Admixture Mapping Identifies an Amerindian Ancestry Locus Associated with Albuminuria in Hispanics in the United States

Abstract

Increased urine albumin excretion is highly prevalent in Hispanics/Latinos. Previous studies have found an association between urine albumin excretion and Amerindian ancestry in Hispanic/Latino populations. Admixture between racial/ethnic groups creates long-range linkage disequilibrium between variants with different allelic frequencies in the founding populations and it can be used to localize genes. Hispanic/Latino genomes are an admixture of European, African, and Amerindian ancestries. We leveraged this admixture to identify associations between urine albumin excretion (urine albumin-to-creatinine ratio [UACR]) and genomic regions harboring variants with highly differentiated allele frequencies among the ancestral populations. Admixture mapping analysis of 12,212 Hispanic Community Health Study/Study of Latinos participants, using a linear mixed model, identified three novel genome-wide significant signals on chromosomes 2, 11, and 16. The admixture mapping signal identified on chromosome 2, spanning q11.2-14.1 and not previously reported for UACR, is driven by a difference between Amerindian ancestry and the other two ancestries (P<5.7 × 10^-5). Within this locus, two common variants located at the proapoptotic BCL2L11 gene associated with UACR: rs116907128 (allele frequency =0.14; P=1.5 × 10^-7) and rs586283 (C allele frequency =0.35; P=4.2 × 10^-7). In a secondary analysis, rs116907128 accounted for most of the admixture mapping signal observed in the region. The rs116907128 variant is common among full-heritage Pima Indians (A allele frequency =0.54) but is monomorphic in the 1000 Genomes European and African populations. In a replication analysis using a sample of full-heritage Pima Indians, rs116907128 significantly associated with UACR (P=0.01; n=1568). Our findings provide evidence for the presence of Amerindian-specific variants influencing the variation of urine albumin excretion in Hispanics/Latinos.

Keywords: albumins; albuminuria; ethnic groups; ethnic minority; genomics; human genetics.

Figure 1.

Manhattan plot of admixture mapping of UACR in the HCHS/SOL population, n=12,212. (A) Three genome-wide loci reached the significance threshold (P<5.7 × 10⁻⁵, dashed lines). (B) Admixture mapping conditional on rs116907128. (C) Admixture mapping conditional on rs586283. In each plot, the x axis is chromosome position and the y axis is the −log10(P value) for the joint test of variation among the three local ancestry types.

Figure 2.

Manhattan plot of admixture mapping of UACR for each local ancestry type separately in the HCHS/SOL population, n=12,212: (A) Amerindian versus non-Amerindian; (B) European versus non-European; (C) African versus non-African. x axis is chromosome position and y axis is the −log10(P value) for admixture mapping analyses. The dashed line is the threshold for genome-wide significance (P<5.7 × 10⁻⁵).

Figure 3.

Single-variant and admixture association analyses within the regions on chromosomes 2, 11, and 16 showing admixture mapping signals in the HCHS/SOL population, n=12,212. For each plot, the x axis is chromosome position and the y axis is the −log10(P value) for admixture mapping analyses (blue lines) and single SNP association with UACR (black dots). The red dashed line is the threshold for the genome-wide admixture mapping (P<5.7 × 10⁻⁵). The gray dashed line is the threshold for association if the study was a GWAS.