AUTHORS
Koji M Nishiguchi, Fuyuki Miya, Yuka Mori, Kosuke Fujita, Masato Akiyama, Takashi Kamatani, Yoshito Koyanagi, Kota Sato, Toru Takigawa, Shinji Ueno, Misato Tsugita, Hiroshi Kunikata, Katarina Cisarova, Jo Nishino, Akira Murakami, Toshiaki Abe, Yukihide Momozawa, Hiroko Terasaki, Yuko Wada, Koh-Hei Sonoda, Carlo Rivolta, Tatsuhiko Tsunoda, Motokazu Tsujikawa, Yasuhiro Ikeda, Toru Nakazawa
Commun Biol. 2021 Jan 29;4(1):140. 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.
PMID:33514863 | PMC:PMC7846782 | DOI:10.1038/s42003-021-01662-9
