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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

Related 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 is closely related to the phenotype of a previously reported SNP-Phenotype association. The first column indicates the chromosome and bp 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 phenotypes (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-g003: Related 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 is closely related to the phenotype of a previously reported SNP-Phenotype association. The first column indicates the chromosome and bp 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 phenotypes (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: After determining results where the phenotype of our association matched that of the same SNP-phenotype association in the GWA catalog, we evaluated whether any of our phenotypes were extremely similar to previously published SNP-phenotype associations. There were a total of 9/69 (∼13%) PheWAS results where the SNPs had been previously associated with lipid measurements not exactly matching the respective lipid measurements of our study (S4 Table and Fig. 3). For example, the SNP rs515135 near APOB/KLHL29 has been previously reported to be associated with LDL cholesterol (LDL-C) levels in European-descent populations [16], [17]. In this PheWAS, rs515135 (coded allele G) was associated with total cholesterol levels in non-Hispanic whites. For this SNP, the most significant results meeting our PheWAS replication criteria from NHANES III were: p = 0.0024, β = 4.85, n = 2,569 and Continuous NHANES were: p = 1.06×10−5, β = 0.026, n = 3959. This variant was also associated with total cholesterol levels in Combined NHANES (p = 1.39×10−7, β = 5.13, n = 6,528).


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)

Related 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 is closely related to the phenotype of a previously reported SNP-Phenotype association. The first column indicates the chromosome and bp 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 phenotypes (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-g003: Related 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 is closely related to the phenotype of a previously reported SNP-Phenotype association. The first column indicates the chromosome and bp 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 phenotypes (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: After determining results where the phenotype of our association matched that of the same SNP-phenotype association in the GWA catalog, we evaluated whether any of our phenotypes were extremely similar to previously published SNP-phenotype associations. There were a total of 9/69 (∼13%) PheWAS results where the SNPs had been previously associated with lipid measurements not exactly matching the respective lipid measurements of our study (S4 Table and Fig. 3). For example, the SNP rs515135 near APOB/KLHL29 has been previously reported to be associated with LDL cholesterol (LDL-C) levels in European-descent populations [16], [17]. In this PheWAS, rs515135 (coded allele G) was associated with total cholesterol levels in non-Hispanic whites. For this SNP, the most significant results meeting our PheWAS replication criteria from NHANES III were: p = 0.0024, β = 4.85, n = 2,569 and Continuous NHANES were: p = 1.06×10−5, β = 0.026, n = 3959. This variant was also associated with total cholesterol levels in Combined NHANES (p = 1.39×10−7, β = 5.13, n = 6,528).

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