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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.


Related in: MedlinePlus

Replicating results for PheWAS.This is a plot of SNP-phenotype associations observed in both NHANES III and Continuous NHANES with p-value <0.01, for SNPs with an allele frequency >0.01, and a sample size >200, for the same race-ethnicity, phenotype-class, and direction of effect. Plotted are results where the significant SNP-phenotype association matches a previously reported SNP-Phenotype association. The first column indicates the chromosome and base pair location of the SNP. The second column indicates the SNP ID, the associated phenotype-class, the self-reported race-ethnicity (NHW  =  Non-Hispanic Whites, NHB  =  Non-Hispanic Blacks, or MA  =  Mexican Americans), and the coded-allele. The next column contains a colored box if association results were available for natural log transformed Continuous NHANES (Continuous NHANES ln+1), un-transformed Continuous NHANES phenotypes, NHANES III untransformed phenotypes (NHANES III), or transformed NHANES III phenotypes (NHANES III ln+1) (see methods for more details on phenotype transformation). The next column indicates the p-value for each association, and the triangle direction indicates whether the association had a positive (triangle pointed to the left) or negative direction of effect (triangle pointed to the right). The following columns indicate magnitude of the effect (beta), the coded allele frequency (CAF), and the sample size for the association.
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pgen-1004678-g002: Replicating results for PheWAS.This is a plot of SNP-phenotype associations observed in both NHANES III and Continuous NHANES with p-value <0.01, for SNPs with an allele frequency >0.01, and a sample size >200, for the same race-ethnicity, phenotype-class, and direction of effect. Plotted are results where the significant SNP-phenotype association matches a previously reported SNP-Phenotype association. The first column indicates the chromosome and base pair location of the SNP. The second column indicates the SNP ID, the associated phenotype-class, the self-reported race-ethnicity (NHW  =  Non-Hispanic Whites, NHB  =  Non-Hispanic Blacks, or MA  =  Mexican Americans), and the coded-allele. The next column contains a colored box if association results were available for natural log transformed Continuous NHANES (Continuous NHANES ln+1), un-transformed Continuous NHANES phenotypes, NHANES III untransformed phenotypes (NHANES III), or transformed NHANES III phenotypes (NHANES III ln+1) (see methods for more details on phenotype transformation). The next column indicates the p-value for each association, and the triangle direction indicates whether the association had a positive (triangle pointed to the left) or negative direction of effect (triangle pointed to the right). The following columns indicate magnitude of the effect (beta), the coded allele frequency (CAF), and the sample size for the association.

Mentions: As a positive control, we first sought evidence for associations that replicate findings from the literature. Replication of previously reported associations validates our PheWAS pipeline and data integrity. Thirty-nine out of the 69 (56.5%) of our PheWAS associations have previously been described in the literature with the same direction of effect, and our results for these associations are presented in S2 and S3 Tables as well as visualized in Fig. 2. A proportion of the phenotypes could have phenotypic harmonization such that we could explore the association result for the phenotype across both surveys, NHANES III and Continuous NHANES, which we refer to as NHANES Combined. A Combined NHANES result was not available for every phenotype, as not all phenotypes could be harmonized across both surveys even if phenotypes could be binned into phenotype classes across both surveys. Our result tables contain this NHANES Combined information when available.


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)

Replicating results for PheWAS.This is a plot of SNP-phenotype associations observed in both NHANES III and Continuous NHANES with p-value <0.01, for SNPs with an allele frequency >0.01, and a sample size >200, for the same race-ethnicity, phenotype-class, and direction of effect. Plotted are results where the significant SNP-phenotype association matches a previously reported SNP-Phenotype association. The first column indicates the chromosome and base pair location of the SNP. The second column indicates the SNP ID, the associated phenotype-class, the self-reported race-ethnicity (NHW  =  Non-Hispanic Whites, NHB  =  Non-Hispanic Blacks, or MA  =  Mexican Americans), and the coded-allele. The next column contains a colored box if association results were available for natural log transformed Continuous NHANES (Continuous NHANES ln+1), un-transformed Continuous NHANES phenotypes, NHANES III untransformed phenotypes (NHANES III), or transformed NHANES III phenotypes (NHANES III ln+1) (see methods for more details on phenotype transformation). The next column indicates the p-value for each association, and the triangle direction indicates whether the association had a positive (triangle pointed to the left) or negative direction of effect (triangle pointed to the right). The following columns indicate magnitude of the effect (beta), the coded allele frequency (CAF), and the sample size for the association.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1004678-g002: Replicating results for PheWAS.This is a plot of SNP-phenotype associations observed in both NHANES III and Continuous NHANES with p-value <0.01, for SNPs with an allele frequency >0.01, and a sample size >200, for the same race-ethnicity, phenotype-class, and direction of effect. Plotted are results where the significant SNP-phenotype association matches a previously reported SNP-Phenotype association. The first column indicates the chromosome and base pair location of the SNP. The second column indicates the SNP ID, the associated phenotype-class, the self-reported race-ethnicity (NHW  =  Non-Hispanic Whites, NHB  =  Non-Hispanic Blacks, or MA  =  Mexican Americans), and the coded-allele. The next column contains a colored box if association results were available for natural log transformed Continuous NHANES (Continuous NHANES ln+1), un-transformed Continuous NHANES phenotypes, NHANES III untransformed phenotypes (NHANES III), or transformed NHANES III phenotypes (NHANES III ln+1) (see methods for more details on phenotype transformation). The next column indicates the p-value for each association, and the triangle direction indicates whether the association had a positive (triangle pointed to the left) or negative direction of effect (triangle pointed to the right). The following columns indicate magnitude of the effect (beta), the coded allele frequency (CAF), and the sample size for the association.
Mentions: As a positive control, we first sought evidence for associations that replicate findings from the literature. Replication of previously reported associations validates our PheWAS pipeline and data integrity. Thirty-nine out of the 69 (56.5%) of our PheWAS associations have previously been described in the literature with the same direction of effect, and our results for these associations are presented in S2 and S3 Tables as well as visualized in Fig. 2. A proportion of the phenotypes could have phenotypic harmonization such that we could explore the association result for the phenotype across both surveys, NHANES III and Continuous NHANES, which we refer to as NHANES Combined. A Combined NHANES result was not available for every phenotype, as not all phenotypes could be harmonized across both surveys even if phenotypes could be binned into phenotype classes across both surveys. Our result tables contain this NHANES Combined information when available.

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.


Related in: MedlinePlus