A hypomorphic variant in EYS detected by genome-wide association study contributes toward retinitis pigmentosa.
Commun Biol
; 4(1): 140, 2021 01 29.
Article
in En
| MEDLINE
| ID: mdl-33514863
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Retinitis Pigmentosa
/
Polymorphism, Single Nucleotide
/
Eye Proteins
/
Mutation
Type of study:
Diagnostic_studies
/
Etiology_studies
/
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Limits:
Animals
/
Humans
Country/Region as subject:
Asia
Language:
En
Journal:
Commun Biol
Year:
2021
Document type:
Article
Affiliation country:
Japan