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

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; MACUSTAR consortium; NICOLA consortium; Alice Pébay; Erica L Fletcher; Robyn H Guymer; Melanie Bahlo; Reticular Pseudodrusen Consortium

doi:10.1038/s41467-025-65903-9

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

Nat Commun. 2025 Dec 8;16(1):10854. doi: 10.1038/s41467-025-65903-9.

Authors

Samaneh Farashi^{1

2}, Carla J Abbott^#^{3

4}, Brendan R E Ansell^#^{1

2}, Zhichao Wu^#^{3

4}, Lebriz Altay⁵, Ella Arnon⁶, Louis Arnould^{7

8}, Yelena Bagdasarova⁹, Konstantinos Balaskas¹⁰, Fred K Chen^{4

11

12

13}, Emily Chew¹⁴, Itay Chowers¹⁵, Steven Clarke¹⁶, Catherine Cukras¹⁷, Cécile Delcourt¹⁸, Marie-Noëlle Delyfer^{18

19}, Anneke I den Hollander^{20

21}, Sascha Fauser^{5

22}, Robert P Finger^{23

24}, Pierre-Henry Gabrielle^{7

25}, Jiru Han^{1

2}, Lauren A B Hodgson³, Ruth Hogg²⁶, Frank G Holz²³, Carel Hoyng²⁰, Himeesh Kumar^{3

4}, Eleonora M Lad⁶, Aaron Lee⁹, Ulrich F O Luhmann²², Matthias M Mauschitz²³, Amy J McKnight²⁶, Samuel McLenachan¹¹, Aniket Mishra¹⁸, Ismail Moghul¹⁰, Luz D Orozco¹⁶, Danuta M Sampson^{11

27}, Liam W Scott^{1

2}, Vasilena Sitnilska⁵, Scott Song⁹, Amy Stockwell²⁸, Anand Swaroop²⁹, Jan H Terheyden²³, Liran Tiosano¹⁵, Adnan Tufail¹⁰, Brian L Yaspan²⁸; MACUSTAR consortium; NICOLA consortium; Alice Pébay^{30

31}, Erica L Fletcher³⁰, Robyn H Guymer^{32

33}, Melanie Bahlo^{34

35}; Reticular Pseudodrusen Consortium

Collaborators

MACUSTAR consortium:
L Altay, A Tufail, C B Hoyng, U F O Luhmann, R P Finger, F G Holz, J H Terheyden, R Hogg
NICOLA consortium:
A J McKnight
Reticular Pseudodrusen Consortium:
Anneke I den Hollander

Affiliations

¹ Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
² Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
³ Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, Australia.
⁴ Department of Surgery (Ophthalmology), The University of Melbourne, East Melbourne, VIC, Australia.
⁵ Department of Ophthalmology, Faculty of Medicine, University Hospital of Cologne, University of Cologne, Cologne, Germany.
⁶ Department of Ophthalmology, Duke University Medical Centre, Durham, NC, USA.
⁷ Ophthalmology Department, University Hospital, Dijon, France.
⁸ Pathophysiology and Epidemiology of Cerebro-Cardiovascular Diseases, (EA 7460), Faculty of Health Sciences, Université de Bourgogne, Dijon, France.
⁹ Department of Ophthalmology, University of Washington, Seattle, WA, USA.
¹⁰ Moorfields Eye Hospital NHS Foundation Trust, University College London Institute of Ophthalmology, London, UK.
¹¹ Centre of Ophthalmology and Visual Science (incorporating Lions Eye Institute), The University of Western Australia, Perth, WA, Australia.
¹² Department of Ophthalmology, Royal Perth Hospital, Perth, WA, Australia.
¹³ Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, Australia.
¹⁴ Division of Epidemiology and Clinical Applications, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
¹⁵ Department of Ophthalmology, Hadassah Medical Centre and the Hebrew University of Jerusalem, Jerusalem, Israel.
¹⁶ Computational Sciences, Genentech Inc, South San Francisco, California, USA.
¹⁷ Unit on Clinical Investigation of Retinal Diseases, National Eye Institute, National Institute of Health, Bethesda, MD, USA.
¹⁸ University of Bordeaux, INSERM, BPH, Bordeaux, France.
¹⁹ Department of Ophthalmology, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
²⁰ Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands.
²¹ AbbVie, Genomics Research Center, Cambridge, MA, USA.
²² Roche Pharmaceutical Research and Early Development, Translational Medicine Ophthalmology, Roche Innovation Center, Basel, Switzerland.
²³ Department of Ophthalmology, University Hospital Bonn, Bonn, Germany.
²⁴ Department of Ophthalmology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
²⁵ Centre des Science du Goût et de l'Alimentation CNRS, INRA, Université Bourgogne Franche-Comte, Dijon, France.
²⁶ Centre for Public Health, Queen's University Belfast Faculty of Medicine Health and Life Sciences, Belfast, UK.
²⁷ The University of Western Australia, The School of Allied Health, Optometry Division, Perth, WA, Australia.
²⁸ Department of Human Genetics, Genentech Inc., South San Francisco, CA, USA.
²⁹ Neurobiology, Neurodegeneration & Repair Laboratory, National Eye Institute, Bethesda, MD, USA.
³⁰ Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, Australia.
³¹ Royal Melbourne Hospital, Department of Surgery, The University of Melbourne, Parkville, VIC, Australia.
³² Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, Australia. rh.guymer@unimelb.edu.au.
³³ Department of Surgery (Ophthalmology), The University of Melbourne, East Melbourne, VIC, Australia. rh.guymer@unimelb.edu.au.
³⁴ Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. bahlo@wehi.edu.au.
³⁵ Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia. bahlo@wehi.edu.au.

^# Contributed equally.

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.

MeSH terms

Aged
Aged, 80 and over
Chromosomes, Human, Pair 1 / genetics
Chromosomes, Human, Pair 10 / genetics
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
High-Temperature Requirement A Serine Peptidase 1* / genetics
Humans
Macular Degeneration* / genetics
Macular Degeneration* / pathology
Male
Middle Aged
Polymorphism, Single Nucleotide
Proteins / genetics
Quantitative Trait Loci
RNA, Long Noncoding* / genetics
Retina / metabolism
Retina / pathology
Retinal Drusen* / genetics

Substances

High-Temperature Requirement A Serine Peptidase 1
HTRA1 protein, human
RNA, Long Noncoding
ARMS2 protein, human
Proteins

Abstract

MeSH terms

Substances

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