PUBLICATION

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

Authors

Nishiguchi, K.M., Miya, F., Mori, Y., Fujita, K., Akiyama, M., Kamatani, T., Koyanagi, Y., Sato, K., Takigawa, T., Ueno, S., Tsugita, M., Kunikata, H., Cisarova, K., Nishino, J., Murakami, A., Abe, T., Momozawa, Y., Terasaki, H., Wada, Y., Sonoda, K.H., Rivolta, C., Tsunoda, T., Tsujikawa, M., Ikeda, Y., Nakazawa, T.

ID

ZDB-PUB-210131-6

Date

2021

Source

Communications biology 4: 140 (Journal)

Registered Authors

Tsujikawa, Motokazu

Keywords

none

MeSH Terms

Phenotype
Eye Proteins/genetics*
Eye Proteins/metabolism
Asian People/genetics
Humans
Risk Assessment
Genetic Predisposition to Disease
Cell Line
Japan
Genome-Wide Association Study
Zebrafish Proteins/genetics
Zebrafish Proteins/metabolism
Risk Factors
Retinitis Pigmentosa/diagnosis
Retinitis Pigmentosa/ethnology
Retinitis Pigmentosa/genetics*
Retinitis Pigmentosa/metabolism
Polymorphism, Single Nucleotide*
Animals
Mutation*
Case-Control Studies
Linkage Disequilibrium
Zebrafish/genetics
Zebrafish/metabolism
High-Throughput Nucleotide Sequencing

PubMed

33514863 Full text @ Commun Biol

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.

Genes / Markers

Figures