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; +77 more... 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 Aulchenko; Amanda J Bennett; Judith B Borja; Nabila Bouatia-Naji; Pimphen Charoen; Lachlan JM Coin; Diana L Cousminer; Eco JC de Geus; Panos Deloukas; Paul Elliott; David M Evans; Philippe Froguel; Genetic Investigation of ANthropometric Traits (GIANT) Consortiu; Beate Glaser; Christopher J Groves; Anna-Liisa Hartikainen; Neelam Hassanali; Joel N Hirschhorn; Albert Hofman; Jeff MP Holly; Elina Hyppönen; Stavroula Kanoni; Bridget A Knight; Jaana Laitinen; Cecilia M Lindgren; Meta-Analyses of Glucose and Insulin-related traits Consortium; 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; Wellcome Trust Case Control Consortium; Alet H Wijga; Gonneke Willemsen; Haitao Zhang; Jianhua Zhao; James F Wilson; Eric AP Steegers; Andrew T Hattersley; Johan G Eriksson; Leena Peltonen; Karen L Mohlke; Struan FA 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 WV Jaddoe; Marjo-Riitta Jarvelin; Early Growth Genetics (EGG) Consortium; Mark I McCarthy; (2010) Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight. Nature genetics, 42 (5). pp. 430-435. ISSN 1061-4036 DOI: 10.1038/ng.567
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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 x 10(-35)) and rs9883204 in ADCY5 (P = 7 x 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, 113 g (95% CI 89-137 g) lighter at birth than the 24% with zero or one alleles (P(trend) = 7 x 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.


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