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

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 KMN designed the overall study.

On a Positive Note: Current Genetic Strategies Promises a Revolutionary Transformation for the Future of Medicine

“…In addition, it can be used to reveal genes involved in complex polygenic traits and illnesses, which will expand our understanding of non-Mendelian genetics and present the big picture behind genetic interactions. 17 Due to developments in gene-sequencing technologies, we are now at the edge of transforming the field of medical genetics as we unlock previously impervious issues.…”