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*

*Corresponding author for this work

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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.

Original languageEnglish
Article number101154
JournalProgress in Retinal and Eye Research
Early online date10 Dec 2022
Publication statusPublished - Sept 2023

Bibliographical note

Funding Information:
Angela Armento is supported by the intramural fortüne-Programm of Tübingen's medical faculty (project number 2640-0-0). This work was further supported by donations from Jutta Emilie Paula Henny Granier and the Kerstan Foundation to Marius Ueffing and the Helmut Ecker Foundation to Simon J Clark. The work of Michael Ehrmann and Markus Kaiser was supported by the Europäischer Fonds für regionale Entwicklung (EFRE) (Project number EFRE-0801295 LS-2-1-005 b , HTRA1-Inhibitoren). This work is supported by the Royal Dutch Academy of Sciences (Ammodo Award to C.C.W. Klaver). Chloe Stanton was supported by funding from the LifeArc Philanthropic Fund and a Medical Research Council University Unit Programme Grant ( MC_UU_00007/10 ; QTL in Health and Disease).

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