10q26 - The enigma in age-related macular degeneration

David A Merle; Merve Sen; Angela Armento; Chloe M Stanton; Eric F Thee; Magda A Meester-Smoor; Markus Kaiser; Simon J Clark; Caroline C W Klaver; Pearse A Keane; Alan F Wright; Michael Ehrmann; Marius Ueffing

doi:10.1016/j.preteyeres.2022.101154

10q26 - The enigma in age-related macular degeneration

Prog Retin Eye Res. 2023 Sep:96:101154. doi: 10.1016/j.preteyeres.2022.101154. Epub 2022 Dec 10.

Authors

Affiliations

¹ Institute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of Tübingen, 72076, Tübingen, Germany; Department for Ophthalmology, University Eye Clinic, Eberhard Karls University of Tübingen, 72076, Tübingen, Germany; Department of Ophthalmology, Medical University of Graz, 8036, Graz, Austria. Electronic address: david.merle@medunigraz.at.
² Institute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of Tübingen, 72076, Tübingen, Germany.
³ MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, EH4 2XU, UK.
⁴ Department of Ophthalmology, Erasmus University Medical Center, 3015GD, Rotterdam, Netherlands; Department of Epidemiology, Erasmus University Medical Center, 3015CE, Rotterdam, Netherlands.
⁵ Center of Medical Biotechnology, Faculty of Biology, University Duisburg-Essen, 45117, Essen, Germany.
⁶ Institute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of Tübingen, 72076, Tübingen, Germany; Department for Ophthalmology, University Eye Clinic, Eberhard Karls University of Tübingen, 72076, Tübingen, Germany; Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK.
⁷ Department of Ophthalmology, Erasmus University Medical Center, 3015GD, Rotterdam, Netherlands; Department of Epidemiology, Erasmus University Medical Center, 3015CE, Rotterdam, Netherlands; Department of Ophthalmology, Radboudumc, 6525EX, Nijmegen, Netherlands; Institute of Molecular and Clinical Ophthalmology Basel, CH-4031, Basel, Switzerland.
⁸ Institute for Health Research, Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital NHS Foundation Trust, UCL Institute of Ophthalmology, London, EC1V 2PD, UK.
⁹ Institute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of Tübingen, 72076, Tübingen, Germany; Department for Ophthalmology, University Eye Clinic, Eberhard Karls University of Tübingen, 72076, Tübingen, Germany. Electronic address: marius.ueffing@uni-tuebingen.de.

PMID: 36513584
DOI: 10.1016/j.preteyeres.2022.101154

Abstract

Despite comprehensive research efforts over the last decades, the pathomechanisms of age-related macular degeneration (AMD) remain far from being understood. Large-scale genome wide association studies (GWAS) were able to provide a defined set of genetic aberrations which contribute to disease risk, with the strongest contributors mapping to distinct regions on chromosome 1 and 10. While the chromosome 1 locus comprises factors of the complement system with well-known functions, the role of the 10q26-locus in AMD-pathophysiology remains enigmatic. 10q26 harbors a cluster of three functional genes, namely PLEKHA1, ARMS2 and HTRA1, with most of the AMD-associated genetic variants mapping to the latter two genes. High linkage disequilibrium between ARMS2 and HTRA1 has kept association studies from reliably defining the risk-causing gene for long and only very recently the genetic risk region has been narrowed to ARMS2, suggesting that this is the true AMD gene at this locus. However, genetic associations alone do not suffice to prove causality and one or more of the 14 SNPs on this haplotype may be involved in long-range control of gene expression, leaving HTRA1 and PLEKHA1 still suspects in the pathogenic pathway. Both, ARMS2 and HTRA1 have been linked to extracellular matrix homeostasis, yet their exact molecular function as well as their role in AMD pathogenesis remains to be uncovered. The transcriptional regulation of the 10q26 locus adds an additional level of complexity, given, that gene-regulatory as well as epigenetic alterations may influence expression levels from 10q26 in diseased individuals. Here, we provide a comprehensive overview on the 10q26 locus and its three gene products on various levels of biological complexity and discuss current and future research strategies to shed light on one of the remaining enigmatic spots in the AMD landscape.

Keywords: 10q26 risk locus; ARMS2; Age-related macular degeneration (AMD); Extracellular matrix (ECM); HTRA1; PLEKHA1.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Gene Expression Regulation
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Humans
Macular Degeneration* / genetics
Macular Degeneration* / metabolism
Polymorphism, Single Nucleotide
Proteins / genetics
Proteins / metabolism
Serine Endopeptidases* / genetics
Serine Endopeptidases* / metabolism

Substances

Serine Endopeptidases
Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding