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
  • Animals
  • Asians/genetics
  • Case-Control Studies
  • Cell Line
  • Eye Proteins/genetics*
  • Eye Proteins/metabolism
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Japan
  • Linkage Disequilibrium
  • Mutation*
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Retinitis Pigmentosa/diagnosis
  • Retinitis Pigmentosa/ethnology
  • Retinitis Pigmentosa/genetics*
  • Retinitis Pigmentosa/metabolism
  • Risk Assessment
  • Risk Factors
  • Zebrafish/genetics
  • Zebrafish/metabolism
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
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
Show all Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes