Systematic detection of Mendelian and non-Mendelian variants associated with retinitis pigmentosa by genome-wide association study
Nishiguchi, K. M.; Miya, F.; Fujita, K.; Akiyama, M.; Mori, Y.; Kamatani, T.; Koyanagi, Y.; Sato, K.; Takigawa, T.; Ueno, S.; Tsugita, M.; Kunikata, H.; Cisarova, K.; Nishino, J.; Murakami, A.; Abe, T.; Momozawa, Y.; Terasaki, H.; Wada, Y.; Sonoda, K.-H.; Rivolta, C.; Ishibashi, T.; Tsunoda, T.; Tsujikawa, M.; Ikeda, Y.; Nakazawa, T.
Show abstract
To uncover genetic basis of autosomal recessive retinitis pigmentosa (ARRP), we applied 2-step genome-wide association study (GWAS) in 640 Japanese patients prescreened with targeted re-sequencing. Meta-GWAS identified three independent peaks at P < 5.0x10-8, all within the major ARRP gene EYS. Two were each tagged by a low frequency variant (allele frequency < 0.05); a known founder Mendelian mutation (c.4957dupA, p.S1653Kfs*2) and a presumably hypomorphic non-synonymous variant (c.2528G>A, p.G843E). c.2528G>A newly solved 7.0% of Japanese ARRP cases, improving genetic diagnosis by 26.8% and simultaneously serving as a new attractive target for genome editing gene therapy. The third peak was tagged by an intronic common variant, representing a novel disease-susceptibility signal. GWAS successfully unraveled genetic causes of a rare "monogenic" disorder for the first time, which provided unexpected insights into significant contribution of non-Mendelian genetic factors and identified a novel high frequency variant directly linked to development of local genome therapeutics.
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