Genome-Wide Admixture Mapping of Estimated Glomerular Filtration Rate and Chronic Kidney Disease Identifies European and African Ancestry-of-Origin Loci in Hispanic and Latino Individuals in the United States
Andréa R. V. R. Horimoto, Diane Xue, Jianwen Cai, James P. Lash, Martha L. Daviglus, Nora Franceschini, Timothy A. Thornton
Abstract
Significance Statement Populations of Hispanic or Latino individuals have an increased risk of CKD, yet little is known about CKD genetics in these underserved groups. A genome-wide admixture mapping study of CKD traits conducted in 12,601 participants from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) identified three novel ancestry-of-origin loci on African-derived and European-derived chromosomal haplotypes—implicating novel candidate genes for kidney function in these loci. Two of these loci were validated in Black individuals, indicating potential generalizability of the loci across populations with shared ancestry. Interestingly, a genome-wide association study in HCHS/SOL failed to identify these ancestry-specific regions. These results illustrate the utility of leveraging diverse ancestries via admixture mapping for new insights into the genetics of CKD traits in studies of recently admixed populations. Background Admixture mapping is a powerful approach for gene mapping of complex traits that leverages the diverse genetic ancestry in populations with recent admixture, such as Hispanic or Latino individuals in the United States. These individuals have an increased risk of CKD. Methods We performed genome-wide admixture mapping for both CKD and eGFR in a sample of 12,601 participants from the Hispanic Community Health Study/Study of Latinos, with validation in a sample of 8191 Black participants from the Women’s Health Initiative (WHI). We also compared the findings with those from a conventional genome-wide association study. Results Three novel ancestry-of-origin loci were identified on chromosomes 2, 14, and 15 for CKD and eGFR. The chromosome 2 locus comprises two European ancestry regions encompassing the FSHR and NRXN1 genes, with European ancestry at this locus associated with increased CKD risk. The chromosome 14 locus, found within the DLK1-DIO3 imprinted domain, was associated with lower eGFR and driven by European ancestry. The eGFR-associated locus on chromosome 15 included intronic variants of RYR3 and was within an African-specific genomic region associated with higher eGFR. The genome-wide association study failed to identify significant associations in these regions. We validated the chromosome 14 and 15 loci associated with eGFR in the WHI Black participants. Conclusions This study provides evidence of shared ancestry-specific genomic regions influencing eGFR in Hispanic or Latino individuals and Black individuals and illustrates the potential for leveraging genetic ancestry in recently admixed populations for the discovery of novel candidate loci for kidney phenotypes.