Oral Presentation GENEMAPPERS 2026

Genome-wide discoveries highlight biological pathways in a rare retinal disorder and define its cross-trait genetic architecture (#25)

Liam W Scott 1 2 , Zachary F Gerring 1 2 , Vicki E Jackson 1 2 , Soo Jen Low 1 2 , Carolyn A de Graaf 1 2 , Brendan RE Ansell 1 2 , Roberto Bonelli 3 , Melanie Bahlo 1 2
  1. Genetics and Gene Regulation, WEHI, Parkville, VIC, Australia
  2. Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
  3. The Lowy Medical Research Institute , La Jolla, CA, USA

Macular Telangiectasia Type 2 (MacTel) is a rare, degenerative disorder of the macula characterised by gradual loss of central vision, with an estimated prevalence of approximately 0.1%. The SNP-based heritability for MacTel is ~45%, and previous genome-wide association studies (GWAS) have identified several risk loci implicating disruption of serine and lipid metabolic pathways; however, these explain only a fraction of disease heritability. We conducted the largest GWAS of MacTel to date, comprising 2,536 clinically confirmed cases and 17,247 controls. We identified 26 genome-wide significant loci (P < 5 x 10⁻⁸), including 16 novel associations. Furthermore, conditional analyses revealed three secondary independent signals within previously implicated loci, suggesting multiple variants within the same locus may influence MacTel risk through independent biological mechanisms. Proximity-based and functional gene-based analyses implicated 397 unique risk genes, with 49 prioritised as high-confidence candidates supported by multiple approaches. We found strong enrichment of MacTel GWAS signal in biological pathways related to amino acid metabolism and transport, consistent with the established role of serine and lipid dysregulation in MacTel. Our study reports the first genome-wide genetic correlations between MacTel and systemic traits. Notably, MacTel showed overlapping genetic risk with cardiovascular, lipid, gastrointestinal, and metabolic traits, including type 2 diabetes (T2D). Bivariate analyses were performed to formally assess the degree of overlap in causal variants between MacTel and type 2 diabetes (T2D), providing a genome-wide measure of shared genetic architecture. These analyses indicated 75% of MacTel-associated causal variants also influence T2D, supporting shared metabolic mechanisms. Ongoing post-GWAS analyses are leveraging multivariate genomic network approaches to model these shared pathways and better define the biological links between retinal and systemic metabolism. Together, these findings advance our understanding of MacTel genetics and metabolic diseases more broadly, establishing a framework for future work toward mechanism-based therapeutic strategies.