TY - JOUR
T1 - A hypomorphic variant in EYS detected by genome-wide association study contributes toward retinitis pigmentosa
AU - Nishiguchi, Koji
AU - Miya, Fuyuki
AU - Mori, Yuka
AU - Fujita, Kosuke
AU - Akiyama, Masato
AU - Kamatani, Takashi
AU - Koyanagi, Yoshito
AU - Sato, Kota
AU - Takigawa, Toru
AU - Ueno, Shinji
AU - Tsugita, Misato
AU - Kunikata, Hiroshi
AU - Cisarova, Katarina
AU - Nishino, Jo
AU - Murakami, Akira
AU - Abe, Toshiaki
AU - Momozawa, Yukihide
AU - Terasaki, Hiroko
AU - Wada, Yuko
AU - Sonoda, Koh Hei
AU - Rivolta, Carlo
AU - Tsunoda, Tatsuhiko
AU - Tsujikawa, Motokazu
AU - Ikeda, Yasuhiro
AU - Nakazawa, Toru
N1 - Funding Information:
The study was supported by the Japan Retinitis Pigmentosa Registry Project. We thank J. Inazawa and M. Takaoka (Bioresource Laboratory, Tokyo Medical and Dental University) for technical support in establishing the patient-derived LCLs. This study was supported in part by the Japan Agency for Medical Research and Development (#19ek0109213h0003, K.M.N. and #JP18lk1403004, T.A.) and Swiss National Science Foundation (#31003A_176097, C.R.).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s42003-021-01662-9
DO - 10.1038/s42003-021-01662-9
M3 - Article
C2 - 33514863
AN - SCOPUS:85099921674
SN - 2399-3642
VL - 4
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 140
ER -