SLC16A8 is a causal contributor to age-related macular degeneration risk
Age-related macular degeneration (AMD), a complex neurodegenerative disease, is a leading cause of visual impairment worldwide with a strong genetic component. Genetic studies have identified several loci, but few causal genes with functional characterization. Here we highlight multiple lines of evidence which show a causal role in AMD for SLC16A8, which encodes MCT3, a retinal pigment epithelium (RPE) specific lactate transporter. First, in an unbiased, genome-wide analysis of rare coding variants we show multiple SLC16A8 rare variants are associated with AMD risk, corroborating previous borderline significant reports from AMD rare variant studies. Second, we report a novel SLC16A8 mutation in a three-generation family with early onset macular degeneration. Finally, mis-expression in multiple model organisms shows functional and anatomic retinal consequences. This study highlights the important role for SLC16A8 and lactate regulation towards outer retina/RPE health and highlights a potential new therapeutic opportunity for the treatment of AMD.
Authors
- James D. Palmer
- Nasrin Nouri (ORCID: https://orcid.org/0000-0001-5418-3576)
- Wadih M. Zein (ORCID: https://orcid.org/0000-0002-3771-6120)
- Ehsan Ullah (ORCID: https://orcid.org/0000-0003-0107-6608)
- Gyeong Jin Kang (ORCID: https://orcid.org/0000-0002-5824-8012)
- Yann Malato
- Kristen Browder
- Ranya Al Rawi
- José Ronaldo Lima de Carvalho (ORCID: https://orcid.org/0000-0002-7024-1702)
- Charles C. Wykoff (ORCID: https://orcid.org/0000-0001-7756-5091)
- Sherri Van Everen
- Brian L. Yaspan (ORCID: https://orcid.org/0000-0002-3787-2510)
- Heinrich Jasper (ORCID: https://orcid.org/0000-0002-6014-4343)
- Amy Stockwell
- Mark I. McCarthy (ORCID: https://orcid.org/0000-0002-4393-0510)
- Bin Guan (ORCID: https://orcid.org/0000-0001-5986-5189)
- Arthur D. Fu
- Jeffrey W. Hofmann
- Abdoulaye Sène (ORCID: https://orcid.org/0000-0003-0978-2590)
- Emily Y. Chew (ORCID: https://orcid.org/0000-0003-0999-9802)
- David M. Brown (ORCID: https://orcid.org/0000-0002-2570-5766)
- Tom Truong
- S. Chaney (ORCID: https://orcid.org/0000-0002-0227-7500)
- Bailey Hannon Gussler
Institutions
- National Institutes of Health (US)
- Gene Therapy Laboratory (FR)
- Retina Consultants of Texas (US)
- Hospital das Clínicas da Universidade Federal de Pernambuco (BR)
- National Eye Institute (US)
- Retina Vitreous Associates of Florida (US)
- West Coast Retina (US)
Publication Details
- Journal
- npj Genomic Medicine
- Published
- 2024-10-28
- DOI
- https://doi.org/10.1038/s41525-024-00442-8
- Citations
- 2
- Primary Topic
- Retinal Diseases and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 1.08
Funders
- U.S. Department of Health and Human Services
- Office of Dietary Supplements
- National Institutes of Health
- Genentech
- National Heart, Lung, and Blood Institute
- National Eye Institute
- National Center for Complementary and Alternative Medicine