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- Title
A hypomorphic variant in EYS detected by genome-wide association study contributes toward retinitis pigmentosa.
- Authors
Nishiguchi, Koji M.; Miya, Fuyuki; Mori, Yuka; Fujita, Kosuke; Akiyama, Masato; Kamatani, Takashi; Koyanagi, Yoshito; Sato, Kota; Takigawa, Toru; Ueno, Shinji; Tsugita, Misato; Kunikata, Hiroshi; Cisarova, Katarina; Nishino, Jo; Murakami, Akira; Abe, Toshiaki; Momozawa, Yukihide; Terasaki, Hiroko; Wada, Yuko; Sonoda, Koh-Hei
- Abstract
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 < 5.0 × 10−8, 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.2528 G > A, p.G843E) of unknown significance. mRNA harboring c.2528 G > A failed to restore rhodopsin mislocalization induced by morpholino-mediated knockdown of eys in zebrafish, consistent with the variant being pathogenic. c.2528 G > A solved an additional 7.0% of Japanese ARRP cases. The third peak was in linkage disequilibrium with a common non-synonymous variant (c.7666 A > 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.
- Subjects
RETINITIS pigmentosa; MESSENGER RNA; RHODOPSIN; BALANCE disorders; DISEASE susceptibility
- Publication
Communications Biology, 2021, Vol 4, Issue 1, p1
- ISSN
2399-3642
- Publication type
Article
- DOI
10.1038/s42003-021-01662-9