Genome-wide association study identifies multiple loci influencing human serum metabolite levels

Abstract

Nuclear magnetic resonance assays allow for measurement of a wide range of metabolic phenotypes. We report here the results of a GWAS on 8,330 Finnish individuals genotyped and imputed at 7.7 million SNPs for a range of 216 serum metabolic phenotypes assessed by NMR of serum samples. We identified significant associations (P < 2.31 × 10−10) at 31 loci, including 11 for which there have not been previous reports of associations to a metabolic trait or disorder. Analyses of Finnish twin pairs suggested that the metabolic measures reported here show higher heritability than comparable conventional metabolic phenotypes. In accordance with our expectations, SNPs at the 31 loci associated with individual metabolites account for a greater proportion of the genetic component of trait variance (up to 40%) than is typically observed for conventional serum metabolic phenotypes. The identification of such associations may provide substantial insight into cardiometabolic disorders.

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Figure 1: The heritability estimates and proportion of variance explained for all traits.
Figure 2: Overall summary of basic metabolism, key constituents of the NMR-measurable serum metabolome and associated genetic loci.

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Acknowledgements

We thank all the Finnish volunteers who participated in the studies. We thank the IT Center for Science and the technology center of the Institute for Molecular Medicine Finland for providing the computational facilities required in this study. The expert technical assistance for statistical analyses provided by A. Vikman, I. Lisinen, V. Aalto and the Genotyping Facilities at the Wellcome Trust Sanger Institute are gratefully acknowledged. The study was supported through funds from The European Community's Seventh Framework Programme (FP7/2007-2013), the BioSHaRE Consortium (261433), the Sigrid Juselius Foundation (251217 to S.R.), the Academy of Finland (137870 to P.S. and 135973 to P.W.), the Responding to Public Health Challenges Research Programme of the Academy of Finland (129269 to M.J.S., 129429 to M.A.-K., 129322 to M.P. and 139635 to V.S.), the Academy of Finland Center of Excellence in Complex Disease Genetics (213506 and 129680 to A.P., J. Kaprio, L.P., K.S. and S.R.), the Finnish Foundation for Cardiovascular Research (to M.J.S., M.A.-K., M.P., S.R. and K.H.P), the Jenny and Antti Wihuri Foundation (to A.J.K.), the Instrumentarium Science Foundation (to T.T. and P.W.), the Finnish Cultural Foundation (to T.T. and T.L.), an Aalto University School of Science and Technology researcher training scholarship (to T.T.) and the Wellcome Trust (098051 to A.P.). The Young Finns Study has been financially supported by the Academy of Finland (126925, 121584, 124282, 129378 (Salve), 117787 (Gendi) and 41071 (Skidi)), the Social Insurance Institution of Finland, the Turku University Foundation, the Yrjö Jahnsson Foundation, the Emil Aaltonen Foundation (to T.L.), the Medical Research Fund of Tampere University Hospital, the Turku University Hospital Medical Fund, the Juho Vainio Foundation, the Finnish Foundation for Cardiovascular Research (to T.L.) and the Tampere Tuberculosis Foundation (to T.L. and M.K.). The Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland (120386, 125876 and 126775 to J.E.), the Finnish Diabetes Research Society, the Novo Nordisk Foundation, the European Science Foundation (EuroSTRESS), the Wellcome Trust (89061/Z/09/Z and 089062/Z/09/Z), the Samfundet Folkhälsan and the Finska Läkaresällskapet. The FINRISK/DILGOM study was supported by the Academy of Finland (118081). Data collection for FinnTwin12 and FinnTwin16 were supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) (AA-12502, AA-09203 and AA-08315 to R.J.R. and AA-15416 to D.M.D.) and the Academy of Finland (100499, 205585, 118555 and 141054 (Skidi-Kids) to J. Kaprio). The Finnish Twin cohorts are also supported by the Novo Nordisk Foundation, the Diabetes Research Foundation, Biomedicum Helsinki and Helsinki University Central Hospital grants (all to K.H.P.). NFBC1966 received financial support from the Academy of Finland (104781, 120315, 129269, 1114194, 139900 and SALVE to M.-R.J. and Center of Excellence in Complex Disease Genetics to L.P.), University Hospital Oulu, Biocenter, University of Oulu (75617 to M.-R.J. and M.J.S.), the European Commission EURO-BLCS Framework 5 award (QLG1-CT-2000-01643 to M.-R.J.), the US National Heart, Lung, and Blood Institute (NHLBI) (5R01HL087679), the US National Institute of Mental Health (NIMH) (1RL1MH083268), European Network for Genetic and Genomic Epidemiology (ENGAGE) (HEALTH-F4-2007-201413 to L.P. and M.-R.J.), the MRC UK (G0500539, G0600705 and PrevMetSyn/Salve to M.-R.J.) and the Wellcome Trust (GR069224).

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Contributions

Experiments were designed by L.P., M.P., M.A.-K., A.P. and S.R. Statistical analyses were performed by J. Kettunen, T.T., A.O.-A., E.T. and L.-P.L. Materials and/or analysis tools were contributed by J. Kettunen, T.T., A.-P.S., P.S., A.J.K., P.W., K.S., D.M.D., R.J.R., M.J.S., J.V., M.K., T.L., K.H.P., M.I.M., A.J., J.E., O.T.R., V.S., J. Kaprio, M.-R.J., N.B.F., M.A.-K., A.P. and S.R. The manuscript was written by J. Kettunen, T.T., A.J.K., M.I., N.B.F., M.A.-K., A.P. and S.R. All authors reviewed the manuscript.

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Correspondence to Samuli Ripatti.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Table 1–6 and 8, Supplementary Figures 1–4 and Supplementary Note (PDF 3440 kb)

Supplementary Table 7

All metabolite associations P < 2.31×10−10 (XLSX 2480 kb)

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Kettunen, J., Tukiainen, T., Sarin, A. et al. Genome-wide association study identifies multiple loci influencing human serum metabolite levels. Nat Genet 44, 269–276 (2012). https://doi.org/10.1038/ng.1073

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