Genetic disruption of serine biosynthesis is a key driver of macular telangiectasia type 2 aetiology and progression.

Details

Serval ID
serval:BIB_122EB23EAFE6
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Genetic disruption of serine biosynthesis is a key driver of macular telangiectasia type 2 aetiology and progression.
Journal
Genome medicine
Author(s)
Bonelli R., Ansell BRE, Lotta L., Scerri T., Clemons T.E., Leung I., Peto T., Bird A.C., Sallo F.B., Langenberg C., Bahlo M.
Working group(s)
MacTel Consortium
ISSN
1756-994X (Electronic)
ISSN-L
1756-994X
Publication state
Published
Issued date
09/03/2021
Peer-reviewed
Oui
Volume
13
Number
1
Pages
39
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Abstract
Macular 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.
We integrated genetic markers for MacTel, vascular and metabolic traits, and applied Mendelian randomisation and conditional and interaction genome-wide association analyses to discover the causal contributors to both disease and spatial retinal imaging sub-phenotypes.
Genetically induced serine deficiency is the primary causal metabolic driver of disease occurrence and progression, with a lesser, but significant, causal contribution of type 2 diabetes genetic risk. Conversely, glycine, threonine and retinal vascular traits are unlikely to be causal for MacTel. Conditional regression analysis identified three novel disease loci independent of endogenous serine biosynthetic capacity. By aggregating spatial retinal phenotypes into endophenotypes, we demonstrate that SNPs constituting independent risk loci act via related endophenotypes.
Follow-up studies after GWAS integrating publicly available data with deep phenotyping are still rare. Here, we describe such analysis, where we integrated retinal imaging data with MacTel and other traits genomics data to identify biochemical mechanisms likely causing this disorder. Our 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.
Keywords
Biosynthetic Pathways/genetics, Diabetes Mellitus, Type 2/genetics, Disease Progression, Endophenotypes, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Metabolome, Polymorphism, Single Nucleotide/genetics, Retinal Telangiectasis/genetics, Retinal Telangiectasis/pathology, Retinal Vessels/pathology, Serine/biosynthesis, GWAS, Mendelian randomisation, Metabolomics, Retinal disease, Serine
Pubmed
Web of science
Open Access
Yes
Create date
30/03/2021 11:51
Last modification date
20/12/2023 8:14
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