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
-
- High-Throughput Nucleotide Sequencing
- Polymorphism, Single Nucleotide*
- Eye Proteins/genetics*
- Eye Proteins/metabolism
- Genome-Wide Association Study
- 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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping