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Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits

Suzanne Vogelezang 1 Jonathan Bradfield 2 Tarunveer Ahluwalia 3 John Curtin 4 Timo Lakka 5 Niels Grarup 6 Markus Scholz 7 Peter van der Most 8 Claire Monnereau 1 Evie Stergiakouli 9 Anni Heiskala 10 Momoko Horikoshi 11 Iryna Fedko 12 Natalia Vilor-Tejedor 13 Diana Cousminer 2 Marie Standl 14 Carol Wang 15 Jorma Viikari 16 Frank Geller 17 Carmen Íñiguez 13 Niina Pitkänen 16 Alessandra Chesi 2 Jonas Bacelis 18 Loic Yengo 19 Maties Torrent Ioanna Ntalla 20 Øyvind Helgeland 21 Saskia Selzam 22 Judith Vonk 23 Mohammed Zafarmand 24 Barbara Heude 25 Ismaa Sadaf Farooqi 26 Akram Alyass 27 Robin Beaumont 28 Christian Have 6 Peter Rzehak 29 Jose Ramon Bilbao 30 Theresia Schnurr 6 Inês Barroso 31 Klaus Bønnelykke 6 Lawrence Beilin 32 Lisbeth Carstensen 17 Marie-Aline Charles 25 Bo Chawes 6 Karine Clément 33 Ricardo Closa-Monasterolo 34 Adnan Custovic 35 Johan Eriksson 36 Joaquin Escribano 34 Maria Groen-Blokhuis 37 Veit Grote 29 Dariusz Gruszfeld Hakon Hakonarson 2 Torben Hansen 6 Andrew Hattersley 28 Mette Hollensted 6 Jouke-Jan Hottenga 37 Elina Hyppönen 38 Stefan Johansson 39 Raimo Joro 5 Mika Kähönen 40 Ville Karhunen 35 Wieland Kiess 7 Bridget Knight 28 Berthold Koletzko 29 Andreas Kühnapfel 7 Kathrin Landgraf 7 Jean-Paul Langhendries Terho Lehtimäki 40 Jaakko Leinonen 36 Aihuali Li 27 Virpi Lindi 5 Estelle Lowry 41 Mariona Bustamante 13 Carolina Medina-Gomez 1 Mads Melbye 17 Kim Michaelsen 6 Camilla Morgen 6 Trevor Mori 32 Tenna Nielsen 42 Harri Niinikoski 43 Albertine Oldehinkel 23 Katja Pahkala 43 Kalliope Panoutsopoulou 31 Oluf Pedersen 6 Craig Pennell 15 Christine Power 38 Sijmen Reijneveld 23 Fernando Rivadeneira 1 Angela Simpson 44 Peter Sly 45 Jakob Stokholm 6 Kook Teo 27 Elisabeth Thiering 29 Nicholas Timpson 9 André Uitterlinden 1 Catharina van Beijsterveldt 37 Barbera van Schaik 24 Marc Vaudel 46 Elvira Verduci 47 Rebecca Vinding 6 Mandy Vogel 7 Eleftheria Zeggini 31 Sylvain Sebert Mads Lind Christopher Brown Loreto Santa-Marina Eva Reischl Christine Frithioff-Bøjsøe David Meyre Eleanor Wheeler Ken Ong Ellen Nohr Tanja Vrijkotte Gerard Koppelman Robert Plomin Pål Njølstad George Dedoussis Philippe Froguel 19, 35 Thorkild Sørensen Bo Jacobsson Rachel Freathy Babette Zemel Olli Raitakari Martine Vrijheid Bjarke Feenstra Leo-Pekka Lyytikäinen Harold Snieder Holger Kirsten Patrick Holt Joachim Heinrich Elisabeth Widén Jordi Sunyer Dorret Boomsma Marjo-Riitta Järvelin Antje Körner George Davey Smith Jens-Christian Holm Mustafa Atalay Clare Murray Hans Bisgaard Mark Mccarthy Vincent Jaddoe Struan Grant Janine Felix
Abstract : The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located nearNEDD4LandSLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (R(g)ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood. Author summary Although twin studies have shown that body mass index (BMI) is highly heritable, many common genetic variants involved in the development of BMI have not yet been identified, especially in children. We studied associations of more than 40 million genetic variants with childhood BMI in 61,111 children aged between 2 and 10 years. We identified 25 genetic variants that were associated with childhood BMI. Two of these have not been implicated for BMI previously, located close to the genesNEDD4LandSLC45A3. We also show that the genetic background of childhood BMI overlaps with that of birth weight, adult BMI, waist-to-hip-ratio, diastolic blood pressure, type 2 diabetes, and age at menarche. Our results suggest that the biological processes underlying childhood BMI largely overlap with those underlying adult BMI. However, the overlap is not complete. Additionally, the genetic backgrounds of childhood BMI and other cardio-metabolic phenotypes are overlapping. This may mean that the associations of childhood BMI and later cardio-metabolic outcomes are partially explained by shared genetics, but it could also be explained by the strong association of childhood BMI with adult BMI.
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Submitted on : Monday, June 28, 2021 - 3:58:52 PM
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Suzanne Vogelezang, Jonathan Bradfield, Tarunveer Ahluwalia, John Curtin, Timo Lakka, et al.. Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits. PLoS Genetics, Public Library of Science, 2020, 16 (10), pp.e1008718. ⟨10.1371/journal.pgen.1008718⟩. ⟨hal-03269687⟩

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