Cross-platform genetic discovery of small molecule products of metabolism and application to clinical outcomes

Lotta, Luca A.; Pietzner, Maik; Stewart, Isobel D.; Wittemans, Laura B. L.; Li, Chen; Bonelli, Roberto; Raffler, Johannes; Biggs, Emma K.; Oliver‐Williams, Clare; Auyeung, Victoria P.W.; Surendran, Praveen; Michelotti, Gregory A.; Scott, Robert A.; Burgess, Stephen; Zuber, Verena; Sanderson, Eleanor; Koulman, Albert; Imamura, Fumiaki; Forouhi, Nita G.; Khaw, Kay‐Tee; Griffin, Julian L.; Wood, Angela; uumlller, Gabi Kastenm; Danesh, John; Butterworth, Adam S.; Gribble, Fiona M.; Reimann, Frank; Bahlo, Melanie; Fauman, Eric B.; Wareham, Nicholas J.; Langenberg, Claudia

doi:10.1101/2020.02.03.932541

Cited by 14 publications

(28 citation statements)

References 58 publications

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“…MTAG confirmed the central role of locus 7p11.2 (rs4543497), which was previously found to be only nominally significant, and identified a new locus, 8q24.1 (rs2954021). rs2954021 is predictive of endogenous serum serine concentrations 22 and thus might confer MacTel risk by contributing to the same serine pathway as previously identified SNPs. Conversely, we did not find any additional signal arising from shared genetic correlations with retinal vascular calibre traits.…”

Section: Discussionmentioning

confidence: 64%

“…Retinal phenotypic data was available for 455 patients MacTel patients. Genetic predictors for metabolites and retinal vascular calibre, were provided by the corresponding authors of each study 11,12,21,22 .…”

Section: Dna Samples and Snp Genotypingmentioning

confidence: 99%

“…Beta OR 95% C.I. The GWAS used to predict the genetic complement of serine was underpowered compared to the glycine GWAS 22 (Supplementary Materials). However, biochemically-based genetic correlation exists between the two.…”

Section: Gp Metabolite / Traitmentioning

confidence: 99%

“…MR borrows from Instrumental Variable (IV) analysis and assumes that if a disease is caused by a particular intermediate phenotype, and the latter is caused by genetic variants, then the same genetic variants should be also associated with the disease [17][18][19] . Genetic variants involved in retinal vascular calibre traits and T2D have been previously identified 11,12,20 and the largest metabolomic GWAS meta-analysis to date recently identified almost 500 loci that are associated with differences in 142 serum metabolite levels in humans 21,22 . The results from these studies can be used to investigate causal drivers of MacTel susceptibility via the MR approach.…”

Section: Introductionmentioning

confidence: 99%

“…Vasculature GWAS refers to the summary statistics data available from two previous retinal vasculature calibre genetic studies11,12 . Metabolomics GWAS refers to summary statistics data available from a recently published metabolomics GWAS21,22 . T2D GWAS refers to summary statistics data available from GWAS study on T2D20 .…”

mentioning

confidence: 99%

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

Bonelli

Ansell

Lotta

et al. 2020

Preprint

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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

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Section: Discussionmentioning

confidence: 64%

Section: Dna Samples and Snp Genotypingmentioning

confidence: 99%

Section: Gp Metabolite / Traitmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Bonelli

Ansell

Lotta

et al. 2020

Preprint

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Integrating lipidomics and genomics: emerging tools to understand cardiovascular diseases

Tabassum

Ripatti

2021

Cell. Mol. Life Sci.

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Cardiovascular diseases (CVDs) are the leading cause of mortality and morbidity worldwide leading to 31% of all global deaths. Early prediction and prevention could greatly reduce the enormous socio-economic burden posed by CVDs. Plasma lipids have been at the center stage of the prediction and prevention strategies for CVDs that have mostly relied on traditional lipids (total cholesterol, total triglycerides, HDL-C and LDL-C). The tremendous advancement in the field of lipidomics in last two decades has facilitated the research efforts to unravel the metabolic dysregulation in CVDs and their genetic determinants, enabling the understanding of pathophysiological mechanisms and identification of predictive biomarkers, beyond traditional lipids. This review presents an overview of the application of lipidomics in epidemiological and genetic studies and their contributions to the current understanding of the field. We review findings of these studies and discuss examples that demonstrates the potential of lipidomics in revealing new biology not captured by traditional lipids and lipoprotein measurements. The promising findings from these studies have raised new opportunities in the fields of personalized and predictive medicine for CVDs. The review further discusses prospects of integrating emerging genomics tools with the high-dimensional lipidome to move forward from the statistical associations towards biological understanding, therapeutic target development and risk prediction. We believe that integrating genomics with lipidome holds a great potential but further advancements in statistical and computational tools are needed to handle the high-dimensional and correlated lipidome.

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

et al. 2021

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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 < 5 × 10−8), 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 = 3.9 × 10−47) and glycine depletion (FDR = 0.006) as well as alanine abundance (FDR = 0.009). Polygenic risk scoring achieved an accuracy of 0.74 and was associated in UKBiobank with retinal damage (p = 0.009). 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.

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Cross-platform genetic discovery of small molecule products of metabolism and application to clinical outcomes

Cited by 14 publications

References 58 publications

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

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

Integrating lipidomics and genomics: emerging tools to understand cardiovascular diseases

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

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