HTRA1/lncRNA HTRA1-AS1 dominates in age-related macular degeneration reticular pseudodrusen genetic risk with no complement involvement
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.
Citation
@article{farashi2025,
author = {Farashi, Samaneh and J. Abbott, Carla and R. E. Ansell,
Brendan and Wu, Zhichao and Altay, Lebriz and Arnon, Ella and
Arnould, Louis and Bagdasarova, Yelena and Balaskas, Konstantinos
and K. Chen, Fred and Chew, Emily and Chowers, Itay and Clarke,
Steven and Cukras, Catherine and Delcourt, Cécile and Delyfer,
Marie-Noëlle and I. den Hollander, Anneke and Fauser, Sascha and P.
Finger, Robert and Gabrielle, Pierre-Henry and Han, Jiru and A. B.
Hodgson, Lauren and Hogg, Ruth and G. Holz, Frank and Hoyng, Carel
and Kumar, Himeesh and M. Lad, Eleonora and Lee, Aaron and F. O.
Luhmann, Ulrich and M. Mauschitz, Matthias and J. McKnight, Amy and
McLenachan, Samuel and Mishra, Aniket and Moghul, Ismail and D.
Orozco, Luz and M. Sampson, Danuta and W. Scott, Liam and Sitnilska,
Vasilena and Song, Scott and Stockwell, Amy and Swaroop, Anand and
H. Terheyden, Jan and Tiosano, Liran and Tufail, Adnan and L.
Yaspan, Brian and consortium, MACUSTAR and consortium, NICOLA and
Pébay, Alice and L. Fletcher, Erica and H. Guymer, Robyn and Bahlo,
Melanie and behalf of the Reticular Pseudodrusen Consortium, On},
title = {HTRA1/lncRNA {HTRA1-AS1} Dominates in Age-Related Macular
Degeneration Reticular Pseudodrusen Genetic Risk with No Complement
Involvement},
journal = {Nature Communications},
volume = {16},
date = {2025-12-08},
url = {https://doi.org/10.1038/s41467-025-65903-9},
doi = {10.1038/s41467-025-65903-9},
langid = {en},
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 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.}
}