Genetic Disruption of Serine Biosynthesis is a Key Driver of Macular Telangiectasia Type 2 Etiology and Progression

Abstract

PurposeMacular telangiectasia type 2 (MacTel) is a rare, heritable and largely untreatable retinal disorder, often comorbid with diabetes. Genetic risk loci subtend retinal vascular calibre, and glycine/serine/threonine metabolism genes. Serine deficiency may contribute to MacTel via neurotoxic deoxysphingolipid production, however, an independent vascular contribution is also suspected. Here we use statistical genetics to dissect the causal mechanisms underpinning this complex disease. MethodsWe integrated genetic markers for MacTel, vascular, and metabolic traits, and applied Mendelian randomization, MTAG, and conditional/interaction genome-wide association analysis to discover causal contributors to both disease, and spatial retinal imaging subphenotypes. ResultsSerine was a key causal driver of disease occurrence and progression, with a lesser contribution to type 2 diabetes risk. Conversely, glycine, threonine and retinal vascular traits are unlikely to be causal for MacTel. Conditional regression analysis resolved three novel disease loci independent of endogenous serine biosynthetic capacity. By aggregating retinal phenotypes into endophenotypes, we demonstrate that SNPs constituting independent risk loci act via related endophenotypes. DiscussionOur findings will aid in early diagnosis and accurate prognosis of MacTel, and improve prospects for effective therapeutic intervention. Our integrative genetics approach also serves as a useful template for post-GWAS analyses in other disorders.Retinal Disease | Mendelian Randomization | Metabolomics | GWAS | Serine

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

“…Specifically, the most significant SNPs were located in the genes PSPH (rs6955423 in locus 7p11.2; P = 5.9 × 10 −09 ), TTC39B (rs677622, 9p22.3; P = 3.2 × 10 −09 ), and REEP3 (rs10995566, 10q21.3; P = 4.8 × 10 −08 ). A further two loci tagged by rs9820465 between the genes SLC4A7 and EOMES (3p24.1, P = 5.6 × 10 −09 ), and rs139412173 near CERS4 (19p13.2, P = 2.9 × 10 −08 ), were previously implicated in a GWAS of MacTel conditioned on genetically predicted glycine and serine 7 . We identified two novel GW-significant loci tagged by rs2160387 in locus 2p14 (P = 5.9 × 10 −09 ), located within the alanine/glycine/ serine transporter gene SLC1A4, and rs17279437 in locus 3p21.31 (P = 6.2 × 10 −10 ) within the glycine transporter gene SLC6A20.…”

“…Mendelian randomisation. Using Mendelian randomisation analysis we recently demonstrated that low serine and glycine levels, as well as high alanine levels, were likely to have a causal effect on MacTel aetiology 7 . Applying Mendelian randomisation analysis to these new GWAS results we found that genetically predicted serum serine concentrations was again the strongest and most significantly associated trait among 141 predicted metabolites (Supplementary Data 15).…”

“…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. Mendelian randomisation analysis revealed that genetically influenced serine and glycine deficiency, and excessive alanine in patient sera, are likely causal for MacTel 7 . Further, a GWAS analysis performed by conditioning on genetically predicted T2D risk, glycine and serine concentrations, identified that the genetic contributions from the vasculature-associated locus 5q14.3 was independent of these metabolic traits.…”

Cell Atlas of The Human Fovea and Peripheral Retina

“…Mac Tel 2 is currently considered to be a primary neurodegenerative condition of the retina with secondary vascular involvement rather than (as previously hypothesized) a primary vasculopathy. Several risk alleles and genes in proximity to SNPs identified by GWAS studies implicate Müller cell dysfunction and dysregulation of serine metabolism in pathogenesis 49,50 . We found expression patterns compatible with these hypotheses.…”

Cell Atlas of the Human Fovea and Peripheral Retina

“…Mac Tel 2 is currently considered to be a primary neurodegenerative condition of the retina with secondary vascular involvement rather than (as previously hypothesized) a primary vasculopathy. Several risk alleles and genes in proximity to SNPs identified by GWAS studies implicate Müller cell dysfunction and dysregulation of serine metabolism in (49,50) pathogenesis . We found expression patterns compatible with these hypotheses.…”