Assessing the causal association of glycine with risk of cardio-metabolic diseases

Abstract

Circulating levels of glycine have previously been associated with lower incidence of coronary heart disease (CHD) and type 2 diabetes (T2D) but it remains uncertain if glycine plays an aetiological role. We present a meta-analysis of genome-wide association studies for glycine in 80,003 participants and investigate the causality and potential mechanisms of the association between glycine and cardio-metabolic diseases using genetic approaches. We identify 27 genetic loci, of which 22 have not previously been reported for glycine. We show that glycine is genetically associated with lower CHD risk and find that this may be partly driven by blood pressure. Evidence for a genetic association of glycine with T2D is weaker, but we find a strong inverse genetic effect of hyperinsulinaemia on glycine. Our findings strengthen evidence for a protective effect of glycine on CHD and show that the glycine-T2D association may be driven by a glycine-lowering effect of insulin resistance.

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

“…To maximise sample size and power, we meta-analysed genome-wide association (GWAS) results from the Fenland cohort with those run in the EPIC-Norfolk 28 and INTERVAL 29 studies, in which metabolites were profiled using MS (Metabolon Discovery HD4 platform) or protein nuclear magnetic resonance ( 1 H-NMR) spectrometry 3031 ( Supplementary Table 1 ). Ten of the 174 Biocrates metabolites were covered across all platforms, while 38 were available on the Biocrates and Metabolon platforms and 126 were unique to Biocrates ( Fig.…”

“…The levels of 174 metabolites were measured in the Fenland study by the AbsoluteIDQ ® Biocrates p180 Kit (Biocrates Life Sciences AG, Innsbruck, Austria) as reported elsewhere in detail 3231 . We used a Waters Acquity ultra-performance liquid chromatography (UPLC; Waters ltd, Manchester, UK) system coupled to an ABSciex 5500 Qtrap mass spectrometer (Sciex ltd, Warrington, UK).…”

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

“…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 .…”

“…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.…”

“…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 .…”