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 × 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.
Highlights
Macular Telangiectasia Type 2 (MacTel) is a rare degenerative retinal disease with complex genetic architecture
To better characterise the systemic and retina-specific phenotypes influenced by MacTel genome-wide association study (GWAS) loci, we recently leveraged GWAS summary statistics to predict genetically derived retinal vascular calibre[4,5], T2D risk[6], as well as serum concentrations for 174 metabolites in MacTel patients compared to controls
Eleven independent GW significant disease associations in ten regions were identified in the full-cohort analysis (Fig. 2), of which seven results in six regions were preserved in the European ancestry GWAS (Table 1)
Summary
Macular Telangiectasia Type 2 (MacTel) is a rare degenerative retinal disease with complex genetic architecture. The other two loci were within the phosphoglycerate dehydrogenase (PHGDH; locus 1p12) and carbamoylphosphate synthase 1 (CPS1; 2q34) genes These loci, together with two loci attaining suggestive significance (P < 5 × 10−6) within phosphoserine phosphatase (PSPH; 7p11.2) and aldehyde dehydrogenase 1L1 (ALDH1L1; 3q21.3), suggested systemic perturbation of glycine and serine metabolism in MacTel patients, which was supported by significantly depleted concentrations of both metabolites in patient serum. To better characterise the systemic and retina-specific phenotypes influenced by MacTel GWAS loci, we recently leveraged GWAS summary statistics to predict genetically derived retinal vascular calibre[4,5], T2D risk[6], as well as serum concentrations for 174 metabolites in MacTel patients compared to controls. HSN1 patients develop peripheral neuropathy and clinical MacTel in many, but not all, cases[8]
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