AUTHOR=Lin Bridget M. , Nadkarni Girish N. , Tao Ran , Graff Mariaelisa , Fornage Myriam , Buyske Steven , Matise Tara C. , Highland Heather M. , Wilkens Lynne R. , Carlson Christopher S. , Park S. Lani , Setiawan V. Wendy , Ambite Jose Luis , Heiss Gerardo , Boerwinkle Eric , Lin Dan-Yu , Morris Andrew P. , Loos Ruth J. F. , Kooperberg Charles , North Kari E. , Wassel Christina L. , Franceschini Nora 

TITLE=Genetics of Chronic Kidney Disease Stages Across Ancestries: The PAGE Study

JOURNAL=Frontiers in Genetics

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2019.00494

DOI=10.3389/fgene.2019.00494

ISSN=1664-8021

ABSTRACT=<sec><title>Background</title><p>Chronic 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.</p></sec><sec><title>Methods</title><p>We 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.</p></sec><sec><title>Results</title><p>The GWAS identified a novel genome-wide associated locus for mild to moderate CKD nearby <italic>NMT2</italic> (rs10906850, <italic>p</italic> = 3.7 × 10<sup>-8</sup>) that replicated in the United Kingdom Biobank white British (<italic>p</italic> = 0.008). Several variants at the <italic>APOL1</italic> locus were associated with ESKD including the <italic>APOL1</italic> G1 rs73885319 (<italic>p</italic> = 1.2 × 10<sup>-9</sup>). There was no overlap among associated loci for CKD and ESKD traits, even at the previously reported <italic>APOL1</italic> locus (<italic>p</italic> = 0.76 for CKD). Several additional loci were associated with CKD or ESKD at <italic>p</italic>-values below the genome-wide threshold. These loci were often driven by variants more common in non-European ancestry.</p></sec><sec><title>Conclusion</title><p>Our genetic study identified a novel association at <italic>NMT2</italic> for CKD and showed for the first time strong associations of the <italic>APOL1</italic> 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.</p></sec>