Identification of genetic factors influencing metabolic dysregulation and retinal support for MacTel, a retinal disorder

Commun Biol. 2021 Mar 2;4(1):274. doi: 10.1038/s42003-021-01788-w.


Macular Telangiectasia Type 2 (MacTel) is a rare degenerative retinal disease with complex genetic architecture. We performed a genome-wide association study on 1,067 MacTel patients and 3,799 controls, which identified eight novel genome-wide significant loci (p < 5 × 10-8), and confirmed all three previously reported loci. Using MAGMA, eQTL and transcriptome-wide association analysis, we prioritised 48 genes implicated in serine-glycine biosynthesis, metabolite transport, and retinal vasculature and thickness. Mendelian randomization indicated a likely causative role of serine (FDR = 3.9 × 10-47) and glycine depletion (FDR = 0.006) as well as alanine abundance (FDR = 0.009). Polygenic risk scoring achieved an accuracy of 0.74 and was associated in UKBiobank with retinal damage (p = 0.009). This represents the largest genetic study on MacTel to date and further highlights genetically-induced systemic and tissue-specific metabolic dysregulation in MacTel patients, which impinges on retinal health.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Case-Control Studies
  • Energy Metabolism / genetics*
  • Female
  • Genetic Loci
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Male
  • Mendelian Randomization Analysis
  • Middle Aged
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Quantitative Trait Loci
  • Retina / metabolism*
  • Retinal Telangiectasis / diagnosis
  • Retinal Telangiectasis / genetics*
  • Retinal Telangiectasis / metabolism
  • Risk Assessment
  • Risk Factors
  • Transcriptome