학술논문
Rare and common genetic determinants of metabolic individuality and their effects on human health
Document Type
Original Paper
Author
Surendran, Praveen; Stewart, Isobel D.; Au Yeung, Victoria P. W.; Pietzner, Maik; Raffler, Johannes; Wörheide, Maria A.; Li, Chen; Smith, Rebecca F.; Wittemans, Laura B. L.; Bomba, Lorenzo; Menni, Cristina; Zierer, Jonas; Rossi, Niccolò; Sheridan, Patricia A.; Watkins, Nicholas A.; Mangino, Massimo; Hysi, Pirro G.; Di Angelantonio, Emanuele; Falchi, Mario; Spector, Tim D.; Soranzo, Nicole; Michelotti, Gregory A.; Arlt, Wiebke; Lotta, Luca A.; Denaxas, Spiros; Hemingway, Harry; Gamazon, Eric R.; Howson, Joanna M. M.; Wood, Angela M.; Danesh, John; Wareham, Nicholas J.; Kastenmüller, Gabi; Fauman, Eric B.; Suhre, Karsten; Butterworth, Adam S.; Langenberg, Claudia
Source
Nature Medicine. 28(11):2321-2332
Subject
Language
English
ISSN
1078-8956
1546-170X
1546-170X
Abstract
Garrod’s concept of ‘chemical individuality’ has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant–metabolite associations (P < 1.25 × 10−11 ) within 330 genomic regions, with rare variants (minor allele frequency ≤ 1%) explaining 9.4% of associations. Jointly modeling metabolites in each region, we identified 423 regional, co-regulated, variant–metabolite clusters called genetically influenced metabotypes. We assigned causal genes for 62.4% of these genetically influenced metabotypes, providing new insights into fundamental metabolite physiology and clinical relevance, including metabolite-guided discovery of potential adverse drug effects (DPYD and SRD5A2). We show strong enrichment of inborn errors of metabolism-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of the inborn errors of metabolism. Systematic, phenotypic follow-up of metabolite-specific genetic scores revealed multiple potential etiological relationships.
Analyses of the genetic architecture of the human plasma metabolome in two large population-based cohorts identify associations between genetically determined metabolite levels and health.
Analyses of the genetic architecture of the human plasma metabolome in two large population-based cohorts identify associations between genetically determined metabolite levels and health.