Communications Biology | 2021
Identification of genetic factors influencing metabolic dysregulation and retinal support for MacTel, a retinal disorder
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 \u2009<\u20095\u2009×\u200910 −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\u2009=\u20093.9\u2009×\u200910 − 47 ) and glycine depletion (FDR\u2009=\u20090.006) as well as alanine abundance (FDR\u2009=\u20090.009). Polygenic risk scoring achieved an accuracy of 0.74 and was associated in UKBiobank with retinal damage ( p \u2009=\u20090.009). 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. Melanie Bahlo and colleagues report a genome-wide association study on the retinal degenerative disease Macular Telangiectasia Type 2, identifying 8 new genome-wide significant loci. Further analyses suggest key roles for genes that transport and synthesize the amino acids serine, glycine and alanine, providing a more accurate genomic tool for identifying people at risk of the disease.