Genetic variation in metabolic phenotypes: study designs and applications

Key Points Technical advances in mass spectrometry and NMR spectroscopy enable genome-wide screens to be carried out for the association between genetic variants and hundreds of metabolic traits in a single experiment. Metabolite concentrations are direct readouts of biological processes and can pla...

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Published in:	Nature reviews. Genetics Vol. 13; no. 11; pp. 759 - 769
Main Authors:	Suhre, Karsten, Gieger, Christian
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01.11.2012 Nature Publishing Group
Subjects:	631/1647/320 631/208/205/2138 631/208/457/649 Agriculture Amino acids Animal Genetics and Genomics Biological and medical sciences Biomedical and Life Sciences Biomedical Research - methods Biomedical Research - trends Biomedicine Cancer Research Chromatography Disease Environmental health Epidemiology Fundamental and applied biological sciences. Psychology Gene Function Gene loci Genetic Variation Genetics Genetics of eukaryotes. Biological and molecular evolution Genome-Wide Association Study - methods Genomes Genotype Human Genetics Humans Lifestyles Lipids Mass spectrometry Metabolism Metabolites Metabolomics - methods Nuclear magnetic resonance spectroscopy Phenotype Physiological aspects Plasma Research Design review-article Scientific imaging Urine Qatar Germany United Kingdom > UK Phenotype Genetic variability Review Genetic variant
ISSN:	1471-0056, 1471-0064, 1471-0064
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Abstract	Key Points Technical advances in mass spectrometry and NMR spectroscopy enable genome-wide screens to be carried out for the association between genetic variants and hundreds of metabolic traits in a single experiment. Metabolite concentrations are direct readouts of biological processes and can play the part of intermediate phenotypes, providing functional links between genetic variance and disease end points in genome-wide association studies (GWASs). The first GWASs with metabolomics have already discovered many genetic variants in enzyme-, transporter- and other metabolism-related genes that induce major differences in the individual metabolic capabilities of the organism. Knowledge of the genetic basis of human metabolic individuality holds the key to understanding the interactions of genetic, environmental and lifestyle factors in the aetiology of complex disorders. We review emerging insights from recent GWASs with metabolomics and present design considerations for high-throughput metabolomics experiments with metabolic traits in epidemiological and clinical studies. Using ratios between metabolite concentrations can drastically increase the power of a metabolomics study and can provide functional information on the perturbed underlying biochemical pathways. Integration with other biochemical information, including data from other GWASs, can largely improve the value of the study. Current challenges and future directions include the addition of new sample types (other than urine and blood), extension of the metabolite panels, standardization between platforms and the development of adapted statistical and data analysis tools. Revealing genetic influences on metabolic phenotypes is important in further understanding the aetiology of many complex diseases. Here, the authors introduce study design considerations and applications for genome-wide association studies with metabolic traits. Many complex disorders are linked to metabolic phenotypes. Revealing genetic influences on metabolic phenotypes is key to a systems-wide understanding of their interactions with environmental and lifestyle factors in their aetiology, and we can now explore the genetics of large panels of metabolic traits by coupling genome-wide association studies and metabolomics. These genome-wide association studies are beginning to unravel the genetic contribution to human metabolic individuality and to demonstrate its relevance for biomedical and pharmaceutical research. Adopting the most appropriate study designs and analytical tools is paramount to further refining the genotype–phenotype map and eventually identifying the part played by genetic influences on metabolic phenotypes. We discuss such design considerations and applications in this Review.
AbstractList	Key Points Technical advances in mass spectrometry and NMR spectroscopy enable genome-wide screens to be carried out for the association between genetic variants and hundreds of metabolic traits in a single experiment. Metabolite concentrations are direct readouts of biological processes and can play the part of intermediate phenotypes, providing functional links between genetic variance and disease end points in genome-wide association studies (GWASs). The first GWASs with metabolomics have already discovered many genetic variants in enzyme-, transporter- and other metabolism-related genes that induce major differences in the individual metabolic capabilities of the organism. Knowledge of the genetic basis of human metabolic individuality holds the key to understanding the interactions of genetic, environmental and lifestyle factors in the aetiology of complex disorders. We review emerging insights from recent GWASs with metabolomics and present design considerations for high-throughput metabolomics experiments with metabolic traits in epidemiological and clinical studies. Using ratios between metabolite concentrations can drastically increase the power of a metabolomics study and can provide functional information on the perturbed underlying biochemical pathways. Integration with other biochemical information, including data from other GWASs, can largely improve the value of the study. Current challenges and future directions include the addition of new sample types (other than urine and blood), extension of the metabolite panels, standardization between platforms and the development of adapted statistical and data analysis tools. Revealing genetic influences on metabolic phenotypes is important in further understanding the aetiology of many complex diseases. Here, the authors introduce study design considerations and applications for genome-wide association studies with metabolic traits. Many complex disorders are linked to metabolic phenotypes. Revealing genetic influences on metabolic phenotypes is key to a systems-wide understanding of their interactions with environmental and lifestyle factors in their aetiology, and we can now explore the genetics of large panels of metabolic traits by coupling genome-wide association studies and metabolomics. These genome-wide association studies are beginning to unravel the genetic contribution to human metabolic individuality and to demonstrate its relevance for biomedical and pharmaceutical research. Adopting the most appropriate study designs and analytical tools is paramount to further refining the genotype–phenotype map and eventually identifying the part played by genetic influences on metabolic phenotypes. We discuss such design considerations and applications in this Review. Many complex disorders are linked to metabolic phenotypes. Revealing genetic influences on metabolic phenotypes is key to a systems-wide understanding of their interactions with environmental and lifestyle factors in their aetiology, and we can now explore the genetics of large panels of metabolic traits by coupling genome-wide association studies and metabolomics. These genome-wide association studies are beginning to unravel the genetic contribution to human metabolic individuality and to demonstrate its relevance for biomedical and pharmaceutical research. Adopting the most appropriate study designs and analytical tools is paramount to further refining the genotype-phenotype map and eventually identifying the part played by genetic influences on metabolic phenotypes. We discuss such design considerations and applications in this Review. Many complex disorders are linked to metabolic phenotypes. Revealing genetic influences on metabolic phenotypes is key to a systems-wide understanding of their interactions with environmental and lifestyle factors in their aetiology, and we can now explore the genetics of large panels of metabolic traits by coupling genome-wide association studies and metabolomics. These genome-wide association studies are beginning to unravel the genetic contribution to human metabolic individuality and to demonstrate its relevance for biomedical and pharmaceutical research. Adopting the most appropriate study designs and analytical tools is paramount to further refining the genotype-phenotype map and eventually identifying the part played by genetic influences on metabolic phenotypes. We discuss such design considerations and applications in this Review.Many complex disorders are linked to metabolic phenotypes. Revealing genetic influences on metabolic phenotypes is key to a systems-wide understanding of their interactions with environmental and lifestyle factors in their aetiology, and we can now explore the genetics of large panels of metabolic traits by coupling genome-wide association studies and metabolomics. These genome-wide association studies are beginning to unravel the genetic contribution to human metabolic individuality and to demonstrate its relevance for biomedical and pharmaceutical research. Adopting the most appropriate study designs and analytical tools is paramount to further refining the genotype-phenotype map and eventually identifying the part played by genetic influences on metabolic phenotypes. We discuss such design considerations and applications in this Review.
Audience	Academic
Author	Suhre, Karsten Gieger, Christian
Author_xml	– sequence: 1 givenname: Karsten surname: Suhre fullname: Suhre, Karsten email: karsten@suhre.fr organization: Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health – sequence: 2 givenname: Christian surname: Gieger fullname: Gieger, Christian email: christian.gieger@helmholtz-muenchen.de organization: Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health
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Snippet	Key Points Technical advances in mass spectrometry and NMR spectroscopy enable genome-wide screens to be carried out for the association between genetic... Many complex disorders are linked to metabolic phenotypes. Revealing genetic influences on metabolic phenotypes is key to a systems-wide understanding of their...
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Title	Genetic variation in metabolic phenotypes: study designs and applications
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