Genetic Risk of Reticular Pseudodrusen in Age-Related Macular Degeneration: HTRA1/lncRNA BX842242.1 dominates, with no evidence for Complement Cascade involvement

Abstract

Age-related macular degeneration (AMD) is a multifactorial retinal disease with a large genetic risk contribution. Reticular pseudodrusen (RPD) is a sub-phenotype of AMD with a high risk of progression to late vision threatening AMD. In a genome-wide association study of 2,165 AMD+/RPD+ and 4,181 AMD+/RPD-compared to 7,660 control participants, both chromosomes 1 (CFH) and 10 (ARMS2/HTRA1) major AMD risk loci were reidentified. However association was only detected for the chromosome 10 locus when comparing AMD+/RPD+ to AMD+/RPD-cases. The chromosome 1 locus was notably absent. The chromosome 10 RPD risk region contains a long non-coding RNA (ENSG00000285955/BX842242.1) which colocalizes with genetic markers of retinal thickness. BX842242.1 has a strong retinal eQTL signal, pinpointing the parafoveal photoreceptor outer segment layer. Whole genome sequencing of phenotypically extreme RPD cases identified even stronger enrichment for the chromosome 10 risk genotype.