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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.


Overview of the approach for this study.Genotypic and phenotypic data were collected in NHANES III and Continuous NHANES. The phenotypes for the two studies were matched into phenotype classes. Comprehensive associations were calculated for the genotypes and phenotypes for each survey independently. The results that were found in both surveys, with p<0.01, for the same phenotype-class, and race-ethnicity, and same direction of effect, were maintained for further inspection in this study.
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pgen-1004678-g001: Overview of the approach for this study.Genotypic and phenotypic data were collected in NHANES III and Continuous NHANES. The phenotypes for the two studies were matched into phenotype classes. Comprehensive associations were calculated for the genotypes and phenotypes for each survey independently. The results that were found in both surveys, with p<0.01, for the same phenotype-class, and race-ethnicity, and same direction of effect, were maintained for further inspection in this study.

Mentions: As detailed in the PheWAS workflow diagram shown in Fig. 1, we first identified 184 phenotype classes across NHANES from a total of 1,008 unique variables available for analysis in NHANES III and Continuous NHANES, respectively (Table 2). We then performed unadjusted single SNP tests of association assuming an additive genetic model for each SNP and phenotype (within each phenotype class) in NHANES III and Continuous NHANES. Our criteria for a significant PheWAS result was a SNP-phenotype association 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. We identified 69 PheWAS results meeting this significance threshold. Of these 69 PheWAS results, 39 replicated previously reported SNP-phenotype associations from the literature. Of the remaining results, 9 were related to previously reported associations in the literature, and 21 were novel SNP-phenotype associations. Moreover, 13 SNPs showed evidence of pleiotropy – where a particular SNP was associated with more than one phenotype. For the majority of results meeting our PheWAS criteria for replication, each SNP had multiple associations for each phenotype class; thus, in the text we report only the most statistically significant result. We detail all association results meeting our PheWAS criteria for replication in S2, S3, and S4 Tables and Table 3.


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)

Overview of the approach for this study.Genotypic and phenotypic data were collected in NHANES III and Continuous NHANES. The phenotypes for the two studies were matched into phenotype classes. Comprehensive associations were calculated for the genotypes and phenotypes for each survey independently. The results that were found in both surveys, with p<0.01, for the same phenotype-class, and race-ethnicity, and same direction of effect, were maintained for further inspection in this study.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1004678-g001: Overview of the approach for this study.Genotypic and phenotypic data were collected in NHANES III and Continuous NHANES. The phenotypes for the two studies were matched into phenotype classes. Comprehensive associations were calculated for the genotypes and phenotypes for each survey independently. The results that were found in both surveys, with p<0.01, for the same phenotype-class, and race-ethnicity, and same direction of effect, were maintained for further inspection in this study.
Mentions: As detailed in the PheWAS workflow diagram shown in Fig. 1, we first identified 184 phenotype classes across NHANES from a total of 1,008 unique variables available for analysis in NHANES III and Continuous NHANES, respectively (Table 2). We then performed unadjusted single SNP tests of association assuming an additive genetic model for each SNP and phenotype (within each phenotype class) in NHANES III and Continuous NHANES. Our criteria for a significant PheWAS result was a SNP-phenotype association 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. We identified 69 PheWAS results meeting this significance threshold. Of these 69 PheWAS results, 39 replicated previously reported SNP-phenotype associations from the literature. Of the remaining results, 9 were related to previously reported associations in the literature, and 21 were novel SNP-phenotype associations. Moreover, 13 SNPs showed evidence of pleiotropy – where a particular SNP was associated with more than one phenotype. For the majority of results meeting our PheWAS criteria for replication, each SNP had multiple associations for each phenotype class; thus, in the text we report only the most statistically significant result. We detail all association results meeting our PheWAS criteria for replication in S2, S3, and S4 Tables and Table 3.

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.