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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 GO biological processes.Three SNPs were associated with uric acid levels in Mexican Americans: rs2231142, rs7442295, rs685911 (green hexagons). One of the SNPs is within the gene ABCG2, and the other two SNPs are within SLC2A9 (blue boxes). Both ABCG2 and SLC2A9 are found within the GO biological process “urate metabolic process”, a collection of the gene products involved in the chemical reactions and pathways involving urate. This was also found for non-Hispanic whites.
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pgen-1004678-g009: Using PheWAS results, Biofilter, and Cytoscape to explore gene-gene connections with GO biological processes.Three SNPs were associated with uric acid levels in Mexican Americans: rs2231142, rs7442295, rs685911 (green hexagons). One of the SNPs is within the gene ABCG2, and the other two SNPs are within SLC2A9 (blue boxes). Both ABCG2 and SLC2A9 are found within the GO biological process “urate metabolic process”, a collection of the gene products involved in the chemical reactions and pathways involving urate. This was also found for non-Hispanic whites.

Mentions: For example, Fig. 8 shows one example for PheWAS results in Mexican Americans, where LPL SNP rs328 had a significant association with HDL-C levels, and the FADS1 SNP rs17547 had an association with ferritin levels. Both genes are found in the TGF-β receptor regulated NetPath pathway. Fig. 9 shows another example in Mexican Americans in which three SNPs were associated with uric acid levels: rs2231142, rs7442295, rs685911. One of the SNPs is located within the gene ABCG2, and the other two SNPs are located within SLC2A9 (blue boxes). Both ABCG2 and SLC2A9 are found within the GO biological process “urate metabolic process”, a collection of the gene products involved in the chemical reactions and pathways involving urate. These same connections were also found for non-Hispanic whites, as this group had a PheWAS-significant association between these SNPs and uric acid levels. One of the SNPs, rs2231142, was also associated with diastolic blood pressure and protoporphyrin levels.


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 GO biological processes.Three SNPs were associated with uric acid levels in Mexican Americans: rs2231142, rs7442295, rs685911 (green hexagons). One of the SNPs is within the gene ABCG2, and the other two SNPs are within SLC2A9 (blue boxes). Both ABCG2 and SLC2A9 are found within the GO biological process “urate metabolic process”, a collection of the gene products involved in the chemical reactions and pathways involving urate. This was also found for non-Hispanic whites.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1004678-g009: Using PheWAS results, Biofilter, and Cytoscape to explore gene-gene connections with GO biological processes.Three SNPs were associated with uric acid levels in Mexican Americans: rs2231142, rs7442295, rs685911 (green hexagons). One of the SNPs is within the gene ABCG2, and the other two SNPs are within SLC2A9 (blue boxes). Both ABCG2 and SLC2A9 are found within the GO biological process “urate metabolic process”, a collection of the gene products involved in the chemical reactions and pathways involving urate. This was also found for non-Hispanic whites.
Mentions: For example, Fig. 8 shows one example for PheWAS results in Mexican Americans, where LPL SNP rs328 had a significant association with HDL-C levels, and the FADS1 SNP rs17547 had an association with ferritin levels. Both genes are found in the TGF-β receptor regulated NetPath pathway. Fig. 9 shows another example in Mexican Americans in which three SNPs were associated with uric acid levels: rs2231142, rs7442295, rs685911. One of the SNPs is located within the gene ABCG2, and the other two SNPs are located within SLC2A9 (blue boxes). Both ABCG2 and SLC2A9 are found within the GO biological process “urate metabolic process”, a collection of the gene products involved in the chemical reactions and pathways involving urate. These same connections were also found for non-Hispanic whites, as this group had a PheWAS-significant association between these SNPs and uric acid levels. One of the SNPs, rs2231142, was also associated with diastolic blood pressure and protoporphyrin levels.

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.