Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight

Rachel M. Freathy, Dennis O. Mook-Kanamori, Ulla Sovio, Inga Prokopenko, Nicholas J. Timpson, Diane J. Berry, Nicole M. Warrington, Elisabeth Widen, Jouke Jan Hottenga, Marika Kaakinen, Leslie A. Lange, Jonathan P. Bradfield, Marjan Kerkhof, Julie A. Marsh, Reedik Mägi, Chih Mei Chen, Helen N. Lyon, Mirna Kirin, Linda S. Adair, Yurii S. AulchenkoAmanda J. Bennett, Judith B. Borja, Nabila Bouatia-Naji, Pimphen Charoen, Lachlan J.M. Coin, Diana L. Cousminer, Eco J.C. De Geus, Panos Deloukas, Paul Elliott, David M. Evans, Philippe Froguel, Beate Glaser, Christopher J. Groves, Anna Liisa Hartikainen, Neelam Hassanali, Joel N. Hirschhorn, Albert Hofman, Jeff M.P. Holly, Elina Hyppönen, Stavroula Kanoni, Bridget A. Knight, Jaana Laitinen, Cecilia M. Lindgren, Wendy L. McArdle, Paul F. O'Reilly, Craig E. Pennell, Dirkje S. Postma, Anneli Pouta, Adaikalavan Ramasamy, Nigel W. Rayner, Susan M. Ring, Fernando Rivadeneira, Beverley M. Shields, David P. Strachan, Ida Surakka, Anja Taanila, Carla Tiesler, Andre G. Uitterlinden, Cornelia M. Van Duijn, Alet H. Wijga, Gonneke Willemsen, Haitao Zhang, Jianhua Zhao, James F. Wilson, Eric A.P. Steegers, Andrew T. Hattersley, Johan G. Eriksson, Leena Peltonen, Karen L. Mohlke, Struan F.A. Grant, Hakon Hakonarson, Gerard H. Koppelman, George V. Dedoussis, Joachim Heinrich, Matthew W. Gillman, Lyle J. Palmer, Timothy M. Frayling, Dorret I. Boomsma, George Davey Smith, Chris Power, Vincent W.V. Jaddoe, Marjo Riitta Jarvelin, Mark I. McCarthy

Research output: Contribution to journalArticlepeer-review

197 Scopus citations

Abstract

To identify genetic variants associated with birth weight, we meta-analyzed six genome-wide association (GWA) studies (n = 10,623 Europeans from pregnancy/birth cohorts) and followed up two lead signals in 13 replication studies (n = 27,591). rs900400 near LEKR1 and CCNL1 (P = 2 × 10 35) and rs9883204 in ADCY5 (P = 7 × 10 15) were robustly associated with birth weight. Correlated SNPs in ADCY5 were recently implicated in regulation of glucose levels and susceptibility to type 2 diabetes, providing evidence that the well-described association between lower birth weight and subsequent type 2 diabetes has a genetic component, distinct from the proposed role of programming by maternal nutrition. Using data from both SNPs, we found that the 9% of Europeans carrying four birth weight-lowering alleles were, on average, 113g (95% CI 89-137g) lighter at birth than the 24% with zero or one alleles (P trend = 7 × 10 30). The impact on birth weight is similar to that of a mother smoking 4-5 cigarettes per day in the third trimester of pregnancy.

Original languageEnglish
Pages (from-to)430-435
Number of pages6
JournalNature Genetics
Volume42
Issue number5
DOIs
StatePublished - May 2010
Externally publishedYes

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