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Genetic disruption of serine biosynthesis is a key driver of macular telangiectasia type 2 aetiology and progression
BACKGROUND: 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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945323/ https://www.ncbi.nlm.nih.gov/pubmed/33750426 http://dx.doi.org/10.1186/s13073-021-00848-4 |
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author | Bonelli, Roberto Ansell, Brendan R. E. Lotta, Luca Scerri, Thomas Clemons, Traci E. Leung, Irene Peto, Tunde Bird, Alan C. Sallo, Ferenc B. Langenberg, Claudia Bahlo, Melanie |
author_facet | Bonelli, Roberto Ansell, Brendan R. E. Lotta, Luca Scerri, Thomas Clemons, Traci E. Leung, Irene Peto, Tunde Bird, Alan C. Sallo, Ferenc B. Langenberg, Claudia Bahlo, Melanie |
author_sort | Bonelli, Roberto |
collection | PubMed |
description | BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-021-00848-4. |
format | Online Article Text |
id | pubmed-7945323 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-79453232021-03-10 Genetic disruption of serine biosynthesis is a key driver of macular telangiectasia type 2 aetiology and progression Bonelli, Roberto Ansell, Brendan R. E. Lotta, Luca Scerri, Thomas Clemons, Traci E. Leung, Irene Peto, Tunde Bird, Alan C. Sallo, Ferenc B. Langenberg, Claudia Bahlo, Melanie Genome Med Research BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-021-00848-4. BioMed Central 2021-03-09 /pmc/articles/PMC7945323/ /pubmed/33750426 http://dx.doi.org/10.1186/s13073-021-00848-4 Text en © The Author(s) 2021 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Bonelli, Roberto Ansell, Brendan R. E. Lotta, Luca Scerri, Thomas Clemons, Traci E. Leung, Irene Peto, Tunde Bird, Alan C. Sallo, Ferenc B. Langenberg, Claudia Bahlo, Melanie Genetic disruption of serine biosynthesis is a key driver of macular telangiectasia type 2 aetiology and progression |
title | Genetic disruption of serine biosynthesis is a key driver of macular telangiectasia type 2 aetiology and progression |
title_full | Genetic disruption of serine biosynthesis is a key driver of macular telangiectasia type 2 aetiology and progression |
title_fullStr | Genetic disruption of serine biosynthesis is a key driver of macular telangiectasia type 2 aetiology and progression |
title_full_unstemmed | Genetic disruption of serine biosynthesis is a key driver of macular telangiectasia type 2 aetiology and progression |
title_short | Genetic disruption of serine biosynthesis is a key driver of macular telangiectasia type 2 aetiology and progression |
title_sort | genetic disruption of serine biosynthesis is a key driver of macular telangiectasia type 2 aetiology and progression |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945323/ https://www.ncbi.nlm.nih.gov/pubmed/33750426 http://dx.doi.org/10.1186/s13073-021-00848-4 |
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