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Variants in ADCY5 and Near CCNL1 are Associated with Fetal Growth and Birth Weight

Freathy, Rachel M.; Mook-Kanamori, Dennis O.; Sovio, Ulla; Prokopenko, Inga; Timpson, Nicholas J.; Berry, Diane J.; Warrington, Nicole M.; Widen, Elisabeth; Hottenga, Jouke Jan; Kaakinen, Marika; Lange, Leslie A.; Bradfield, Jonathan P.; Kerkhof, Marjan; Marsh, Julie A.; Magi, Reedik; Chen, Chih-Mei; Lyon, Helen N.; Kirin, Mirna; Adair, Linda S.; Aulchenko, Yurii S.; Bennett, Amanda J.; Borja, Judith B.; Bouatia-Naji, Nabila; Charoen, Pimphen; Coin, Lachlan J. M.; Cousminer, Diana L.; de Geus, Eco J. C.; Deloukas, Panos; Elliott, Paul; Evans, David M.; Froguel, Philippe; Glaser, Beate; Groves, Christopher J.; Hartikainen, Anna-Liisa; Hassanali, Neelam; Hirschhorn, Joel N.; Hofman, Albert; Holly, Jeff M. P.; Hypponen, Elina; Kanoni, Stavroula; Knight, Bridget A.; Laitinen, Jaana; Lindgren, Cecilia M.; McArdle, Wendy L.; O'Reilly, Paul F.; Pennell, Craig E.; Postma, Dirkje S.; Pouta, Anneli; Ramasamy, Adaikalavan; Rayner, Nigel W.; Ring, Susan M.; Rivadeneira, Fernando; Shields, Beverley M.; Strachan, David P.; Surakka, Ida; Taanila, Anja; Tiesler, Carla; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Wijga, Alet H.; Willemsen, Gonneke; Zhang, Haitao; Zhao, Jianhua; Wilson, James F.; Steegers, Eric A. P.; Hattersley, Andrew T.; Eriksson, Johan G.; Peltonen, Leena; Mohlke, Karen L.; Grant, Struan F. A.; Hakonarson, Hakon; Koppelman, Gerard H.; Dedoussis, George V.; Heinrich, Joachim; Gillman, Matthew W.; Palmer, Lyle J.; Frayling, Timothy M.; Boomsma, Dorret I.; Smith, George Davey; Power, Chris; Jaddoe, Vincent W. V.; & Jarvelin, Marjo-Riitta. (2010). Variants in ADCY5 and Near CCNL1 are Associated with Fetal Growth and Birth Weight. Nature Genetics, 42(5), 430-5.

Freathy, Rachel M.; Mook-Kanamori, Dennis O.; Sovio, Ulla; Prokopenko, Inga; Timpson, Nicholas J.; Berry, Diane J.; Warrington, Nicole M.; Widen, Elisabeth; Hottenga, Jouke Jan; Kaakinen, Marika; Lange, Leslie A.; Bradfield, Jonathan P.; Kerkhof, Marjan; Marsh, Julie A.; Magi, Reedik; Chen, Chih-Mei; Lyon, Helen N.; Kirin, Mirna; Adair, Linda S.; Aulchenko, Yurii S.; Bennett, Amanda J.; Borja, Judith B.; Bouatia-Naji, Nabila; Charoen, Pimphen; Coin, Lachlan J. M.; Cousminer, Diana L.; de Geus, Eco J. C.; Deloukas, Panos; Elliott, Paul; Evans, David M.; Froguel, Philippe; Glaser, Beate; Groves, Christopher J.; Hartikainen, Anna-Liisa; Hassanali, Neelam; Hirschhorn, Joel N.; Hofman, Albert; Holly, Jeff M. P.; Hypponen, Elina; Kanoni, Stavroula; Knight, Bridget A.; Laitinen, Jaana; Lindgren, Cecilia M.; McArdle, Wendy L.; O'Reilly, Paul F.; Pennell, Craig E.; Postma, Dirkje S.; Pouta, Anneli; Ramasamy, Adaikalavan; Rayner, Nigel W.; Ring, Susan M.; Rivadeneira, Fernando; Shields, Beverley M.; Strachan, David P.; Surakka, Ida; Taanila, Anja; Tiesler, Carla; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Wijga, Alet H.; Willemsen, Gonneke; Zhang, Haitao; Zhao, Jianhua; Wilson, James F.; Steegers, Eric A. P.; Hattersley, Andrew T.; Eriksson, Johan G.; Peltonen, Leena; Mohlke, Karen L.; Grant, Struan F. A.; Hakonarson, Hakon; Koppelman, Gerard H.; Dedoussis, George V.; Heinrich, Joachim; Gillman, Matthew W.; Palmer, Lyle J.; Frayling, Timothy M.; Boomsma, Dorret I.; Smith, George Davey; Power, Chris; Jaddoe, Vincent W. V.; & Jarvelin, Marjo-Riitta. (2010). Variants in ADCY5 and Near CCNL1 are Associated with Fetal Growth and Birth Weight. Nature Genetics, 42(5), 430-5.

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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 × 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 diabetes1, providing evidence that the well-described association between lower birth weight and subsequent type 2 diabetes2, 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 (Ptrend = 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.




JOUR



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



2010


Nature Genetics

42

5

430-5







10.1038/ng.567



202