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

R Bonelli, VE Jackson, A Prasad, JE Munro… - Communications …, 2021 - nature.com
Communications biology, 2021nature.com
Abstract 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 …
Abstract
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 × 1047) 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.
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