ABS 054: An Investigation of Potential Causal Genetic Variants for a Non-Human Primate Model of Age-Related Macular Degeneration in Japanese Macaques

Sai Harshith Kodali ¹, Sam Peterson ²

¹ Rice University
² Oregon Health & Sciences University

The Van Wickle Journal (2026) Volume 2, ABS054

Introduction: Age-related macular degeneration (AMD) is the leading cause of vision loss in adults over 50 and is influenced by both genetic and environmental risk factors. A defining feature of AMD is the formation of drusen, yellow lipid-rich deposits beneath the macula that contribute to retinal degeneration and progressive vision impairment. Japanese macaques (JMacs) at the Oregon National Primate Research Center exhibit a naturally occurring and heritable drusen phenotype, making them a valuable non-human primate (NHP) model for studying AMD pathogenesis. This study investigated potential genetic variants associated with drusen formation in JMacs using genome-wide association analysis and targeted genotyping. It was hypothesized that variants within established human AMD-risk genes, including CFH, ARMS2, and HTRA1 on chromosomes 1 and 10, would demonstrate the strongest associations with drusen presence. Whole-genome sequencing (WGS) data from 150 JMacs were filtered and analyzed using the genome association analysis tool PLINK, and Manhattan plots were generated in RStudio to identify genomic regions with elevated association signals. Nine candidate variants were selected for further validation. Genotyping was subsequently performed on 16 additional JMacs (8 drusen-positive and 8 controls) using polymerase chain reaction (PCR), gel electrophoresis, and DNA sequencing. While variants in previously established AMD-associated genes were evaluated, the strongest association signals were identified on chromosome 15, suggesting a more complex inheritance pattern involving multiple genetic contributors. In particular, variants in DENND4C and TTC39B showed the highest association values among all analyzed variants. TTC39B is associated with cholesterol regulation and lipid homeostasis, while DENND4C has been implicated in neurological and ocular disorders, supporting biological relevance to drusen formation. These findings further establish JMacs as a translational NHP model for AMD and identify potential genetic biomarkers relevant to disease progression and therapeutic target discovery.

Methods: Whole-genome sequencing (WGS) data from 150 Japanese macaques (JMacs) housed at the Oregon National Primate Research Center were analyzed to identify genetic variants associated with drusen formation. Variant filtering and genome-wide association analysis were performed using PLINK. Manhattan plots were generated in RStudio to visualize chromosomal regions with elevated association values. Based on GWAS findings, nine candidate variants were selected for further investigation, including variants located within previously reported AMD-associated genes and newly identified candidate loci. Targeted genotyping was performed on 16 additional JMacs, comprising 8 drusen-positive and 8 control animals. Genomic DNA was amplified using polymerase chain reaction (PCR), verified through gel electrophoresis, and sequenced for variant identification. Association patterns between candidate variants and drusen phenotype were then compared to determine the strongest genetic correlates of disease presence.

Results: Genome-wide association analysis identified the strongest association signals on chromosome 15 rather than within the hypothesized AMD-risk loci on chromosomes 1 and 10. Targeted genotyping confirmed elevated association values for variants located in the DENND4C and TTC39B genes across drusen-positive JMacs. Variants within TTC39B are linked to cholesterol regulation and lipid homeostasis, while DENND4C has been associated with neurological and ocular disorders. These findings suggest that drusen formation in JMacs may involve genetic mechanisms beyond traditionally recognized AMD-associated genes and support a multifactorial inheritance pattern underlying disease susceptibility.

Discussion: This study identifies chromosome 15 variants, particularly within DENND4C and TTC39B, as strong genetic candidates associated with drusen formation in Japanese macaques. The involvement of TTC39B supports the importance of lipid metabolism in AMD pathogenesis, consistent with the lipid-rich composition of drusen. These findings refine the utility of JMacs as a translational non-human primate model for human AMD and highlight potential biomarkers for future therapeutic and diagnostic research. The lack of strongest associations within canonical AMD-risk genes also suggests a more complex genetic architecture underlying disease progression. Future studies with larger sample sizes are necessary to validate variant causality and functional significance.