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Genetic architecture of early childhood growth phenotypes gives insights into their link with later obesity

By N. Maneka G. De Silva, Sylvain Sebert, Alexessander Couto Alves, Ulla Sovio, Shikta Das, Rob Taal, Nicole M. Warrington, Alexandra M. Lewin, Marika Kaakinen, Diana Cousminer, Elisabeth Thiering, Nicholas J. Timpson, Ville Karhunen, Tom Bond, Xavier Estivill, Virpi Lindi, Jonathan P. Bradfield, Frank Geller, Lachlan J.M. Coin, Marie Loh, Sheila J. Barton, Lawrence J. Beilin, Hans Bisgaard, Klaus Bønnelykke, Rohia Alili, Ida J. Hatoum, Katharina Schramm, Rufus Cartwright, Marie-Aline Charles, Vincenzo Salerno, Karine Clément, Cornelia M. van Duijn, Elena Moltchanova, Johan G. Eriksson, Cathy Elks, Bjarke Feenstra, Claudia Flexeder, Stephen Franks, Timothy M Frayling, Rachel M Freathy, Paul Elliott, Elisabeth Widén, Hakon Hakonarson, Andrew T Hattersley, Alina Rodriguez, Marco Banterle, Joachim Heinrich, Barbara Heude, John W Holloway, Albert Hofman, Elina Hyppönen, Hazel M Inskip, Lee M. Kaplan, Asa K. Hedman, Esa Läärä, Holger Prokisch, Harald Grallert, Timo A. Lakka, Deborah A Lawlor, Mads Melbye, Tarunveer S. Ahluwalia, Marcella Marinelli, Iona Y. Millwood, Lyle J. Palmer, Craig E. Pennell, John R. Perry, Susan Ring, Markku Savolainen, Kari Stefansson, Gudmar Thorleifsson, Fernando Rivadeneira, Marie Standl, Jordi Sunyer, Carla MT Tiesler, Andre G Uitterlinden, Inga Prokopenko, Karl-Heinz Herzig, George Davey Smith, Paul O'Reilly, Janine F. Felix, Jessica L. Buxton, Alexandra I.F. Blakemore, Ken K. Ong, Struan F.A. Grant, Vincent W.V. Jaddoe, Mark Mccarthy, Marjo-Riitta Järvelin

Posted 16 Jun 2017
bioRxiv DOI: 10.1101/150516

Early childhood growth patterns are associated with adult metabolic health, but the underlying mechanisms are unclear. We performed genome-wide meta-analyses and follow-up in up to 22,769 European children for six early growth phenotypes derived from longitudinal data: peak height and weight velocities, age and body mass index (BMI) at adiposity peak (AP ~9 months) and rebound (AR ~5-6 years). We identified four associated loci (P< 5x10-8): LEPR/LEPROT with BMI at AP, FTO and TFAP2B with Age at AR and GNPDA2 with BMI at AR. The observed AR-associated SNPs at FTO, TFAP2B and GNPDA2 represent known adult BMI-associated variants. The common BMI at AP associated variant at LEPR/LEPROT was not associated with adult BMI but was associated with LEPROT gene expression levels, especially in subcutaneous fat (P<2x10-51). We identify strong positive genetic correlations between early growth and later adiposity traits, and analysis of the full discovery stage results for Age at AR revealed enrichment for insulin-like growth factor 1 (IGF-1) signaling and apolipoprotein pathways. This genome-wide association study suggests mechanistic links between early childhood growth and adiposity in later childhood and adulthood, highlighting these early growth phenotypes as potential targets for the prevention of obesity.

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