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. AulchenkoAmanda 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

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

205 Scopus citations

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
State	Published - May 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{38eef145feb14c18baced67d73534d34,

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 × 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.",

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.}",

note = "Funding Information: See also Supplementary Note for detailed acknowledgments by study. The authors of this manuscript would like to acknowledge the particular role of Leena Peltonen-Palotie in the research described in this manuscript, and to express our sadness at her untimely loss. Leena made a unique contribution to the field of human genetics research, and enriched the professional and social lives of all who worked with her. She will be sorely missed. Major funding for the research in this paper is as follows: Academy of Finland (project grants 104781, 120315, 209072, 129255 and Center of Excellence in Complex Disease Genetics); Biocentrum Helsinki; Biocenter, University of Oulu, Finland; British Heart Foundation; Canadian Institutes of Health Research (grant MOP 82893); Center for Medical Systems Biology; Centre for Neurogenomics and Cognitive Research (CNCR-VU) (grant EU/QLRT-2001-01254); The Chief Scientist Office of the Scottish Government; The Children{\textquoteright}s Hospital of Philadelphia (Institute Development Award); Coca-Cola Hellas; Cotswold Foundation (Research Development Award); Darlington Trust; Department of Health{\textquoteright}s National Institute of Health Research UK; Diabetes UK (grant RD08/0003704); Dutch Asthma Foundation; Dutch Ministry of the Environment; Erasmus Medical Center Rotterdam; Erasmus University Rotterdam; European Commission (EURO-BLCS, Framework 5 award QLG1-CT-2000-01643); The European Community{\textquoteright}s Seventh Framework Programme (FP7/2007-2013), ENGAGE project, grant agreement HEALTH-F4-2007-201413; The European Union Framework Program 6 EUROSPAN Project (LSHG-CT-2006-018947); Exeter National Health Service Research and Development; Friedrich-Schiller University Jena; Genetic Association Information Network; Healthway Western Australia; Helmholtz Zentrum Muenchen–German Research Center for Environment and Health; Institute of Epidemiology Neuherberg; Institut f{\"u}r Umweltmedizinische Forschung (IUF) D{\"u}sseldorf; Juvenile Diabetes Research Foundation International; Kompetenznetz Adipositas (Competence Network Obesity) funded by the German Federal Ministry of Education and Research (FKZ: 01GI0826); Marien-Hospital Wesel; MRC UK (grants G0601261, G0600705, studentship grant G0500539, G0000934, G0601653); Munich Center of Health Sciences (MCHEALTH); Municipal Health Service Rotterdam; National Health and Medical Research Council of Australia (grant 572613); National Human Genome Research Institute (US); National Institute of Allergy and Infectious Diseases (US); National Institute of Child Health and Human Development (US) (HD056465, HD034568, HD05450); National Institute of Diabetes and Digestive and Kidney Diseases (US) (DK075787, DK078150, DK56350); National Institute for Environmental Health Sciences (US) (ES10126); National Institute of Mental Health (US) (MH083268, MH63706); National Heart, Lung, and Blood Institute (US) (HL0876792 (STAMPEED program), HL085144, HL068041); National Institutes of Health (US) (Fogarty International Center Grant TW05596; National Center for Research Resources RR20649); National Public Health Institute, Helsinki, Finland; Netherlands Organisation for Scientific Research (NWO)/ Netherlands Organisation for Health Research and Development (ZonMw) (grants SPI 56-464-14192, 904-61-090, 904-61-193, 480-04-004, 400-05-717); Office of Population Studies Foundation, University of San Carlos, Philippines; Peninsula NIHR Clinical Research Facility (UK); Raine Medical Research Foundation; Rotterdam Homecare Foundation; South West National Health Service Research and Development (UK) Spinoza; St. Georg Hospital Leipzig; Stichting Astmabestrijding; Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR) Rotterdam; Technical University Munich; Telethon Institute for Child Health Research; Type 1 Diabetes Genetics Consortium; UFZ–Centre for Environmental Research Leipzig-Halle; University Hospital Oulu Biocenter, University of Oulu, Finland; University of Bristol; University of Leipzig; Wellcome Trust (grants 085301, 068545/Z/02, 076113/B/04/Z); Western Australian DNA Bank; Western Australian Genetic Epidemiology Resource; and the Wind Over Water Foundation. Data exchange for the meta-analyses was facilitated by the SIMBioMS platform (http://simbioms.org). Personal funding is as follows: R.M.F. by a Sir Henry Wellcome Postdoctoral Fellowship (Wellcome Trust grant 085541/Z/08/Z); E.W. by the Academy of Finland (grant 120315 and 129287); H.N.L. by US National Institutes of Health grant 1R01DK075787; E.H. by the Career Scientist Award, Department of Health, UK; C.M.L. by a Wellcome Trust Research Career Development Fellowship; A.R. by the UK Department of Health Policy Research Programme; B.M.S., B.A.K. and A.T.H. are employed as core members of the Peninsula NIHR Clinical Research Facility; J.F.W. by The Royal Society; L.P. by the Wellcome Trust (grant 89061/Z/09/Z); and V.W.V.J. by the Netherlands Organization for Health Research (ZonMw 90700303).",

year = "2010",

month = may,

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.

N1 - Funding Information: See also Supplementary Note for detailed acknowledgments by study. The authors of this manuscript would like to acknowledge the particular role of Leena Peltonen-Palotie in the research described in this manuscript, and to express our sadness at her untimely loss. Leena made a unique contribution to the field of human genetics research, and enriched the professional and social lives of all who worked with her. She will be sorely missed. Major funding for the research in this paper is as follows: Academy of Finland (project grants 104781, 120315, 209072, 129255 and Center of Excellence in Complex Disease Genetics); Biocentrum Helsinki; Biocenter, University of Oulu, Finland; British Heart Foundation; Canadian Institutes of Health Research (grant MOP 82893); Center for Medical Systems Biology; Centre for Neurogenomics and Cognitive Research (CNCR-VU) (grant EU/QLRT-2001-01254); The Chief Scientist Office of the Scottish Government; The Children’s Hospital of Philadelphia (Institute Development Award); Coca-Cola Hellas; Cotswold Foundation (Research Development Award); Darlington Trust; Department of Health’s National Institute of Health Research UK; Diabetes UK (grant RD08/0003704); Dutch Asthma Foundation; Dutch Ministry of the Environment; Erasmus Medical Center Rotterdam; Erasmus University Rotterdam; European Commission (EURO-BLCS, Framework 5 award QLG1-CT-2000-01643); The European Community’s Seventh Framework Programme (FP7/2007-2013), ENGAGE project, grant agreement HEALTH-F4-2007-201413; The European Union Framework Program 6 EUROSPAN Project (LSHG-CT-2006-018947); Exeter National Health Service Research and Development; Friedrich-Schiller University Jena; Genetic Association Information Network; Healthway Western Australia; Helmholtz Zentrum Muenchen–German Research Center for Environment and Health; Institute of Epidemiology Neuherberg; Institut für Umweltmedizinische Forschung (IUF) Düsseldorf; Juvenile Diabetes Research Foundation International; Kompetenznetz Adipositas (Competence Network Obesity) funded by the German Federal Ministry of Education and Research (FKZ: 01GI0826); Marien-Hospital Wesel; MRC UK (grants G0601261, G0600705, studentship grant G0500539, G0000934, G0601653); Munich Center of Health Sciences (MCHEALTH); Municipal Health Service Rotterdam; National Health and Medical Research Council of Australia (grant 572613); National Human Genome Research Institute (US); National Institute of Allergy and Infectious Diseases (US); National Institute of Child Health and Human Development (US) (HD056465, HD034568, HD05450); National Institute of Diabetes and Digestive and Kidney Diseases (US) (DK075787, DK078150, DK56350); National Institute for Environmental Health Sciences (US) (ES10126); National Institute of Mental Health (US) (MH083268, MH63706); National Heart, Lung, and Blood Institute (US) (HL0876792 (STAMPEED program), HL085144, HL068041); National Institutes of Health (US) (Fogarty International Center Grant TW05596; National Center for Research Resources RR20649); National Public Health Institute, Helsinki, Finland; Netherlands Organisation for Scientific Research (NWO)/ Netherlands Organisation for Health Research and Development (ZonMw) (grants SPI 56-464-14192, 904-61-090, 904-61-193, 480-04-004, 400-05-717); Office of Population Studies Foundation, University of San Carlos, Philippines; Peninsula NIHR Clinical Research Facility (UK); Raine Medical Research Foundation; Rotterdam Homecare Foundation; South West National Health Service Research and Development (UK) Spinoza; St. Georg Hospital Leipzig; Stichting Astmabestrijding; Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR) Rotterdam; Technical University Munich; Telethon Institute for Child Health Research; Type 1 Diabetes Genetics Consortium; UFZ–Centre for Environmental Research Leipzig-Halle; University Hospital Oulu Biocenter, University of Oulu, Finland; University of Bristol; University of Leipzig; Wellcome Trust (grants 085301, 068545/Z/02, 076113/B/04/Z); Western Australian DNA Bank; Western Australian Genetic Epidemiology Resource; and the Wind Over Water Foundation. Data exchange for the meta-analyses was facilitated by the SIMBioMS platform (http://simbioms.org). Personal funding is as follows: R.M.F. by a Sir Henry Wellcome Postdoctoral Fellowship (Wellcome Trust grant 085541/Z/08/Z); E.W. by the Academy of Finland (grant 120315 and 129287); H.N.L. by US National Institutes of Health grant 1R01DK075787; E.H. by the Career Scientist Award, Department of Health, UK; C.M.L. by a Wellcome Trust Research Career Development Fellowship; A.R. by the UK Department of Health Policy Research Programme; B.M.S., B.A.K. and A.T.H. are employed as core members of the Peninsula NIHR Clinical Research Facility; J.F.W. by The Royal Society; L.P. by the Wellcome Trust (grant 89061/Z/09/Z); and V.W.V.J. by the Netherlands Organization for Health Research (ZonMw 90700303).

PY - 2010/5

Y1 - 2010/5

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 - http://www.scopus.com/inward/record.url?scp=77951766379&partnerID=8YFLogxK

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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