A cross-platform approach identifies genetic regulators of human metabolism and health

Abstract

In cross-platform analyses of 174 metabolites we identify 499 associations (p<4.9×10 -10 ) characterized by pleiotropy, allelic heterogeneity, large and non-linear effects, and enrichment for nonsynonymous variation. We identify a signal at GLP2R (p.Asp470Asn) shared between higher citrulline levels, body mass index, fasting glucose-dependent insulinotropic peptide and type 2 diabetes, with beta-arrestin signalling as the underlying mechanism. Genetically-higher serine levels are shown to reduce the likelihood (by 95%) and predict development of macular telangiectasia type 2, a rare degenerative retinal disease. Integration of genomic and small molecule data across platforms enables discovery of regulators of human metabolism and translation into clinical insights. M.P. was supported by a fellowship from the German Research Foundation (DFG PI 1446/2-1). C.O. was founded by an early career fellowship at Homerton College, University of Cambridge. L. B. L. W.

Comprehensive genetic analysis of the human lipidome identifies novel loci controlling lipid homeostasis with links to coronary artery disease

“…Prior studies examined lipid phenotypes that were mixtures of similar, but distinct species; lacked structural characterization of lipid species; or were contaminated through isotopic overlap. Many of the associations between lipid species and prototypical lipid regulating genes observed in our study -such as FADS1/FADS2, APOE and LDLR -have been reported in earlier GWAS [7][8][9][10][11][12][13][14][15]17,23 . With our expanded lipidomic profile, we have built on these earlier studies, identifying many new loci associated with lipid species and classes.…”

“…Our high resolution genome-wide association analyses of the human lipidome has identified 737 independent genomic regions associated with lipid metabolism, of which 509 represent novel genetic loci. This is a substantial increase over previous studies with similar or larger sample sizes 7,10,23 . Our expanded lipidomic platform utilises extensive chromatographic separation to increase the diversity of measured lipid species and distinguish lipid isomers and isotopes over those measured in previous studies.…”

“…The atypical structure of these sphingolipids has previously led to mis-annotation resulting in reported associations of SPTLC3 with hydroxylated sphingomyelins 10,13,14 , when hydroxylated sphingomyelins in the n-acyl chain are unlikely to exist in human plasma 28 .…”

“…Compared with other complex traits, relatively few genomic loci have been associated with lipid species in GWAS of the human serum/plasma lipidome [7][8][9][10][11][12][13][14][15][16][17] , although these studies have generally interrogated a restricted subset of lipid species. The serum lipidome is complex and consists of many isobaric and isomeric species that share elemental composition but are structurally distinct.…”

MiR-139-5p is a causal biomarker for type 2 diabetes; Results from genome-wide microRNA profiling and Mendelian randomization analysis in a population-based study

“…Large scale research consortia studying genetic and metabolite markers have given us insight into underlying pathways involved in type 2 diabetes development (4, 5). Given the ability of miRNAs to target thousands of genes, miRNAs are likely also to play a regulatory role in the metabolic disturbance that causes type 2 diabetes.…”