Systematic detection of Mendelian and non-Mendelian variants associated with retinitis pigmentosa by genome-wide association study

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 < 5.0×10-8, 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.