Rare and common genetic determinants of metabolic individuality and their effects on human health.

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dc.contributor.authorSurendran, Praveen
dc.contributor.authorStewart, Isobel D
dc.contributor.authorAu Yeung, Victoria P W
dc.contributor.authorPietzner, Maik
dc.contributor.authorRaffler, Johannes
dc.contributor.authorWörheide, Maria A
dc.contributor.authorLi, Chen
dc.contributor.authorSmith, Rebecca F
dc.contributor.authorWittemans, Laura B L
dc.contributor.authorBomba, Lorenzo
dc.contributor.authorMenni, Cristina
dc.contributor.authorZierer, Jonas
dc.contributor.authorRossi, Niccolò
dc.contributor.authorSheridan, Patricia A
dc.contributor.authorWatkins, Nicholas A
dc.contributor.authorMangino, Massimo
dc.contributor.authorHysi, Pirro G
dc.contributor.authorDi Angelantonio, Emanuele
dc.contributor.authorFalchi, Mario
dc.contributor.authorSpector, Tim D
dc.contributor.authorSoranzo, Nicole
dc.contributor.authorMichelotti, Gregory A
dc.contributor.authorArlt, Wiebke
dc.contributor.authorLotta, Luca A
dc.contributor.authorDenaxas, Spiros
dc.contributor.authorHemingway, Harry
dc.contributor.authorGamazon, Eric R
dc.contributor.authorHowson, Joanna M M
dc.contributor.authorWood, Angela M
dc.contributor.authorDanesh, John
dc.contributor.authorWareham, Nicholas J
dc.contributor.authorKastenmüller, Gabi
dc.contributor.authorFauman, Eric B
dc.contributor.authorSuhre, Karsten
dc.contributor.authorButterworth, Adam S
dc.contributor.authorLangenberg, Claudia
dc.date.accessioned2023-11-14T15:39:52Z
dc.date.available2023-11-14T15:39:52Z
dc.date.issued2022-11-10
dc.description.abstractGarrod'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.en_US
dc.identifier.citationSurendran P, Stewart ID, Au Yeung VPW, Pietzner M, Raffler J, Wörheide MA, Li C, Smith RF, Wittemans LBL, Bomba L, Menni C, Zierer J, Rossi N, Sheridan PA, Watkins NA, Mangino M, Hysi PG, Di Angelantonio E, Falchi M, Spector TD, Soranzo N, Michelotti GA, Arlt W, Lotta LA, Denaxas S, Hemingway H, Gamazon ER, Howson JMM, Wood AM, Danesh J, Wareham NJ, Kastenmüller G, Fauman EB, Suhre K, Butterworth AS, Langenberg C. Rare and common genetic determinants of metabolic individuality and their effects on human health. Nat Med. 2022 Nov;28(11):2321-2332. doi: 10.1038/s41591-022-02046-0. Epub 2022 Nov 10en_US
dc.identifier.doi10.1038/s41591-022-02046-0
dc.identifier.eissn1546-170X
dc.identifier.issn1078-8956
dc.identifier.pmid36357675
dc.identifier.urihttp://hdl.handle.net/20.500.14200/2868
dc.language.isoenen_US
dc.publisherNature Researchen_US
dc.relation.urlhttp://www.nature.com/nm/index.htmlen_US
dc.rights© 2022. The Author(s).
dc.source.beginpage2321
dc.source.countryUnited Kingdom
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dc.source.countryUnited States
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dc.source.endpage2332
dc.source.issue11
dc.source.journaltitleNature Medicine
dc.source.volume28
dc.subjectCardiologyen_US
dc.subjectPublic health. Health statistics. Occupational health. Health educationen_US
dc.subjectHaematologyen_US
dc.subjectHuman physiologyen_US
dc.subjectBiochemistryen_US
dc.titleRare and common genetic determinants of metabolic individuality and their effects on human health.en_US
dc.typeArticle
dspace.entity.typePublication
oa.grant.openaccessnaen_US
rioxxterms.versionNAen_US
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