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

Samaneh Farashi; Carla J. Abbott; Brendan R. E. Ansell; Zhichao Wu; Lebriz Altay; Ella Arnon; Louis Arnould; Yelena Bagdasarova; Konstantinos Balaskas; Fred Kuanfu Chen; Emily Y. Chew; Itay Chowers; Steven Clarke; Catherine A. Cukras; Cécile Delcourt; Marie‐Noëlle Delyfer; Anneke I. den Hollander; Sascha Fauser; Robert Patrick Finger; Pierre‐Henry Gabrielle; Jiru Han; Lauren Hodgson; Ruth Esther Hogg; Frank Gerhard Holz; Carel C B Hoyng; Himeesh Kumar; Eleonora Maries Lad; Aaron Lee; Ulrich F. O. Luhmann; Matthias Marten Mauschitz

doi:10.1038/s41467-025-65903-9

Genetic & Genomic MedicineNature CommunicationsDec 8, 2025

Peer-reviewed journal article

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

Samaneh Farashi iD, Carla J. Abbott iD, Brendan R. E. Ansell iD, Zhichao Wu iD, Lebriz Altay iD, Ella Arnon, Louis Arnould iD, Yelena Bagdasarova, Konstantinos Balaskas iD, Fred Kuanfu Chen iD, Emily Y. Chew iD, Itay Chowers iD, Steven Clarke iD, Catherine A. Cukras iD, Cécile Delcourt iD, Marie‐Noëlle Delyfer iD, Anneke I. den Hollander iD, Sascha Fauser, Robert Patrick Finger iD, Pierre‐Henry Gabrielle iD, Jiru Han iD, Lauren Hodgson iD, Ruth Esther Hogg iD, Frank Gerhard Holz iD, Carel C B Hoyng, , Melanie Bahlo iD

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.

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