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Genetics and Not Shared Environment Explains Familial Resemblance in Adult Metabolomics Data

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Genetics and Not Shared Environment Explains Familial Resemblance in Adult Metabolomics Data Twin Research and Human Genetics (2020), 23, 145–155 doi:10.1017/thg.2020.53 Article Genetics and Not Shared Environment Explains Familial Resemblance in Adult Metabolomics Data René Pool1,2* , Fiona A. Hagenbeek1,2* , Anne M. Hendriks1,2 , Jenny van Dongen1,2 , Gonneke Willemsen1 , Eco de Geus1,2 BBMRI Metabolomics Consortium3, Ko Willems van Dijk4,5,6 , Aswin Verhoeven7 , H. Eka Suchiman8 , Marian Beekman8 , P. Eline Slagboom8 , Amy C. Harms9,10 , Thomas Hankemeier9,10 and Dorret I. Boomsma1,2 1Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands, 2Amsterdam Public Health Research Institute, Amsterdam, the Netherlands, 3Members of the BBMRI Metabolomics Consortium are listed after the abstract, 4Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands, 5Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands, 6Department of Internal Medicine Division Endocrinology, Leiden University Medical Center, Leiden, the Netherlands, 7Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands, 8Department of Biomedical Data Sciences, Molecular Epidemiology, Leiden University Medical Center, Leiden, the Netherlands, 9Division of Analytical Biosciences, Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands and 10The Netherlands Metabolomics Centre, Leiden, the Netherlands Abstract Metabolites are small molecules involved in cellular metabolism where they act as reaction substrates or products. The term ‘metabolomics’ refers to the comprehensive study of these molecules. The concentrations of metabolites in biological tissues are under genetic control, but this is limited by environmental factors such as diet. In adult mono- and dizygotic twin pairs, we estimated the contribution of genetic and shared environmental influences on metabolite levels by structural equation modeling and tested whether the familial resemblance for metabolite levels is mainly explained by genetic or by environmental factors that are shared by family members. Metabolites were measured across three platforms: two based on proton nuclear magnetic resonance techniques and one employing mass spectrometry. These three platforms comprised 237 single metabolic traits of several chemical classes. For the three platforms, metabolites were assessed in 1407, 1037 and 1116 twin pairs, respectively. We carried out power calculations to establish what percentage of shared environmental variance could be detected given these sample sizes. Our study did not find evidence for a systematic contribution of shared environment, defined as the influence of growing up together in the same household, on metabolites assessed in adulthood. Significant heritability was observed for nearly all 237 metabolites; significant contribution of the shared environment was limited to 6 metabolites. The top quartile of the heritability distribution was populated by 5 of the 11 investigated chemical classes. In this quartile, metabolites of the class lipoprotein were significantly overrepresented, whereas metabolites of classes glycerophospholipids and glycerolipids were significantly underrepresented. Keywords: Classical twin design; enrichment analysis; heritability; metabolite classes; shared environment (Received 9 March 2020; accepted 5 May 2020) BBMRI Metabolomics Consortium P. M. Elders20,21,J.M.Geleijnse22,M.A.Ikram2,23,24, 8,25 1 26 1 M. Kloppenburg ,I.Meulenbelt,S.P.Mooijaart, Cohort Collection and Sample Management Group: M. Beekman ,H. 27 28,29 21,30 – R. G. H. H. Nelissen ,M.G.Netea ,B.W.J.H.Penninx , E. D. Suchiman1,N.Amin2,J.W.Beulens3,4,J.A.vanderBom5 8,N. C.D.A. Stehouwer31,32,C.E.Teunissen33,G.M.Terwindt15, Bomer9,A.Demirkan2,J.A.vanHilten10,J.M.T.A.Meessen11,R. L. M. ‘tHart1,3,21,34,35,A.M.J.M.vandenMaagdenberg36, Pool12,M.H.Moed1,J.Fu13,14,G.L.J.Onderwater15,F.Rutters3, P. van der Harst8,I.C.C.vanderHorst37,C.J.H.vander C. So-Osman10,W.M.vanderFlier3,16,A.A.W.A.vander Kallen31,32,M.M.J.vanGreevenbroek31,32,W.E.vanSpil38, Heijden17, A. van der Spek2,F.W.Asselbergs18, E. Boersma19, C. Wijmenga13,A.H.Zwinderman39,A.Zhernikova13,J.W.Jukema40 Database & Catalogue: J. J. H. Barkey Wolf1, M. Beekman1, 1 1,41 13 13 Author for correspondence: René Pool, Email: [email protected] D. Cats , H. Mei , M. Slofstra , M. Swertz 1,42,43 1 *These authors share first authorship. Quality Control: E. B. van den Akker , J. J. H. Barkey Wolf , Cite this article: Pool R, Hagenbeek FA, Hendriks AM, van Dongen J, Willemsen G, J. Deelen1,44, M. J. T. Reinders42,43 and de Geus E BBMRI Metabolomics Consortium, Willems van Dijk K, Verhoeven A, Steering Committee: D. I. Boomsma21,45, C. M. van Duijn2, Suchiman HE, Beekman M, Slagboom PE, Harms AC, Hankemeier T, and P.E. Slagboom1 Boomsma DI. (2020) Genetics and Not Shared Environment Explains Familial 1 Resemblance in Adult Metabolomics Data. Twin Research and Human Genetics 23: Department of Molecular Epidemiology, Leiden University 145–155, https://doi.org/10.1017/thg.2020.53 Medical Center, Leiden, the Netherlands. © The Author(s) 2020. This is an Open Access article, distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives licence (http://creativecommons. org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is unaltered and is properly cited. The written permission of Cambridge University Press must be obtained for commercial re-use or in order to create a derivative work. Downloaded from https://www.cambridge.org/core. IP address: 170.106.33.14, on 28 Sep 2021 at 18:41:20, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/thg.2020.53 146 René Pool et al. 2Department of Epidemiology, Erasmus MC University 30Department of Psychiatry, VU University Medical Center, Medical Center, Rotterdam, the Netherlands. Amsterdam, the Netherlands. 3Department of Epidemiology and Biostatistics, Amsterdam 31Department of Internal Medicine, Maastricht University University Medical Center, Amsterdam, the Netherlands. Medical Center (MUMCþ), Maastricht, the Netherlands. 4Julius Center for Health Sciences and Primary Care, University 32School for Cardiovascular Diseases (CARIM), Maastricht Medical Center Utrecht, Utrecht, the Netherlands. University, Maastricht, the Netherlands. 5Centre for Clinical Transfusion Research, Sanquin Research, 33Neurochemistry Laboratory, Clinical Chemistry Department, Leiden, the Netherlands. Amsterdam University Medical Center, Amsterdam Neuroscience, 6Jon J van Rood Centre for Clinical Transfusion Research, the Netherlands. Leiden University Medical Centre, Leiden, the Netherlands. 34Department of Cell and Chemical Biology, Leiden University 7TIAS, Tilburg University, Tilburg, the Netherlands. Medical Center, Leiden, the Netherlands. 8Department of Clinical Epidemiology, Leiden University 35Department of General practice, Amsterdam University Medical Centre, Leiden, the Netherlands. Medical Center, Amsterdam, the Netherlands. 9Department of Cardiology, University Medical Center 36Department of Human Genetics, Leiden University Medical Groningen, University of Groningen, Groningen, the Netherlands. Center, Leiden, the Netherlands. 10Center for Clinical Transfusion Research, Sanquin Research, 37Department of Critical Care, University Medical Center Leiden, the Netherlands. Groningen, Groningen, the Netherlands. 11Department of Orthopedics, Leiden University Medical 38UMC Utrecht, Department of Rheumatology & Clinical Centre, Leiden, The Netherlands. Immunology, Utrecht, the Netherlands. 12Department of Biological Psychology, Vrije Universiteit, 39Department of Clinical Epidemiology, Biostatistics, and Amsterdam, the Netherlands. Bioinformatics, Academic Medical Centre, University of 13Department of Genetics, University Medical Center Amsterdam, Amsterdam, the Netherlands. Groningen, University of Groningen, Groningen, the Netherlands. 40Department of Cardiology, Leiden University Medical Center, 14Department of Pediatrics, University Medical Center Leiden, the Netherlands. Groningen, University of Groningen, Groningen, the Netherlands. 41Sequencing Analysis Support Core, Leiden University 15Department of Neurology, Leiden University Medical Center, Medical Center, Leiden, the Netherlands. Leiden, the Netherlands. 42Leiden Computational Biology Center, Leiden University 16Department of Neurology and Alzheimer Center, Medical Center, Leiden, the Netherlands. Neuroscience Campus Amsterdam, VU University Medical 43Department of Pattern Recognition and Bioinformatics, Delft Center, Amsterdam, the Netherlands. University of Technology, Delft, the Netherlands. 17Department of General Practice, The EMGO Institute for 44Max Planck Institute for Biology of Ageing, Cologne, Health and Care Research, VU University Medical Center, Germany. Amsterdam, the Netherlands. 45Netherlands Twin Register, Department of Biological 18Department of Cardiology, Division Heart and Lungs, Psychology, Vrije Universiteit, Amsterdam, the Netherlands. University Medical Center Utrecht, Utrecht, The Netherlands Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands. 19Thorax Centre, Erasmus Medical Centre, Rotterdam, the Metabolites (small molecules involved in biological processes) Netherlands. are important intermediates in understanding
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