HTRA1/lncRNA HTRA1-AS1 dominates in age-related macular degeneration reticular pseudodrusen genetic risk with no complement involvement.

08/12/2025

Nature communications

Authors: Samaneh Farashi, Carla J Abbott, Brendan R E Ansell, Zhichao Wu, Lebriz Altay, Ella Arnon, Louis Arnould, Yelena Bagdasarova, Konstantinos Balaskas, Fred K Chen, Emily Chew, Itay Chowers, Steven Clarke, Catherine Cukras, Cécile Delcourt, Marie-Noëlle Delyfer, Anneke I den Hollander, Sascha Fauser, Robert P Finger, Pierre-Henry Gabrielle, Jiru Han, Lauren A B Hodgson, Ruth Hogg, Frank G Holz, Carel Hoyng, Himeesh Kumar, Eleonora M Lad, Aaron Lee, Ulrich F O Luhmann, Matthias M Mauschitz, Amy J McKnight, Samuel McLenachan, Aniket Mishra, Ismail Moghul, Luz D Orozco, Danuta M Sampson, Liam W Scott, Vasilena Sitnilska, Scott Song, Amy Stockwell, Anand Swaroop, Jan H Terheyden, Liran Tiosano, Adnan Tufail, Brian L Yaspan, Alice Pébay, Erica L Fletcher, Robyn H Guymer, Melanie Bahlo

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 2165 AMD+/RPD+ and 4181 AMD+/RPD- compared to 7639 control participants, both chromosomes 1 (CFH) and 10 (ARMS2/HTRA1) major AMD risk loci are reidentified. However association is only detected for the chromosome 10 locus when comparing AMD+/RPD+ to AMD+/RPD- cases. The chromosome 1 locus is notably absent. The chromosome 10 RPD risk region contains a long non-coding RNA HTRA1-AS1 (ENSG00000285955/BX842242.1) which colocalizes with genetic markers of retinal thickness. HTRA1-AS1 has a strong retinal eQTL signal, pinpointing the parafoveal photoreceptor outer segment layer. Whole genome sequencing of phenotypically extreme RPD cases identifies even stronger enrichment for the chromosome 10 risk genotype.

PMID: 41361163