Genetically personalised organ-specific metabolic models in health and disease

Author:

Foguet CarlesORCID,Xu YuORCID,Ritchie Scott C.ORCID,Lambert Samuel A.ORCID,Persyn Elodie,Nath Artika P.,Davenport Emma E.,Roberts David J.,Paul Dirk S.ORCID,Di Angelantonio Emanuele,Danesh John,Butterworth Adam S.ORCID,Yau Christopher,Inouye MichaelORCID

Abstract

AbstractUnderstanding how genetic variants influence disease risk and complex traits (variant-to-function) is one of the major challenges in human genetics. Here we present a model-driven framework to leverage human genome-scale metabolic networks to define how genetic variants affect biochemical reaction fluxes across major human tissues, including skeletal muscle, adipose, liver, brain and heart. As proof of concept, we build personalised organ-specific metabolic flux models for 524,615 individuals of the INTERVAL and UK Biobank cohorts and perform a fluxome-wide association study (FWAS) to identify 4312 associations between personalised flux values and the concentration of metabolites in blood. Furthermore, we apply FWAS to identify 92 metabolic fluxes associated with the risk of developing coronary artery disease, many of which are linked to processes previously described to play in role in the disease. Our work demonstrates that genetically personalised metabolic models can elucidate the downstream effects of genetic variants on biochemical reactions involved in common human diseases.

Funder

European Commission

DH | National Institute for Health Research

RCUK | Medical Research Council

RCUK | Engineering and Physical Sciences Research Council

RCUK | Science and Technology Facilities Council

RCUK | Economic and Social Research Council

Scottish Government Health and Social Care Directorate

Wellcome Trust

NHS Blood and Transplant

Gouvernement du Canada | Canadian Institutes of Health Research

European Federation of Pharmaceutical Industries and Associations

British Heart Foundation

Health Data Research UK Department of Health and Social Care (England) Health and Social Care Research and Development Division (Welsh Government) Public Health Agency

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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