SLC16A8 is a causal contributor to age-related macular degeneration risk

Navid Nouri; Bailey Hannon Gussler; Amy Stockwell; Tom Truong; Gyeong Jin Kang; Kristen C Browder; Yann Malato; Abdoulaye Sene; Sherri Van Everen; Charles C Wykoff; David Brown; Arthur Fu; James D Palmer; Jose Ronaldo Lima de Carvalho; Ehsan Ullah; Ranya Al Rawi; Emily Y Chew; Wadih M Zein; Bin Guan; Mark I McCarthy; Jeffrey W Hofmann; Shawnta Y Chaney; Heinrich Jasper; Brian L Yaspan

doi:10.1038/s41525-024-00442-8

SLC16A8 is a causal contributor to age-related macular degeneration risk

NPJ Genom Med. 2024 Oct 28;9(1):50. doi: 10.1038/s41525-024-00442-8.

Authors

Navid Nouri^#¹, Bailey Hannon Gussler^#¹, Amy Stockwell^#¹, Tom Truong¹, Gyeong Jin Kang¹, Kristen C Browder¹, Yann Malato¹, Abdoulaye Sene¹, Sherri Van Everen¹, Charles C Wykoff², David Brown², Arthur Fu³, James D Palmer⁴, Jose Ronaldo Lima de Carvalho^{5

6}, Ehsan Ullah⁵, Ranya Al Rawi⁵, Emily Y Chew⁷, Wadih M Zein⁵, Bin Guan⁵, Mark I McCarthy¹, Jeffrey W Hofmann¹, Shawnta Y Chaney¹, Heinrich Jasper⁸, Brian L Yaspan⁹

Affiliations

¹ Genentech, Inc., South San Francisco, CA, USA.
² Retina Consultants of Texas, Retina Consultants of America, Houston, TX, USA.
³ West Coast Retina Medical Group, San Francisco, CA, USA.
⁴ Northern California Retina Vitreous Associates, San Jose, CA, USA.
⁵ Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
⁶ Hospital das Clinicas de Pernambuco-Empresa Brasileira de Servicos Hospitalares, Federal University of Pernambuco, Recife, PE, Brazil.
⁷ Division of Epidemiology and Clinical Applications, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
⁸ Genentech, Inc., South San Francisco, CA, USA. jasperh@gene.com.
⁹ Genentech, Inc., South San Francisco, CA, USA. yaspan.brian@gene.com.

^# Contributed equally.

Abstract

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.