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.

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Publication Details

Journal
Nature Communications
Published
2025-12-08
DOI
https://doi.org/10.1038/s41467-025-65903-9
Primary Topic
Cerebrovascular and genetic disorders
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Luz D. Orozco, Brendan R. E. Ansell, Lebriz Altay, Danuta M. Sampson et al.
Nature Communications
Cerebrovascular and genetic disorders
article

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

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

Nature CommunicationsVol. 16(1)
Lions Eye Institute (AU), Roche (Switzerland) (CH), Queen's University Belfast (GB), Centre National de la Recherche Scientifique (FR), National Institutes of Health (US), The Royal Melbourne Hospital (AU), Moorfields Eye Hospital NHS Foundation Trust (GB), Radboud University Nijmegen (NL), Université de Bordeaux (FR), Inserm (FR), The University of Melbourne (AU), Duke University (US), Université de Bourgogne (FR), The University of Western Australia (AU), University of Cologne (DE), Walter and Eliza Hall Institute of Medical Research (AU), Hebrew University of Jerusalem (IL), University of Washington (US), Heidelberg University (DE), University Hospital Bonn (DE), Royal Perth Hospital (AU), Hadassah Medical Center (IL), University Hospital Heidelberg (DE), Radboud University Medical Center (NL), AbbVie (United States) (US), Centre Hospitalier Universitaire de Bordeaux (FR), The Royal Victorian Eye & Ear Hospital (AU), Centre for Eye Research Australia (AU), Bordeaux Population Health (FR), Duke Medical Center (US), National Eye Institute (US), Maison des Sciences sociales et des Humanités de Dijon (FR), University Hospital Cologne (DE), University Medical Centre Mannheim (DE), Centre des Sciences du Goût et de l'Alimentation (FR), University College London (GB)
U.S. Department of Health and Human Services, Office of Dietary Supplements, Sanofi, Canon Foundation for Scientific Research, European Federation of Pharmaceutical Industries and Associations, Fondation Vaincre Alzheimer, European Commission, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Fondation pour la Recherche Médicale, Fondation de France, Université de Bordeaux, Mutuelle Générale de l'Education Nationale, Fondation Voir et Entendre, National Institutes of Health, Genentech, Medical Research Council, National Health and Medical Research Council, National Institute on Aging, National Heart, Lung, and Blood Institute, National Eye Institute, National Center for Complementary and Alternative Medicine, National Institute of Neurological Disorders and Stroke, National Center for Complementary and Integrative Health
Openalex Percentile: Top 46%
Cerebrovascular and genetic disorders
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