Fig 1.
Overview of the Metabochip PheWAS study.
Three different PAGE study sites contributed data to the project: Atherosclerosis Risk in Communities (ARIC); the Women’s Health Initiative (WHI), and the Multiethnic Cohort (MEC). Comprehensive tests of association between 144,740 Metabochip SNPs and 273 phenotypes were calculated for African American participants from each of the three PAGE study sites. Similar phenotypes that were collected across the studies were binned into “phenotype classes”. Our PheWAS-significant criteria required an association at p<0.01 in at least two PAGE study sites for the same phenotype class and direction of effect.
Table 1.
Population Architecture using Genomics and Epidemiology (PAGE) I studies available for PheWAS and their characteristics.
The Atherosclerosis Risk in Communities (ARIC), Multiethnic Cohort (MEC), and Women’s Health Initiative (WHI) from the PAGE I study contributed data towards this PheWAS. A full list of phenotypes used in this PheWAS is available in S1 Table. Some of the phenotypes were measured in more than one study, some phenotypes were related to phenotypes of another study, and some phenotypes were unique measurements for a single study. Not all phenotypic measurements were available for all participants within each study. Maximum sample size and minimum sample size are dependent both on which individuals were genotyped and which individuals also had a specific phenotype measured. See Materials and methods for more information.
Fig 2.
All genetic tests of association results, by PAGE study.
Results from all tests of association for SNPs with a minor allele frequency >1% regardless of phenotype at p<5x10-4 were plotted across chromosomes 1–22. Each dot on the plot represents the −log10(p-value) for the test of the association, and each of the three PAGE studies is plotted with a different color, Multiethnic Cohort (MEC) in blue, Women’s Health Initiative (WHI) in green, and Atherosclerosis Risk in Communities (ARIC) in red. The most significant p-value plotted here is 8.01E-44 for OLFML2B rs6676438 and (natural log) white blood count in ARIC (see Table 2). The y-axis for each chromosome is the −log10(p-value), and the x-axis is chromosomal base pair location.
Fig 3.
APOE rs7412 and nearby single nucleotide polymorphisms associated with lipid-related traits in a single Population Architecture using Genomics and Epidemiology (PAGE) study.
Plotted are single SNP tests of association in the Atherosclerosis Risk in Communities (ARIC) for APOE rs7412 and nearby SNPs within 100kb of previously-reported genome-wide association study (GWAS) associations also associated here at p<1.0x10-4 with lipid-related traits. Data shown are sample size, coded allele frequency (CAF), genetic effect size (beta), -log10(p-value), and ARIC phenotypes on the y-axes. Each SNP is plotted on the x-axis at the top of the figure from 5´ to 3′, and genomic positions along chromosome 19 along with annotated genes are given above. Data are color-coded by phenotype and displayed as a square (for SNPs), a triangle (p-values), or closed circles (betas, CAFs, and sample size). Direction of the triangle represents the direction of the effect size.
Table 2.
Most significant and previously reported genotype-phenotype associations identified in the Population Architecture using Genomics and Epidemiology (PAGE) I study.
Presented are the two most significant individual-level results for this PheWAS, along with other highly significant results for the same phenotype with a different transformation and/or study where the phenotype was available. Abbreviations: allele frequency (AF), standard error (SE).
Fig 4.
LDLR rs6511720 and nearby single nucleotide polymorphisms associated with lipid-related traits in a single Population Architecture using Genomics and Epidemiology (PAGE) study.
Plotted are single SNP tests of association in the Atherosclerosis Risk in Communities (ARIC) for LDLR rs6511720 and nearby SNPs within 100kb of previously-reported genome-wide association study (GWAS) associations also associated here at p<1.0x10-4 with lipid-related traits. Data shown are sample size, coded allele frequency (CAF), genetic effect size (beta), -log10(p-value), and ARIC phenotypes on the y-axes. Each SNP is plotted on the x-axis at the top of the figure from 5´ to 3′, and genomic positions along chromosome 19 along with annotated genes are given above. Data are color-coded by phenotype and displayed as a square (for SNPs), a triangle (p-values), or closed circles (betas, CAFs, and sample size). Direction of the triangle represents the direction of the effect size.
Fig 5.
CETP rs3764261 and nearby single nucleotide polymorphisms associated with lipid-related traits in a single Population Architecture using Genomics and Epidemiology (PAGE) study.
Plotted are single SNP tests of association in the Atherosclerosis Risk in Communities (ARIC) for CETP rs3764261 and nearby SNPs within 100kb of previously-reported genome-wide association study (GWAS) associations also associated here at p<1.0x10-4 with lipid-related traits. Data shown are sample size, coded allele frequency (CAF), genetic effect size (beta), -log10(p-value), and ARIC phenotypes on the y-axes. Each SNP is plotted on the x-axis at the top of the figure from 5´ to 3′, and genomic positions along chromosome 16 along with annotated genes are given above. Data are color-coded by phenotype and displayed as a square (for SNPs), a triangle (p-values), or closed circles (betas, CAFs, and sample size). Direction of the triangle represents the direction of the effect size.
Table 3.
Phenotype classes represented in the Population Architecture using Genomics and Epidemiology (PAGE) I study PheWAS in African Americans.
Phenotype-class binning first groups the phenotypes into categories within a PAGE study and then groups those categories across PAGE study sites. Below are the 30 phenotype classes that individually-labeled phenotypes across the studies were binned.
Table 4.
Concomitant PheWAS results in African Americans from the Population Architecture using Genomics and Epidemiology (PAGE) study.
Test of association results (p-values, betas, standard errors) are shown for variants associated at p-value <0.01 (empirically defined) with two or more phenotype classes. An asterisk in the direction of effect column indicates an opposite direction of effect for two of the phenotype classes listed. Genomic position given is based on hg38. Allele frequency is based on all African Americans across PAGE studies regardless of phenotype.
Fig 6.
Phenotype classes associated with the same single nucleotide polymorphism in African Americans from the Population Architecture using Genomics and Epidemiology (PAGE) study.
A plot of the 43 PheWAS results where two or more phenotype classes were significantly associated (p<0.01) with the same single nucleotide polymorphism (SNP) in participating PAGE study sites. This plot does not include concomitant lipid phenotype-class results (53 SNPs) or white blood cell related results for chromosome 1 (37 SNPs). Lines connect the SNP chromosomal location to circles, and the color of each circle corresponds to an associated phenotype class listed in the legend at the bottom.
Table 5.
Functional and ancestral annotation of potentially pleiotropic single nucleotide polymorphisms in the Population Architecture using Genomics and Epidemiology (PAGE) study.
All PheWAS-identified variants and variants in linkage disequilibrium with the index variant (at r2 ≥ 0.80 based AFR 1000 Genomes Project data) were functionally and ancestrally annotated using HaploReg v4.1, RegulomeDB v1.1, the SNP and CNV Annotation Database (SCAN), and local genetic ancestry. HaploReg v4.1 NHGRI-EBI GWAS Catalog data were augmented using NHGRI-EBI GWAS Catalog data from 2019-06-20, and associations listed are at p<5.0x10-8 unless otherwise noted. Local genetic ancestry, shown as proportion of African-derived alleles, was estimated using LAMP-LD. An asterisk in the direction of effect column indicates an opposite direction of effect for two of the phenotype classes listed. Genomic position given is based on hg38.