Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis

Abstract

The identification of small molecules that target specific CFTR variants has ushered in a new era of treatment for cystic fibrosis (CF), yet optimal, individualized treatment of CF will require identification and targeting of disease modifiers. Here we use genome-wide association analysis to identify genetic modifiers of CF lung disease, the primary cause of mortality. Meta-analysis of 6,365 CF patients identifies five loci that display significant association with variation in lung disease. Regions on chr3q29 (MUC4/MUC20; P=3.3 × 10(-11)), chr5p15.3 (SLC9A3; P=6.8 × 10(-12)), chr6p21.3 (HLA Class II; P=1.2 × 10(-8)) and chrXq22-q23 (AGTR2/SLC6A14; P=1.8 × 10(-9)) contain genes of high biological relevance to CF pathophysiology. The fifth locus, on chr11p12-p13 (EHF/APIP; P=1.9 × 10(-10)), was previously shown to be associated with lung disease. These results provide new insights into potential targets for modulating lung disease severity in CF.

Figure 1. Genome-wide Manhattan plot of associations with the Consortium lung phenotype.

Evidence from GWAS1+2 for all patients (closed circles) and for p.Phe508del homozygotes (open triangles). The horizontal dashed line represents the threshold for genome-wide significance (P<1.25 × 10⁻⁸). Genome-wide significance was achieved in five regions. The results from regions on chr5p15, chr11p12-p13 and chrXq22-q23 are from meta-analysis using a random effects model, and for chr3q29 and chr6p21 using a fixed effects model.

Figure 2. LocusZoom and forest plots for five regions with significant association in GWAS1+2.

On the left side of the five panels are plots of the association evidence (build GRCh37, LocusZoom viewer) in the five genome-wide significant regions for all patients, except that chr11p12-p13 shows only p.Phe508del homozygotes. Colours represent 1000 Genomes EUR linkage disequilibrium r² values with each SNP in column three of Table 2 (shown as purple diamonds and labelled with dbSNP ID). The purple diamond in the chr6 region denotes the SNP that has independent genotype confirmation, but the top imputed SNP is also indicated by a dbSNP ID (rs number). On the right side of the five panels are forest plots of the relative effect sizes for the most significant SNP in each of the 13 subgroups, ordered by size. Beta (coefficient) refers to the average change in Consortium lung phenotype for each copy of the minor allele. The size and shape of the squares are proportional to the weights used in the meta-analysis, and the line segments are 95% confidence intervals of each beta. The black diamonds represent summary data for GWAS1, GWAS2, and GWAS1+2. The asterisk on chr6 (HLA region) forest plot illustrates a beta (and confidence interval) for the FrGMC CNV370 subgroup of −19.9 (−35.4, −4.4). In addition, the beta (and confidence interval) for four other subgroups in the chr6 region are as follows: GMS Omni5, 0.87 (−19.5, 21.2); TSS 660W-set 2, −1.67 (−19.6, 16.3); TSS Omni5, 15.4 (−14.1, 44.8); and CGS Omni5, 1.7 (−23.8, 27.2).