Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight.
Freathy RM., Mook-Kanamori DO., Sovio U., Prokopenko I., Timpson NJ., Berry DJ., Warrington NM., Widen E., Hottenga JJ., Kaakinen M., Lange LA., Bradfield JP., Kerkhof M., Marsh JA., Mägi R., Chen C-M., Lyon HN., Kirin M., Adair LS., Aulchenko YS., Bennett AJ., Borja JB., Bouatia-Naji N., Charoen P., Coin LJM., Cousminer DL., de Geus EJC., Deloukas P., Elliott P., Evans DM., Froguel P., Genetic Investigation of ANthropometric Traits (GIANT) Consortium None., Glaser B., Groves CJ., Hartikainen A-L., Hassanali N., Hirschhorn JN., Hofman A., Holly JMP., Hyppönen E., Kanoni S., Knight BA., Laitinen J., Lindgren CM., Meta-Analyses of Glucose and Insulin-related traits Consortium None., McArdle WL., O'Reilly PF., Pennell CE., Postma DS., Pouta A., Ramasamy A., Rayner NW., Ring SM., Rivadeneira F., Shields BM., Strachan DP., Surakka I., Taanila A., Tiesler C., Uitterlinden AG., van Duijn CM., Wellcome Trust Case Control Consortium None., Wijga AH., Willemsen G., Zhang H., Zhao J., Wilson JF., Steegers EAP., Hattersley AT., Eriksson JG., Peltonen L., Mohlke KL., Grant SFA., Hakonarson H., Koppelman GH., Dedoussis GV., Heinrich J., Gillman MW., Palmer LJ., Frayling TM., Boomsma DI., Davey Smith G., Power C., Jaddoe VWV., Jarvelin M-R., Early Growth Genetics (EGG) Consortium None., McCarthy MI.
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.