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.
Authors
- Luz D. Orozco (ORCID: https://orcid.org/0000-0002-2541-9866)
- Brendan R. E. Ansell (ORCID: https://orcid.org/0000-0003-0297-897X)
- Lebriz Altay (ORCID: https://orcid.org/0000-0003-1088-3786)
- Danuta M. Sampson (ORCID: https://orcid.org/0000-0003-4737-6606)
- Konstantinos Balaskas (ORCID: https://orcid.org/0000-0003-2034-8920)
- Adnan Tufail (ORCID: https://orcid.org/0000-0001-6131-7640)
- Frank Gerhard Holz (ORCID: https://orcid.org/0000-0001-8019-9272)
- Catherine A. Cukras (ORCID: https://orcid.org/0000-0002-1147-854X)
- Aniket Mishra (ORCID: https://orcid.org/0000-0002-8141-1543)
- Himeesh Kumar (ORCID: https://orcid.org/0000-0001-9169-5335)
- Yelena Bagdasarova
- Aaron Lee (ORCID: https://orcid.org/0000-0002-7452-1648)
- Samaneh Farashi (ORCID: https://orcid.org/0000-0001-6383-4203)
- Ismail Moghul (ORCID: https://orcid.org/0000-0003-3653-2327)
- Cécile Delcourt (ORCID: https://orcid.org/0000-0002-2099-0481)
- Fred K. Chen (ORCID: https://orcid.org/0000-0003-2809-9930)
- Alice Pébay (ORCID: https://orcid.org/0000-0002-7408-9453)
- Sascha Fauser
- Liam W. Scott (ORCID: https://orcid.org/0000-0002-7941-5676)
- Erica L. Fletcher (ORCID: https://orcid.org/0000-0001-9412-9523)
- Ruth Hogg (ORCID: https://orcid.org/0000-0001-9413-2669)
- Anand Swaroop (ORCID: https://orcid.org/0000-0002-1975-1141)
- Liran Tiosano
- Robyn H. Guymer (ORCID: https://orcid.org/0000-0002-9441-4356)
- Brian L. Yaspan (ORCID: https://orcid.org/0000-0002-3787-2510)
- Louis Arnould (ORCID: https://orcid.org/0000-0001-7831-8818)
- Matthias Marten Mauschitz (ORCID: https://orcid.org/0000-0002-5605-8207)
- Jiru Han (ORCID: https://orcid.org/0000-0002-4884-1082)
- Marie‐Noëlle Delyfer (ORCID: https://orcid.org/0000-0002-3127-8617)
- Melanie Bahlo (ORCID: https://orcid.org/0000-0001-5132-0774)
- Pierre‐Henry Gabrielle (ORCID: https://orcid.org/0000-0002-9688-4845)
- Amy Stockwell
- Zhichao Wu (ORCID: https://orcid.org/0000-0002-8623-6684)
- Amy Jayne McKnight (ORCID: https://orcid.org/0000-0002-7482-709X)
- Ulrich F. O. Luhmann (ORCID: https://orcid.org/0000-0002-1993-1951)
- Jan Henrik Terheyden (ORCID: https://orcid.org/0000-0002-0174-4066)
- Carla J. Abbott (ORCID: https://orcid.org/0000-0002-1432-8977)
- Robert Patrick Finger (ORCID: https://orcid.org/0000-0003-4253-7597)
- Carel B. Hoyng (ORCID: https://orcid.org/0000-0002-1358-5963)
- Samuel McLenachan (ORCID: https://orcid.org/0000-0001-5732-7387)
- Lauren Hodgson (ORCID: https://orcid.org/0000-0002-9492-3927)
- Vasilena Sitnilska (ORCID: https://orcid.org/0000-0002-0886-4263)
- Emily Y. Chew (ORCID: https://orcid.org/0000-0003-0999-9802)
- Itay Chowers (ORCID: https://orcid.org/0000-0002-9608-2949)
- Eleonora M. Lad
- Christine Clarke (ORCID: https://orcid.org/0000-0002-2706-4448)
- Ella Arnon
- Scott Song (ORCID: https://orcid.org/0009-0008-5861-5709)
- Carel C B Hoyng
Institutions
- 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)
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
Funders
- 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