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

RM Freathy, Dennis Mook, U Sovio, I Prokopenko, NJ Timpson, DJ Berry, NM Warrington, E Widen, JJ (Jouke Jan) Hottenga, M Kaakinen, LA Lange, JP Bradfield, Marjon Kerkhof, JA Marsh, R Magi, CM Chen, HN Lyon, M Kirin, LS Adair, YS AulchenkoAJ Bennett, JB Borja, N Bouatia-Naji, P Charoen, LJM Coin, DL Cousminer, EJC de Geus, P Deloukas, P Elliott, DM Evans, P Froguel, B Glaser, CJ Groves, AL Hartikainen, N Hassanali, JN Hirschhorn, Bert Hofman, JMP Holly, E Hypponen, S Kanoni, BA Knight, J Laitinen, CM Lindgren, WL McArdle, PF O'Reilly, CE Pennell, DS Postma, A Pouta, A Ramasamy, NW Rayner, SM Ring, Fernando Rivadeneira, BM Shields, DP Strachan, I Surakka, A Taanila, C Tiesler, André Uitterlinden, Cornelia Duijn, AH Wijga, G Willemsen, HT Zhang, JH Zhao, JF Wilson, Eric Steegers, AT Hattersley, JG Eriksson, L Peltonen, KL Mohlke, SFA Grant, H Hakonarson, GH Koppelman, GV Dedoussis, J (Joachim) Heinrich, MW Gillman, LJ Palmer, TM Frayling, DI Boomsma, GD Smith, C Power, Vincent Jaddoe, MR Jarvelin, MI McCarthy

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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 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(1), providing evidence that the well-described association between lower birth weight and subsequent type 2 diabetes(2,3) 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(4).
Original languageUndefined/Unknown
Pages (from-to)430-U73
JournalNature Genetics
Volume42
Issue number5
DOIs
Publication statusPublished - 2010

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