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. Aulchenko; Amanda 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

doi:10.1038/ng.567

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. Aulchenko

Amanda 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

University of Exeter
Erasmus University Rotterdam
Imperial College London
University of Oxford
Medical Research Council
University College London
University of Western Australia
University of Helsinki
Vrije Universiteit Amsterdam
University of Oulu
University of North Carolina at Chapel Hill
Children's Hospital of Philadelphia
University of Groningen
Helmholtz Zentrum München - German Research Center for Environmental Health
Ludwig Maximilian University of Munich
Boston Children's Hospital
Harvard University
University of Edinburgh
University of San Carlos - Philippines
CNRS
Université de Lille
Mahidol University
Wellcome Trust Sanger Institute
Hammersmith Hospital
University of Bristol
Massachusetts Institute of Technology
Harokopio University
Finnish Institute of Occupational Health
National Institute for Health and Welfare
St. George’s Hospital
National Institute of Public Health and the Environment
Helsinki University Hospital
Folkhalsan
University of Pennsylvania
Oxford University Hospitals NHS Foundation Trust

Research output: Contribution to journal › Article › peer-review

210 Citations (Scopus)

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 language	English
Pages (from-to)	430-435
Number of pages	6
Journal	Nature Genetics
Volume	42
Issue number	5
DOIs	https://doi.org/10.1038/ng.567
Publication status	Published - 6 Apr 2010
Externally published	Yes

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Freathy, R. M., Mook-Kanamori, D. O., Sovio, U., Prokopenko, I., Timpson, N. J., Berry, D. J., Warrington, N. M., Widen, E., Hottenga, J. J., Kaakinen, M., Lange, L. A., Bradfield, J. P., Kerkhof, M., Marsh, J. A., Mägi, R., Chen, C. M., Lyon, H. N., Kirin, M., Adair, L. S., ... McCarthy, M. I. (2010). Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight. Nature Genetics, 42(5), 430-435. https://doi.org/10.1038/ng.567

@article{1a1851cc981b4a5d854573f9b0abf897,

title = "Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight",

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 {\texttimes} 10 35) and rs9883204 in ADCY5 (P = 7 {\texttimes} 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 {\texttimes} 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.",

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

year = "2010",

month = apr,

day = "6",

doi = "10.1038/ng.567",

language = "English",

volume = "42",

pages = "430--435",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "5",

}

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, CM, 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, Glaser, B, Groves, CJ, Hartikainen, AL, Hassanali, N, Hirschhorn, JN, Hofman, A, Holly, JMP, Hyppönen, E, Kanoni, S, Knight, BA, Laitinen, J, Lindgren, CM, 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, 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, Smith, GD, Power, C, Jaddoe, VWV, Jarvelin, MR & McCarthy, MI 2010, 'Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight', Nature Genetics, vol. 42, no. 5, pp. 430-435. https://doi.org/10.1038/ng.567

TY - JOUR

T1 - Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight

AU - Freathy, Rachel M.

AU - Mook-Kanamori, Dennis O.

AU - Sovio, Ulla

AU - Prokopenko, Inga

AU - Timpson, Nicholas J.

AU - Berry, Diane J.

AU - Warrington, Nicole M.

AU - Widen, Elisabeth

AU - Hottenga, Jouke Jan

AU - Kaakinen, Marika

AU - Lange, Leslie A.

AU - Bradfield, Jonathan P.

AU - Kerkhof, Marjan

AU - Marsh, Julie A.

AU - Mägi, Reedik

AU - Chen, Chih Mei

AU - Lyon, Helen N.

AU - Kirin, Mirna

AU - Adair, Linda S.

AU - Aulchenko, Yurii S.

AU - Bennett, Amanda J.

AU - Borja, Judith B.

AU - Bouatia-Naji, Nabila

AU - Charoen, Pimphen

AU - Coin, Lachlan J.M.

AU - Cousminer, Diana L.

AU - De Geus, Eco J.C.

AU - Deloukas, Panos

AU - Elliott, Paul

AU - Evans, David M.

AU - Froguel, Philippe

AU - Glaser, Beate

AU - Groves, Christopher J.

AU - Hartikainen, Anna Liisa

AU - Hassanali, Neelam

AU - Hirschhorn, Joel N.

AU - Hofman, Albert

AU - Holly, Jeff M.P.

AU - Hyppönen, Elina

AU - Kanoni, Stavroula

AU - Knight, Bridget A.

AU - Laitinen, Jaana

AU - Lindgren, Cecilia M.

AU - McArdle, Wendy L.

AU - O'Reilly, Paul F.

AU - Pennell, Craig E.

AU - Postma, Dirkje S.

AU - Pouta, Anneli

AU - Ramasamy, Adaikalavan

AU - Rayner, Nigel W.

AU - Ring, Susan M.

AU - Rivadeneira, Fernando

AU - Shields, Beverley M.

AU - Strachan, David P.

AU - Surakka, Ida

AU - Taanila, Anja

AU - Tiesler, Carla

AU - Uitterlinden, Andre G.

AU - Van Duijn, Cornelia M.

AU - Wijga, Alet H.

AU - Willemsen, Gonneke

AU - Zhang, Haitao

AU - Zhao, Jianhua

AU - Wilson, James F.

AU - Steegers, Eric A.P.

AU - Hattersley, Andrew T.

AU - Eriksson, Johan G.

AU - Peltonen, Leena

AU - Mohlke, Karen L.

AU - Grant, Struan F.A.

AU - Hakonarson, Hakon

AU - Koppelman, Gerard H.

AU - Dedoussis, George V.

AU - Heinrich, Joachim

AU - Gillman, Matthew W.

AU - Palmer, Lyle J.

AU - Frayling, Timothy M.

AU - Boomsma, Dorret I.

AU - Smith, George Davey

AU - Power, Chris

AU - Jaddoe, Vincent W.V.

AU - Jarvelin, Marjo Riitta

AU - McCarthy, Mark I.

PY - 2010/4/6

Y1 - 2010/4/6

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/77951766379

U2 - 10.1038/ng.567

DO - 10.1038/ng.567

M3 - Article

C2 - 20372150

AN - SCOPUS:77951766379

SN - 1061-4036

VL - 42

SP - 430

EP - 435

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -

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

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