Genome-wide association identifies novel ROP risk loci in a multiethnic cohort

Abstract

We conducted a genome-wide association study (GWAS) in a multiethnic cohort of 920 at-risk infants for retinopathy of prematurity (ROP), a major cause of childhood blindness, identifying 1 locus at genome-wide significance level (p < 5×10^-8) and 9 with significance of p < 5×10^-6 for ROP ≥ stage 3. The most significant locus, rs2058019, reached genome-wide significance within the full multiethnic cohort (p = 4.96×10^-9); Hispanic and European Ancestry infants driving the association. The lead single nucleotide polymorphism (SNP) falls in an intronic region within the Glioma-associated oncogene family zinc finger 3 (GLI3) gene. Relevance for GLI3 and other top-associated genes to human ocular disease was substantiated through in-silico extension analyses, genetic risk score analysis and expression profiling in human donor eye tissues. Thus, we identify a novel locus at GLI3 with relevance to retinal biology, supporting genetic susceptibilities for ROP risk with possible variability by race and ethnicity.

Fig. 1. Manhattan plot of genome-wide association with ROP severity (stage 3 or greater).

Data were analyzed for all populations combined. The red line on indicates genome-wide significance (p ≤ 5 × 10^-8) with points above this line indicating SNPs with GWS.

Fig. 2. Regional association plots of top genome-wide significant SNP rs2058019 (GLI3 gene) among each ethnic group.

Depicted in (a–d), are SNP associations for ROP severity within the GLI3 gene for each racial or ethnic group [a European Ancestry; b African American, c Hispanic, and d all combined samples].