A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy

Konstantinos Nikopoulos; Katarina Cisarova; Mathieu Quinodoz; Hanna Koskiniemi-Kuendig; Noriko Miyake; Pietro Farinelli; Atta Ur Rehman; Muhammad Imran Khan; Andrea Prunotto; Masato Akiyama; Yoichiro Kamatani; Chikashi Terao; Fuyuki Miya; Yasuhiro Ikeda; Shinji Ueno; Nobuo Fuse; Akira Murakami; Yuko Wada; Hiroko Terasaki; Koh Hei Sonoda; Tatsuro Ishibashi; Michiaki Kubo; Frans P.M. Cremers; Zoltán Kutalik; Naomichi Matsumoto; Koji M. Nishiguchi; Toru Nakazawa; Carlo Rivolta

doi:10.1038/s41467-019-10746-4

A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy

Konstantinos Nikopoulos, Katarina Cisarova, Mathieu Quinodoz, Hanna Koskiniemi-Kuendig, Noriko Miyake, Pietro Farinelli, Atta Ur Rehman, Muhammad Imran Khan, Andrea Prunotto, Masato Akiyama, Yoichiro Kamatani, Chikashi Terao, Fuyuki Miya, Yasuhiro Ikeda, Shinji Ueno, Nobuo Fuse, Akira Murakami, Yuko Wada, Hiroko Terasaki, Koh Hei SonodaTatsuro Ishibashi, Michiaki Kubo, Frans P.M. Cremers, Zoltán Kutalik, Naomichi Matsumoto, Koji M. Nishiguchi, Toru Nakazawa, Carlo Rivolta

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Abstract

Hereditary retinal degenerations (HRDs) are Mendelian diseases characterized by progressive blindness and caused by ultra-rare mutations. In a genomic screen of 331 unrelated Japanese patients, we identify a disruptive Alu insertion and a nonsense variant (p.Arg1933*) in the ciliary gene RP1, neither of which are rare alleles in Japan. p.Arg1933* is almost polymorphic (frequency = 0.6%, amongst 12,000 individuals), does not cause disease in homozygosis or heterozygosis, and yet is significantly enriched in HRD patients (frequency = 2.1%, i.e., a 3.5-fold enrichment; p-value = 9.2 × 10⁻⁵). Familial co-segregation and association analyses show that p.Arg1933* can act as a Mendelian mutation in trans with the Alu insertion, but might also associate with disease in combination with two alleles in the EYS gene in a non-Mendelian pattern of heredity. Our results suggest that rare conditions such as HRDs can be paradoxically determined by relatively common variants, following a quasi-Mendelian model linking monogenic and complex inheritance.

Original language	English
Article number	2884
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-10746-4
Publication status	Published - 2019 Dec 1

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
General
Physics and Astronomy(all)

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10.1038/s41467-019-10746-4

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Nikopoulos, K., Cisarova, K., Quinodoz, M., Koskiniemi-Kuendig, H., Miyake, N., Farinelli, P., Rehman, A. U., Khan, M. I., Prunotto, A., Akiyama, M., Kamatani, Y., Terao, C., Miya, F., Ikeda, Y., Ueno, S., Fuse, N., Murakami, A., Wada, Y., Terasaki, H., ... Rivolta, C. (2019). A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy. Nature communications, 10(1), [2884]. https://doi.org/10.1038/s41467-019-10746-4

Nikopoulos, K, Cisarova, K, Quinodoz, M, Koskiniemi-Kuendig, H, Miyake, N, Farinelli, P, Rehman, AU, Khan, MI, Prunotto, A, Akiyama, M, Kamatani, Y, Terao, C, Miya, F, Ikeda, Y, Ueno, S, Fuse, N, Murakami, A, Wada, Y, Terasaki, H, Sonoda, KH, Ishibashi, T, Kubo, M, Cremers, FPM, Kutalik, Z, Matsumoto, N, Nishiguchi, KM, Nakazawa, T & Rivolta, C 2019, 'A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy', Nature communications, vol. 10, no. 1, 2884. https://doi.org/10.1038/s41467-019-10746-4

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title = "A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy",

abstract = "Hereditary retinal degenerations (HRDs) are Mendelian diseases characterized by progressive blindness and caused by ultra-rare mutations. In a genomic screen of 331 unrelated Japanese patients, we identify a disruptive Alu insertion and a nonsense variant (p.Arg1933*) in the ciliary gene RP1, neither of which are rare alleles in Japan. p.Arg1933* is almost polymorphic (frequency = 0.6%, amongst 12,000 individuals), does not cause disease in homozygosis or heterozygosis, and yet is significantly enriched in HRD patients (frequency = 2.1%, i.e., a 3.5-fold enrichment; p-value = 9.2 × 10−5). Familial co-segregation and association analyses show that p.Arg1933* can act as a Mendelian mutation in trans with the Alu insertion, but might also associate with disease in combination with two alleles in the EYS gene in a non-Mendelian pattern of heredity. Our results suggest that rare conditions such as HRDs can be paradoxically determined by relatively common variants, following a quasi-Mendelian model linking monogenic and complex inheritance.",

author = "Konstantinos Nikopoulos and Katarina Cisarova and Mathieu Quinodoz and Hanna Koskiniemi-Kuendig and Noriko Miyake and Pietro Farinelli and Rehman, {Atta Ur} and Khan, {Muhammad Imran} and Andrea Prunotto and Masato Akiyama and Yoichiro Kamatani and Chikashi Terao and Fuyuki Miya and Yasuhiro Ikeda and Shinji Ueno and Nobuo Fuse and Akira Murakami and Yuko Wada and Hiroko Terasaki and Sonoda, {Koh Hei} and Tatsuro Ishibashi and Michiaki Kubo and Cremers, {Frans P.M.} and Zolt{\'a}n Kutalik and Naomichi Matsumoto and Nishiguchi, {Koji M.} and Toru Nakazawa and Carlo Rivolta",

note = "Funding Information: This work was supported by the following agencies. The Swiss National Science Foundation (grant #176097, to C.R.); the Rotterdamse Stichting Blindenbelangen, the Stichting voor Ooglijders and the Nelly Reef fund (to M.I.K. and F.P.M.C.); the Japan Agency for Medical Research and Development (grant #17ek0109213h0001) and the Japan Society for the Promotion of Science (grant #16K11315, to K.M.N.); Research on Measures for Intractable Diseases, Comprehensive Research on Disability Health and Welfare, the Strategic Research Program for Brain Science, and the Initiative on Rare and Undiagnosed Diseases (all to N.Ma.); the Japanese Agency for Medical Research and Development, Grants-in-Aid for Scientific Research (to N.Ma. and N.Mi.); the BioBank Japan Project, by the Japanese Ministry of Education, Culture, Sport, Science and Technology and the Japanese Agency for Medical Research and Development (to M.K.); the PhD Fellowship in Life Sciences (Faculty of Biology and Medicine, University of Lausanne), to M.Q. Most HRD patients were recruited from the Japanese Retinitis Pigmentosa Registry Project (JRPRP). The authors would also like to warmly thank Dr. Matthew Robinson for his expert advice on this work. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-10746-4",

language = "English",

volume = "10",

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T1 - A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy

AU - Nikopoulos, Konstantinos

AU - Cisarova, Katarina

AU - Quinodoz, Mathieu

AU - Koskiniemi-Kuendig, Hanna

AU - Miyake, Noriko

AU - Farinelli, Pietro

AU - Rehman, Atta Ur

AU - Khan, Muhammad Imran

AU - Prunotto, Andrea

AU - Akiyama, Masato

AU - Kamatani, Yoichiro

AU - Terao, Chikashi

AU - Miya, Fuyuki

AU - Ikeda, Yasuhiro

AU - Ueno, Shinji

AU - Fuse, Nobuo

AU - Murakami, Akira

AU - Wada, Yuko

AU - Terasaki, Hiroko

AU - Sonoda, Koh Hei

AU - Ishibashi, Tatsuro

AU - Kubo, Michiaki

AU - Cremers, Frans P.M.

AU - Kutalik, Zoltán

AU - Matsumoto, Naomichi

AU - Nishiguchi, Koji M.

AU - Nakazawa, Toru

AU - Rivolta, Carlo

N1 - Funding Information: This work was supported by the following agencies. The Swiss National Science Foundation (grant #176097, to C.R.); the Rotterdamse Stichting Blindenbelangen, the Stichting voor Ooglijders and the Nelly Reef fund (to M.I.K. and F.P.M.C.); the Japan Agency for Medical Research and Development (grant #17ek0109213h0001) and the Japan Society for the Promotion of Science (grant #16K11315, to K.M.N.); Research on Measures for Intractable Diseases, Comprehensive Research on Disability Health and Welfare, the Strategic Research Program for Brain Science, and the Initiative on Rare and Undiagnosed Diseases (all to N.Ma.); the Japanese Agency for Medical Research and Development, Grants-in-Aid for Scientific Research (to N.Ma. and N.Mi.); the BioBank Japan Project, by the Japanese Ministry of Education, Culture, Sport, Science and Technology and the Japanese Agency for Medical Research and Development (to M.K.); the PhD Fellowship in Life Sciences (Faculty of Biology and Medicine, University of Lausanne), to M.Q. Most HRD patients were recruited from the Japanese Retinitis Pigmentosa Registry Project (JRPRP). The authors would also like to warmly thank Dr. Matthew Robinson for his expert advice on this work. Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Hereditary retinal degenerations (HRDs) are Mendelian diseases characterized by progressive blindness and caused by ultra-rare mutations. In a genomic screen of 331 unrelated Japanese patients, we identify a disruptive Alu insertion and a nonsense variant (p.Arg1933*) in the ciliary gene RP1, neither of which are rare alleles in Japan. p.Arg1933* is almost polymorphic (frequency = 0.6%, amongst 12,000 individuals), does not cause disease in homozygosis or heterozygosis, and yet is significantly enriched in HRD patients (frequency = 2.1%, i.e., a 3.5-fold enrichment; p-value = 9.2 × 10−5). Familial co-segregation and association analyses show that p.Arg1933* can act as a Mendelian mutation in trans with the Alu insertion, but might also associate with disease in combination with two alleles in the EYS gene in a non-Mendelian pattern of heredity. Our results suggest that rare conditions such as HRDs can be paradoxically determined by relatively common variants, following a quasi-Mendelian model linking monogenic and complex inheritance.

AB - Hereditary retinal degenerations (HRDs) are Mendelian diseases characterized by progressive blindness and caused by ultra-rare mutations. In a genomic screen of 331 unrelated Japanese patients, we identify a disruptive Alu insertion and a nonsense variant (p.Arg1933*) in the ciliary gene RP1, neither of which are rare alleles in Japan. p.Arg1933* is almost polymorphic (frequency = 0.6%, amongst 12,000 individuals), does not cause disease in homozygosis or heterozygosis, and yet is significantly enriched in HRD patients (frequency = 2.1%, i.e., a 3.5-fold enrichment; p-value = 9.2 × 10−5). Familial co-segregation and association analyses show that p.Arg1933* can act as a Mendelian mutation in trans with the Alu insertion, but might also associate with disease in combination with two alleles in the EYS gene in a non-Mendelian pattern of heredity. Our results suggest that rare conditions such as HRDs can be paradoxically determined by relatively common variants, following a quasi-Mendelian model linking monogenic and complex inheritance.

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DO - 10.1038/s41467-019-10746-4

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JO - Nature Communications

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ER -

A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy

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