A hypomorphic variant in EYS detected by genome-wide association study contributes toward retinitis pigmentosa

The genetic basis of Japanese autosomal recessive retinitis pigmentosa (ARRP) remains largely unknown. Herein, we applied a 2-step genome-wide association study (GWAS) in 640 Japanese patients. Meta-GWAS identified three independent peaks at P<5.0x10(-8), all within the major ARRP gene EYS. Two of the three were each in linkage disequilibrium with a different low frequency variant (allele frequency<0.05); a known founder Mendelian mutation (c.4957dupA, p.S1653Kfs*2) and a non-synonymous variant (c.2528G>A, p.G843E) of unknown significance. mRNA harboring c.2528G>A failed to restore rhodopsin mislocalization induced by morpholino-mediated knockdown of eys in zebrafish, consistent with the variant being pathogenic. c.2528G>A solved an additional 7.0% of Japanese ARRP cases. The third peak was in linkage disequilibrium with a common non-synonymous variant (c.7666A>T, p.S2556C), possibly representing an unreported disease-susceptibility signal. GWAS successfully unraveled genetic causes of a rare monogenic disorder and identified a high frequency variant potentially linked to development of local genome therapeutics. Koji Nishiguchi et al. identify three genetic variants within the EYS gene that are associated with retinitis pigmentosa using a genome-wide association study. They demonstrate that one of these variants (G843E) causes retinal dysfunction in zebrafish, suggesting a causal role for EYS in retinitis pigmentosa.

Automated summary

Nishiguchi and colleagues identified three genetic variants within the EYS gene associated with retinitis pigmentosa using a genome-wide association study (GWAS). They demonstrated that one of these variants was pathogenic, able to explain an additional 7.0% of Japanese ARRP cases. Additionally, they found a high frequency variant potentially linked to the development of local genome therapeutics.