central - PubMed

Affiliation: Center for Systems Genomics, Department of Biochemistry and Molecular Biology, The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania, United States of America.

ABSTRACT
We performed a Phenome-wide association study (PheWAS) utilizing diverse genotypic and phenotypic data existing across multiple populations in the National Health and Nutrition Examination Surveys (NHANES), conducted by the Centers for Disease Control and Prevention (CDC), and accessed by the Epidemiological Architecture for Genes Linked to Environment (EAGLE) study. We calculated comprehensive tests of association in Genetic NHANES using 80 SNPs and 1,008 phenotypes (grouped into 184 phenotype classes), stratified by race-ethnicity. Genetic NHANES includes three surveys (NHANES III, 1999-2000, and 2001-2002) and three race-ethnicities: non-Hispanic whites (n = 6,634), non-Hispanic blacks (n = 3,458), and Mexican Americans (n = 3,950). We identified 69 PheWAS associations replicating across surveys for the same SNP, phenotype-class, direction of effect, and race-ethnicity at p<0.01, allele frequency >0.01, and sample size >200. Of these 69 PheWAS associations, 39 replicated previously reported SNP-phenotype associations, 9 were related to previously reported associations, and 21 were novel associations. Fourteen results had the same direction of effect across more than one race-ethnicity: one result was novel, 11 replicated previously reported associations, and two were related to previously reported results. Thirteen SNPs showed evidence of pleiotropy. We further explored results with gene-based biological networks, contrasting the direction of effect for pleiotropic associations across phenotypes. One PheWAS result was ABCG2 missense SNP rs2231142, associated with uric acid levels in both non-Hispanic whites and Mexican Americans, protoporphyrin levels in non-Hispanic whites and Mexican Americans, and blood pressure levels in Mexican Americans. Another example was SNP rs1800588 near LIPC, significantly associated with the novel phenotypes of folate levels (Mexican Americans), vitamin E levels (non-Hispanic whites) and triglyceride levels (non-Hispanic whites), and replication for cholesterol levels. The results of this PheWAS show the utility of this approach for exposing more of the complex genetic architecture underlying multiple traits, through generating novel hypotheses for future research.

No MeSH data available.