Heritability estimates for 361 blood metabolites across 40 genome-wide association studies
Fiona A. Hagenbeek, René Pool, Jenny van Dongen, Harmen H. M. Draisma, Jouke‐Jan Hottenga, Gonneke Willemsen, Abdel Abdellaoui, Iryna O. Fedko, Anouk den Braber, Pieter Jelle Visser, Eco J. C. de Geus, Ko Willems van Dijk, Aswin Verhoeven, H. Eka D. Suchiman, Marian Beekman, P. Eline Slagboom, Cornelia M. van Duijn, J. J. H. Barkey Wolf, Davy Cats, Najaf Amin, Joline W. J. Beulens, Joana Bom, Nils Bömer, Ayşe Demirkan, J. A. van Hilten, Jennifer Meessen, Matthijs H. Moed, J. Fu, Gerrit L.J. Onderwater, Femke Rutters, Cynthia So‐Osman, Wiesje M. van der Flier, Amber A. van der Heijden, Ashley van der Spek, Folkert W. Asselbergs, Eric Boersma, Petra J. M. Elders, Johanna M. Geleijnse, M. Arfan Ikram, M. Kloppenburg, Ingrid Meulenbelt, Simon P. Mooijaart, Rob G. H. H. Nelissen, M. G. Netea, Brenda W.J.H. Penninx, Coen D.A. Stehouwer, Charlotte E. Teunissen, GM Terwindt, Leen M. ‘t Hart, A. M. J. M. van den Maagdenberg, Pim van der Harst, Iwan C.C. van der Horst, Carla Kallen, Marleen M. J. van Greevenbroek, W.E. van Spil, Cisca Wijmenga, Aeilko H. Zwinderman, A. Zhernikova, J. Wouter Jukema, Hailiang Mei, Mariska Slofstra, Morris A. Swertz, Erik B. van den Akker, Joris Deelen, Marcel Reinders, Amy C. Harms, Thomas Hankemeier, Meike Bartels, Michel G. Nivard, Dorret I. Boomsma
Abstract
Abstract Metabolomics examines the small molecules involved in cellular metabolism. Approximately 50% of total phenotypic differences in metabolite levels is due to genetic variance, but heritability estimates differ across metabolite classes. We perform a review of all genome-wide association and (exome-) sequencing studies published between November 2008 and October 2018, and identify >800 class-specific metabolite loci associated with metabolite levels. In a twin-family cohort ( N = 5117), these metabolite loci are leveraged to simultaneously estimate total heritability (h 2 total ), and the proportion of heritability captured by known metabolite loci (h 2 Metabolite-hits ) for 309 lipids and 52 organic acids. Our study reveals significant differences in h 2 Metabolite-hits among different classes of lipids and organic acids. Furthermore, phosphatidylcholines with a high degree of unsaturation have higher h 2 Metabolite-hits estimates than phosphatidylcholines with low degrees of unsaturation. This study highlights the importance of common genetic variants for metabolite levels, and elucidates the genetic architecture of metabolite classes.