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. O_TBL View this table: org.highwire.dtl.DTLVardef@1c529f3org.highwire.dtl.DTLVardef@1451baforg.highwire.dtl.DTLVardef@1ca0a9org.highwire.dtl.DTLVardef@177efb9org.highwire.dtl.DTLVardef@11b67bf_HPS_FORMAT_FIGEXP M_TBL O_TABLECAPTIONSupplementary Table 8: C_TABLECAPTION C_TBL 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 sub-phenotypes. 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.