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

Koji M Nishiguchi,Kota Sato,Katarina Cisarova,Yoshiyuki Mori ,Takashi Kamatani,Hiroshi Kunikata,Yasuhiro Ikeda,Yoshito Koyanagi,Toru Takigawa,Kosuke Fujita,Motokazu Tsujikawa,Toshiaki Abe,Hiroko Terasaki,Fuyuki Miya,Misato Tsugita,Akira Murakami,Yuko Wada,Masato Akiyama,Koh Hei Sonoda ,Carlo Rivolta,Junichi Nishino ,Yukihide Momozawa,Shinji Ueno,Tatsuhiko Tsunoda,Toru Nakazawa

doi:10.1038/s42003-021-01662-9

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.

Highlights

The genetic basis of Japanese autosomal recessive retinitis pigmentosa (ARRP) remains largely unknown
Of the 644 cases and 620 controls genotyped in the first genome-wide association study (GWAS), 432 cases and 603 controls were used for analysis in the end after removing 63 cases and 21 controls that failed quality control (QC) and an additional 149 solved cases in which NGS panel test identified pathogenic mutations to account for the cause of disease[11]
To investigate whether the EYS locus contains multiple variants independently associated with the disease that are not included in the same linkage disequilibrium block, we performed conditional analysis

Summary

Introduction

The genetic basis of Japanese autosomal recessive retinitis pigmentosa (ARRP) remains largely unknown. There is an urgent need for genetic diagnosis of these unsolved cases, those with the autosomal recessive inheritance pattern of retinitis pigmentosa (ARRP), caused by loss-of-function mutations, because such patients may be amenable to adeno-associated virus (AAV)mediated gene supplementation therapy[14]. By comparing differences in allele frequency in cases and controls, GWAS can provide unbiased means of detecting disease-associated loci evenly across the genome, with a little assumption of the inheritance pattern. This contrasts with caseoriented sequencing approaches, which are often obliged to focus around exons and their boundaries, to identify mutations that follow classic Mendelian inheritance. We report the detection of three disease-associated signals/variants in patients with presumed ARRP (see below), using an integrated approach that combined GWAS with NGS panel test

Methods

Results

Conclusion