Abstract
BackgroundChronic kidney disease (CKD) is common and disproportionally burdens United States ethnic minorities. Its genetic determinants may differ by disease severity and clinical stages. To uncover genetic factors associated CKD severity among high-risk ethnic groups, we performed genome-wide association studies (GWAS) in diverse populations within the Population Architecture using Genomics and Epidemiology (PAGE) study.MethodsWe assembled multi-ethnic genome-wide imputed data on CKD non-overlapping cases [4,150 mild to moderate CKD, 1,105 end-stage kidney disease (ESKD)] and non-CKD controls for up to 41,041 PAGE participants (African Americans, Hispanics/Latinos, East Asian, Native Hawaiian, and American Indians). We implemented a generalized estimating equation approach for GWAS using ancestry combined data while adjusting for age, sex, principal components, study, and ethnicity.ResultsThe GWAS identified a novel genome-wide associated locus for mild to moderate CKD nearby NMT2 (rs10906850, p = 3.7 × 10-8) that replicated in the United Kingdom Biobank white British (p = 0.008). Several variants at the APOL1 locus were associated with ESKD including the APOL1 G1 rs73885319 (p = 1.2 × 10-9). There was no overlap among associated loci for CKD and ESKD traits, even at the previously reported APOL1 locus (p = 0.76 for CKD). Several additional loci were associated with CKD or ESKD at p-values below the genome-wide threshold. These loci were often driven by variants more common in non-European ancestry.ConclusionOur genetic study identified a novel association at NMT2 for CKD and showed for the first time strong associations of the APOL1 variants with ESKD across multi-ethnic populations. Our findings suggest differences in genetic effects across CKD severity and provide information for study design of genetic studies of CKD in diverse populations.
Highlights
Chronic kidney disease (CKD) affects 15% of United States. adults and is a leading cause of death globally (Global Burden of Disease 2016 Causes of Death Collaborators, 2017)
Using Mendelian Randomization, we have shown that identified single nucleotide variants (SNVs) were causally related to a clinical diagnosis of CKD from
The genomic control lambdas were 1.025 for CKD and 1.026 for ESKD. These analyses identified two genome-wide associated loci: a chromosome 10 locus nearby NMT2 associated with CKD (Table 2 and Figure 2A) and the chromosome 22 APOL1 locus associated with ESKD (Figure 2B and Supplementary Table 2)
Summary
Chronic kidney disease (CKD) affects 15% of United States. adults and is a leading cause of death globally (Global Burden of Disease 2016 Causes of Death Collaborators, 2017). Chronic kidney disease (CKD) affects 15% of United States. There is a high burden of CKD in nonEuropean ancestry groups, including African Americans and Hispanics/Latinos (Collins et al, 2011). Genetic susceptibility explains in part ethnic differences in the burden of CKD, as illustrated by the African-ancestry APOL1 G1 and G2 genotypes that contribute to increased CKD risk in individuals with African ancestry (Genovese et al, 2010; Kramer et al, 2017). Chronic kidney disease (CKD) is common and disproportionally burdens United States ethnic minorities. To uncover genetic factors associated CKD severity among highrisk ethnic groups, we performed genome-wide association studies (GWAS) in diverse populations within the Population Architecture using Genomics and Epidemiology (PAGE) study
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