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

Luca A Lotta; Maik Pietzner; Isobel D Stewart; Laura B L Wittemans; Chen Li; Roberto Bonelli; Johannes Raffler; Emma K Biggs; Clare Oliver-Williams; Victoria P W Auyeung; Jian'an Luan; Eleanor Wheeler; Ellie Paige; Praveen Surendran; Gregory A Michelotti; Robert A Scott; Stephen Burgess; Verena Zuber; Eleanor Sanderson; Albert Koulman; Fumiaki Imamura; Nita G Forouhi; Kay-Tee Khaw; MacTel Consortium; Julian L Griffin; Angela M Wood; Gabi Kastenmüller; John Danesh; Adam S Butterworth; Fiona M Gribble; Frank Reimann; Melanie Bahlo; Eric Fauman; Nicholas J Wareham; Claudia Langenberg

doi:10.1038/s41588-020-00751-5

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

Nat Genet. 2021 Jan;53(1):54-64. doi: 10.1038/s41588-020-00751-5. Epub 2021 Jan 7.

Authors

Luca A Lotta^#¹, Maik Pietzner^#¹, Isobel D Stewart¹, Laura B L Wittemans^{1

2}, Chen Li¹, Roberto Bonelli^{3

4}, Johannes Raffler⁵, Emma K Biggs⁶, Clare Oliver-Williams^{7

8}, Victoria P W Auyeung¹, Jian'an Luan¹, Eleanor Wheeler¹, Ellie Paige⁹, Praveen Surendran^{7

10

11

12}, Gregory A Michelotti¹³, Robert A Scott¹, Stephen Burgess^{14

15}, Verena Zuber^{14

16}, Eleanor Sanderson¹⁷, Albert Koulman^{1

5

18}, Fumiaki Imamura¹, Nita G Forouhi¹, Kay-Tee Khaw¹⁵; MacTel Consortium; Julian L Griffin¹⁹, Angela M Wood^{7

10

11

20

21}, Gabi Kastenmüller⁵, John Danesh^{7

10

11

20

22

23}, Adam S Butterworth^{7

10

11

20

22

23}, Fiona M Gribble⁶, Frank Reimann⁶, Melanie Bahlo^{3

4}, Eric Fauman²⁴, Nicholas J Wareham¹, Claudia Langenberg^{25

26

27}

Collaborator

MacTel Consortium:
Melanie Bahlo

Affiliations

¹ MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
² The Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.
³ Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
⁴ Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
⁵ Institute of Computational Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
⁶ Metabolic Research Laboratories, University of Cambridge, Cambridge, UK.
⁷ British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁸ Homerton College, University of Cambridge, Cambridge, UK.
⁹ National Centre for Epidemiology and Population Health, The Australian National University, Canberra, Australia.
¹⁰ British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.
¹¹ Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.
¹² Rutherford Fund Fellow, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹³ Metabolon Inc, Durham, NC, USA.
¹⁴ MRC Biostatistics Unit, University of Cambridge, Cambridge, UK.
¹⁵ Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹⁶ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
¹⁷ MRC Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, UK.
¹⁸ NIHR BRC Nutritional Biomarker Laboratory, University of Cambridge, Cambridge, UK.
¹⁹ Biomolecular Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
²⁰ National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK.
²¹ The Alan Turing Institute, London, UK.
²² Cambridge Biomedical Research Centre, National Institute for Health Research, University of Cambridge and Cambridge University Hospitals, Cambridge, UK.
²³ Department of Human Genetics, Wellcome Sanger Institute, Hinxton, UK.
²⁴ Internal Medicine Research Unit, Pfizer Worldwide Research, Cambridge, MA, USA.
²⁵ MRC Epidemiology Unit, University of Cambridge, Cambridge, UK. [email protected].
²⁶ Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK. [email protected].
²⁷ Computational Medicine, Berlin Institute of Health (BIH), Charité University Medicine, Berlin, Germany. [email protected].

^# Contributed equally.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Diabetes Mellitus, Type 2 / genetics
Eye Diseases / genetics
Gene Frequency / genetics
Genetic Loci
Genetic Pleiotropy
Genome, Human
Glucagon-Like Peptide-2 Receptor / genetics
Glycine / metabolism
Health*
Humans
Linear Models
Mendelian Randomization Analysis
Metabolism / genetics*
Metabolism, Inborn Errors / genetics
Metabolome / genetics
Mutation, Missense / genetics
Phenotype
Polymorphism, Single Nucleotide / genetics
Retinal Telangiectasis / genetics
Sample Size
Serine / metabolism

Substances

GLP2R protein, human
Glucagon-Like Peptide-2 Receptor
Serine
Glycine

Abstract

Publication types

MeSH terms

Substances

Grants and funding