TY - JOUR
T1 - A cross-platform approach identifies genetic regulators of human metabolism and health
AU - Lotta, Luca A.
AU - Pietzner, Maik
AU - Stewart, Isobel D.
AU - Wittemans, Laura B.L.
AU - Li, Chen
AU - Bonelli, Roberto
AU - Raffler, Johannes
AU - Biggs, Emma K.
AU - Oliver-Williams, Clare
AU - Auyeung, Victoria P.W.
AU - Luan, Jian’an
AU - Wheeler, Eleanor
AU - Paige, Ellie
AU - Surendran, Praveen
AU - Michelotti, Gregory A.
AU - Scott, Robert A.
AU - Burgess, Stephen
AU - Zuber, Verena
AU - Sanderson, Eleanor
AU - Koulman, Albert
AU - Imamura, Fumiaki
AU - Forouhi, Nita G.
AU - Khaw, Kay Tee
AU - Bahlo, Melanie
AU - Griffin, Julian L.
AU - Wood, Angela M.
AU - Kastenmüller, Gabi
AU - Danesh, John
AU - Butterworth, Adam S.
AU - Gribble, Fiona M.
AU - Reimann, Frank
AU - Fauman, Eric
AU - Wareham, Nicholas J.
AU - Langenberg, Claudia
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/1
Y1 - 2021/1
N2 - In cross-platform analyses of 174 metabolites, we identify 499 associations (P < 4.9 × 10−10) characterized by pleiotropy, allelic heterogeneity, large and nonlinear effects and enrichment for nonsynonymous variation. We identify a signal at GLP2R (p.Asp470Asn) shared among higher citrulline levels, body mass index, fasting glucose-dependent insulinotropic peptide and type 2 diabetes, with β-arrestin signaling 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 the discovery of regulators of human metabolism and translation into clinical insights.
AB - In cross-platform analyses of 174 metabolites, we identify 499 associations (P < 4.9 × 10−10) characterized by pleiotropy, allelic heterogeneity, large and nonlinear effects and enrichment for nonsynonymous variation. We identify a signal at GLP2R (p.Asp470Asn) shared among higher citrulline levels, body mass index, fasting glucose-dependent insulinotropic peptide and type 2 diabetes, with β-arrestin signaling 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 the discovery of regulators of human metabolism and translation into clinical insights.
UR - http://www.scopus.com/inward/record.url?scp=85098954975&partnerID=8YFLogxK
U2 - 10.1038/s41588-020-00751-5
DO - 10.1038/s41588-020-00751-5
M3 - Article
SN - 1061-4036
VL - 53
SP - 54
EP - 64
JO - Nature Genetics
JF - Nature Genetics
IS - 1
ER -