A Genome-Wide Association Study in Hispanics/Latinos Identifies Novel Signals for Lung Function. The Hispanic Community Health Study/Study of Latinos

Abstract

Rationale: Lung function and chronic obstructive pulmonary disease (COPD) are heritable traits. Genome-wide association studies (GWAS) have identified numerous pulmonary function and COPD loci, primarily in cohorts of European ancestry.

Objectives: Perform a GWAS of COPD phenotypes in Hispanic/Latino populations to identify loci not previously detected in European populations.

Methods: GWAS of lung function and COPD in Hispanic/Latino participants from a population-based cohort. We performed replication studies of novel loci in independent studies.

Measurements and main results: Among 11,822 Hispanic/Latino participants, we identified eight novel signals; three replicated in independent populations of European Ancestry. A novel locus for FEV₁ in ZSWIM7 (rs4791658; P = 4.99 × 10^-9) replicated. A rare variant (minor allele frequency = 0.002) in HAL (rs145174011) was associated with FEV₁/FVC (P = 9.59 × 10^-9) in a region previously identified for COPD-related phenotypes; it remained significant in conditional analyses but did not replicate. Admixture mapping identified a novel region, with a variant in AGMO (rs41331850), associated with Amerindian ancestry and FEV₁, which replicated. A novel locus for FEV₁ identified among ever smokers (rs291231; P = 1.92 × 10^-8) approached statistical significance for replication in admixed populations of African ancestry, and a novel SNP for COPD in PDZD2 (rs7709630; P = 1.56 × 10^-8) regionally replicated. In addition, loci previously identified for lung function in European samples were associated in Hispanic/Latino participants in the Hispanic Community Health Study/Study of Latinos at the genome-wide significance level.

Conclusions: We identified novel signals for lung function and COPD in a Hispanic/Latino cohort. Including admixed populations when performing genetic studies may identify variants contributing to genetic etiologies of COPD.

Keywords: Hispanic/Latino; chronic obstructive pulmonary disease; genome-wide association study; lung function; single-nucleotide polymorphisms.

Figure 1.

Regional association plots and forest plots of genome-wide significant loci associated with FEV₁ and FEV₁/FVC meta-analyzed across all Hispanic/Latino ancestry groups. For each locus, we provide regional association plots with correlations between the reference SNP (the SNP with the lowest P value) and other SNPs in the region. The reference SNP is a purple diamond (genotyped SNP) or upside down triangle (imputed SNP). Other SNPs in the region are depicted as circles (genotyped SNPs) and Xs (imputed SNPs). The correlations (r²) are calculated from the group of interest and are indicated by the colors shown on the plot. For each locus, we also provide a forest plot comparing the SNP–trait association testing results across the Hispanic/Latino ancestry groups. (A) Regional association plot for the FEV₁ locus (lead SNP rs4791658) on chromosome 17. (B) Forest plot for the FEV₁ locus (lead SNP rs4791658) on chromosome 17. (C) Regional association plot for the FEV₁/FVC locus (lead SNP rs145174011) on chromosome 12. (D) Forest plot for the FEV₁/FVC locus (lead SNP rs192375903) on chromosome 12. EAfreq = effect allele frequency.

Figure 2.

Regional association plots and forest plots of genome-wide significant loci associated with FEV₁ and FEV₁/FVC stratified by smoking status and meta-analyzed across all Hispanic/Latino ancestry groups. For each locus, we provide regional association plots with correlations between the reference SNP (the SNP with the lowest P value) and other SNPs in the region. The reference SNP is a purple diamond (genotyped SNP) or upside down triangle (imputed SNP). Other SNPs in the region are depicted as circles (genotyped SNPs) and Xs (imputed SNPs). The correlations (r²) are calculated from the group of interest and are indicated by the colors shown on the plot. For each locus, we also provide a forest plot comparing the SNP–trait association testing results across the Hispanic/Latino ancestry in smoking stratified group of interest. (A) Regional association plot for the FEV₁/FVC locus among never smokers (lead SNP rs7228593) on chromosome 18. (B) Forest plot for the FEV₁/FVC locus among never smokers (lead SNP rs7228593) on chromosome 18. (C) Regional association plot for the FEV₁ locus among ever smokers (lead SNP rs291231) on chromosome 11. (D) Forest plot for the FEV₁ locus among ever smokers (lead SNP rs291231) on chromosome 11. EAfreq = effect allele frequency.

Figure 3.

Regional association plot and forest plot of candidate variant identified in local ancestry interval region associated with Amerindian ancestry and FEV₁ meta-analyzed across all Hispanic/Latino ancestry groups. For each locus, we provide regional association plots with correlations between the reference SNP (the SNP with the lowest P value) and other SNPs in the region. The reference SNP is a purple diamond (genotyped SNP) or upside-down triangle (imputed SNP). Other SNPs in the region are depicted as circles (genotyped SNPs) and Xs (imputed SNPs). The correlations (r²) are calculated from the group of interest and are indicated by the colors shown on the plot. We also provide a forest plot comparing the SNP–trait association testing results across the Hispanic/Latino ancestry groups. (A) Regional association plot for the FEV₁ locus (lead SNP rs4133185) on chromosome 7. (B) Forest plot for the FEV₁ locus (lead SNP rs4133185) on chromosome 7. EAfreq = effect allele frequency.

Figure 4.

Amerindian admixture mapping region on chromosome 7 for FEV₁. The left panel provides the admixture mapping results as two lines, with the blue line representing results from the primary analysis and the green line representing results from the conditional analysis; the association results in the same region are represented as circles. The genome-wide significant threshold for admixture mapping in the HCHS/SOL (Hispanic Community Health Study/Study of Latinos) data set is the horizontal gray dashed line. The blue and green lines and circles are given as −log₁₀(P value) against genomic positions. The red-filled triangle corresponds to the SNP used in the conditional analysis (rs4133185). The right panel provides the ancestry-specific effect allele frequencies for the SNP used in the conditional analysis (rs4133185), as estimated by ancestry-specific allele frequency estimation applied on HCHS/SOL data set (44).