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

Journal name:
Nature Genetics
Volume:
42,
Pages:
430–435
Year published:
DOI:
doi:10.1038/ng.567
Received
Accepted
Published online

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 pregnancy4.

At a glance

Figures

  1. Regional plots of two previously unknown associations with birth weight.
    Figure 1: Regional plots of two previously unknown associations with birth weight.

    (a,b) For each of the two regions, 3q25 (a) and 3q21 (b), directly genotyped and imputed SNPs are plotted using filled circles with their meta-analysis P values (as −log10 values) as a function of genomic position (NCBI Build 35). In each plot, the discovery-stage SNP taken forward to replication stage is represented by a blue diamond (defining a global meta-analysis P value), with its discovery meta-analysis P value denoted by a red diamond. Local LD structure is reflected by the plotted estimated recombination rates (taken from HapMap) in the region around the associated SNPs and their correlated proxies. Each analyzed SNP is represented by a circle. The color scheme of the circles respects LD patterns (HapMap CEU pairwise r2 correlation coefficients) between top discovery SNP and surrounding variants: white, r2 < 0.2; gray, 0.5 > r2 ≥ 0.2; orange, 0.8 > r2 ≥ 0.5; red, r2 ≥ 0.8. Gene annotations were taken from the University of California Santa Cruz genome browser.

  2. Forest plots of the association between birth weight and genotype at each locus.
    Figure 2: Forest plots of the association between birth weight and genotype at each locus.

    (a,b) Index SNP rs900400 at 3q25 (a) and index SNP rs9883204 at 3q21 (b). If the index SNP was unavailable, a closely correlated proxy (HapMap r2 > 0.9) was used.

References

  1. Dupuis, J. et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat. Genet. 42, 105116 (2010).
  2. Barker, D.J. et al. Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia 36, 6267 (1993).
  3. Järvelin, M.R. et al. Early life factors and blood pressure at age 31 years in the 1966 northern Finland birth cohort. Hypertension 44, 838846 (2004).
  4. Bernstein, I.M. et al. Maternal smoking and its association with birth weight. Obstet. Gynecol. 106, 986991 (2005).
  5. Battaglia, F.C. & Lubchenco, L.O. A practical classification of newborn infants by weight and gestational age. J. Pediatr. 71, 159163 (1967).
  6. Acker, D.B., Sachs, B.P. & Friedman, E.A. Risk factors for shoulder dystocia. Obstet. Gynecol. 66, 762768 (1985).
  7. Kramer, M.S. Determinants of low birth weight: methodological assessment and meta-analysis. Bull. World Health Organ. 65, 663737 (1987).
  8. Järvelin, M.R. et al. Ecological and individual predictors of birthweight in a northern Finland birth cohort 1986. Paediatr. Perinat. Epidemiol. 11, 298312 (1997).
  9. Knight, B. et al. Evidence of genetic regulation of fetal longitudinal growth. Early Hum. Dev. 81, 823831 (2005).
  10. Klebanoff, M.A., Mednick, B.R., Schulsinger, C., Secher, N.J. & Shiono, P.H. Father's effect on infant birth weight. Am. J. Obstet. Gynecol. 178, 10221026 (1998).
  11. Hattersley, A.T. & Tooke, J.E. The fetal insulin hypothesis: an alternative explanation of the association of low birthweight with diabetes and vascular disease. Lancet 353, 17891792 (1999).
  12. Freathy, R.M. et al. Type 2 diabetes risk alleles are associated with reduced size at birth. Diabetes 58, 14281433 (2009).
  13. Zhao, J. et al. Examination of type 2 diabetes loci implicates CDKAL1 as a birth weight gene. Diabetes 58, 24142418 (2009).
  14. Hattersley, A.T. et al. Mutations in the glucokinase gene of the fetus result in reduced birth weight. Nat. Genet. 19, 268270 (1998).
  15. Higgins, J.P., Thompson, S.G., Deeks, J.J. & Altman, D.G. Measuring inconsistency in meta-analyses. Br. Med. J. 327, 557560 (2003).
  16. Freathy, R.M. et al. Type 2 diabetes TCF7L2 risk genotypes alter birth weight: a study of 24,053 individuals. Am. J. Hum. Genet. 80, 11501161 (2007).
  17. Weedon, M.N. et al. Genome-wide association analysis identifies 20 loci that influence adult height. Nat. Genet. 40, 575583 (2008).
  18. Willer, C.J. et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat. Genet. 41, 2534 (2009).
  19. Parsons, T.J., Power, C. & Manor, O. Fetal and early life growth and body mass index from birth to early adulthood in 1958 British cohort: longitudinal study. Br. Med. J. 323, 13311335 (2001).
  20. Loyer, P. et al. Characterization of cyclin L1 and L2 interactions with CDK11 and splicing factors: influence of cyclin L isoforms on splice site selection. J. Biol. Chem. 283, 77217732 (2008).
  21. Dixon, A.L. et al. A genome-wide association study of global gene expression. Nat. Genet. 39, 12021207 (2007).
  22. Tesmer, J.J. & Sprang, S.R. The structure, catalytic mechanism and regulation of adenylyl cyclase. Curr. Opin. Struct. Biol. 8, 713719 (1998).
  23. Hanoune, J. et al. Adenylyl cyclases: structure, regulation and function in an enzyme superfamily. Mol. Cell. Endocrinol. 128, 179194 (1997).
  24. Ludwig, M.G. & Seuwen, K. Characterization of the human adenylyl cyclase gene family: cDNA, gene structure, and tissue distribution of the nine isoforms. J. Recept. Signal Transduct. Res. 22, 79110 (2002).
  25. Prokopenko, I., McCarthy, M.I. & Lindgren, C.M. Type 2 diabetes: new genes, new understanding. Trends Genet. 24, 613621 (2008).
  26. Prokopenko, I. et al. Variants in MTNR1B influence fasting glucose levels. Nat. Genet. 41, 7781 (2008).
  27. Ogura, K. et al. 8-bromo-cyclicAMP stimulates glucose transporter-1 expression in a human choriocarcinoma cell line. J. Endocrinol. 164, 171178 (2000).
  28. D'Souza, V.M. et al. cAMP-coupled riboflavin trafficking in placental trophoblasts: a dynamic and ordered process. Biochemistry 45, 60956104 (2006).
  29. Leach, L. The phenotype of the human materno-fetal endothelial barrier: molecular occupancy of paracellular junctions dictate permeability and angiogenic plasticity. J. Anat. 200, 599606 (2002).
  30. van Baal, C.G. & Boomsma, D.I. Etiology of individual differences in birth weight of twins as a function of maternal smoking during pregnancy. Twin Res. 1, 123130 (1998).
  31. Lunde, A., Melve, K.K., Gjessing, H.K., Skjaerven, R. & Irgens, L.M. Genetic and environmental influences on birth weight, birth length, head circumference, and gestational age by use of population-based parent-offspring data. Am. J. Epidemiol. 165, 734741 (2007).
  32. Stein, A.D., Zybert, P.A., van de Bor, M. & Lumey, L.H. Intrauterine famine exposure and body proportions at birth: the Dutch Hunger Winter. Int. J. Epidemiol. 33, 831836 (2004).
  33. Krestyaninova, M. et al. A System for Information Management in BioMedical Studies–SIMBioMS. Bioinformatics 25, 27682769 (2009).
  34. Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 9971004 (1999).
  35. de Bakker, P.I. et al. Practical aspects of imputation-driven meta-analysis of genome-wide association studies. Hum. Mol. Genet. 17, R122R128 (2008).
  36. Harris, R. et al. METAN: Stata module for fixed and random effects meta-analysis (Statistical Software Components S456798, Boston College Department of Economics, revised 19 Feb 2007). <http://ideas.repec.org/c/boc/bocode/s456798.html>
  37. Wallace, B.C., Schmid, C.H., Lau, J. & Trikalinos, T.A. Meta-Analyst: software for meta-analysis of binary, continuous and diagnostic data. BMC Med. Res. Methodol. 9, 80 (2009).
  38. Niklasson, A. et al. An update of the Swedish reference standards for weight, length and head circumference at birth for given gestational age (1977–1981). Acta Paediatr. Scand. 80, 756762 (1991).

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Author information

  1. These authors contributed equally to this work.

    • Rachel M Freathy,
    • Dennis O Mook-Kanamori,
    • Ulla Sovio,
    • Inga Prokopenko,
    • Nicholas J Timpson,
    • Diane J Berry &
    • Nicole M Warrington
  2. These authors jointly directed this work.

    • Dorret I Boomsma,
    • George Davey Smith,
    • Chris Power,
    • Vincent W V Jaddoe,
    • Marjo-Riitta Jarvelin &
    • Mark I McCarthy

Affiliations

  1. Genetics of Complex Traits, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, UK.

    • Rachel M Freathy &
    • Timothy M Frayling
  2. Department of Pediatrics, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Dennis O Mook-Kanamori &
    • Vincent W V Jaddoe
  3. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Dennis O Mook-Kanamori,
    • Yurii S Aulchenko,
    • Albert Hofman,
    • Fernando Rivadeneira,
    • Andre G Uitterlinden,
    • Cornelia M van Duijn &
    • Vincent W V Jaddoe
  4. The Generation R Study, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Dennis O Mook-Kanamori
  5. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.

    • Ulla Sovio,
    • Pimphen Charoen,
    • Lachlan J M Coin,
    • Paul Elliott,
    • Paul F O'Reilly,
    • Adaikalavan Ramasamy &
    • Marjo-Riitta Jarvelin
  6. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, UK.

    • Inga Prokopenko,
    • Reedik Mägi,
    • Amanda J Bennett,
    • Christopher J Groves,
    • Neelam Hassanali,
    • Cecilia M Lindgren,
    • Nigel W Rayner &
    • Mark I McCarthy
  7. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Inga Prokopenko,
    • Reedik Mägi,
    • Cecilia M Lindgren,
    • Nigel W Rayner &
    • Mark I McCarthy
  8. The Medical Research Council (MRC) Centre for Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, Oakfield House, Bristol, UK.

    • Nicholas J Timpson,
    • David M Evans,
    • Beate Glaser &
    • George Davey Smith
  9. Centre for Paediatric Epidemiology and Biostatistics, MRC Centre of Epidemiology for Child Health, University College of London Institute of Child Health, London, UK.

    • Diane J Berry,
    • Elina Hyppönen &
    • Chris Power
  10. Centre for Genetic Epidemiology and Biostatistics, The University of Western Australia, Perth, Western Australia, Australia.

    • Nicole M Warrington,
    • Julie A Marsh &
    • Lyle J Palmer
  11. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.

    • Elisabeth Widen,
    • Diana L Cousminer,
    • Ida Surakka &
    • Leena Peltonen
  12. Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

    • Jouke Jan Hottenga,
    • Eco J C de Geus,
    • Gonneke Willemsen &
    • Dorret I Boomsma
  13. Institute of Health Sciences, University of Oulu, Oulu, Finland.

    • Marika Kaakinen,
    • Anja Taanila &
    • Marjo-Riitta Jarvelin
  14. Biocenter Oulu, University of Oulu, Oulu, Finland.

    • Marika Kaakinen &
    • Marjo-Riitta Jarvelin
  15. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Leslie A Lange &
    • Karen L Mohlke
  16. Center for Applied Genomics, The Children's Hospital of Philadelphia, Pennsylvania, USA.

    • Jonathan P Bradfield,
    • Haitao Zhang,
    • Struan F A Grant &
    • Hakon Hakonarson
  17. Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

    • Marjan Kerkhof
  18. Helmholtz Zentrum Muenchen, German Research Centre for Environmental Health, Institute of Epidemiology, Neuherberg, Germany.

    • Chih-Mei Chen,
    • Carla Tiesler &
    • Joachim Heinrich
  19. Ludwig-Maximilians University of Munich, Dr. von Hauner Children's Hospital, Munich, Germany.

    • Chih-Mei Chen &
    • Carla Tiesler
  20. Division of Genetics, Program in Genomics, Children's Hospital, Boston, Massachusetts, USA.

    • Helen N Lyon &
    • Joel N Hirschhorn
  21. Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.

    • Helen N Lyon
  22. Centre for Population Health Sciences, University of Edinburgh, Edinburgh, Scotland, UK.

    • Mirna Kirin &
    • James F Wilson
  23. Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Linda S Adair
  24. Office of Population Studies Foundation, University of San Carlos, Cebu City, Philippines.

    • Judith B Borja
  25. Centre National de la Recherche Scientifique, UMR 8199, Institute of Biology, Pasteur Institute of Lille, Lille, France.

    • Nabila Bouatia-Naji &
    • Philippe Froguel
  26. Lille Nord de France University, Lille, France.

    • Nabila Bouatia-Naji
  27. Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

    • Pimphen Charoen
  28. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

    • Panos Deloukas &
    • Leena Peltonen
  29. Genomic Medicine, Hammersmith Hospital, Imperial College London, London, UK.

    • Philippe Froguel
  30. Children of the Nineties, Department of Social Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, UK.

    • Beate Glaser
  31. Institute of Clinical Medicine, University of Oulu, Oulu, Finland.

    • Anna-Liisa Hartikainen
  32. Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA.

    • Joel N Hirschhorn
  33. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • Joel N Hirschhorn
  34. Division of Endocrinology, Children's Hospital, Boston, Massachusetts, USA.

    • Joel N Hirschhorn
  35. Department of Clinical Science at North Bristol, University of Bristol, Paul O'Gorman Lifeline Centre, Southmead Hospital, Bristol, UK.

    • Jeff M P Holly
  36. Department of Dietetics-Nutrition, Harokopio University, Greece.

    • Stavroula Kanoni &
    • George V Dedoussis
  37. Peninsula National Institute for Health Research (NIHR) Clinical Research Facility, Peninsula College of Medicine and Dentistry, University of Exeter, Barrack Road, Exeter, UK.

    • Bridget A Knight,
    • Beverley M Shields &
    • Andrew T Hattersley
  38. Oulu Regional Institute of Occupational Health, Oulu, Finland.

    • Jaana Laitinen
  39. Department of Social Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, UK.

    • Wendy L McArdle &
    • Susan M Ring
  40. School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia, Australia.

    • Craig E Pennell
  41. Department of Pulmonology, University Medical Center, University of Groningen, Groningen, The Netherlands.

    • Dirkje S Postma
  42. National Institute of Health and Welfare, Oulu, Finland.

    • Anneli Pouta &
    • Marjo-Riitta Jarvelin
  43. Respiratory Epidemiology and Public Health Group, National Heart and Lung Institute, Imperial College London, London, UK.

    • Adaikalavan Ramasamy
  44. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Fernando Rivadeneira &
    • Andre G Uitterlinden
  45. Division of Community Health Sciences, St. George's, University of London, London, UK.

    • David P Strachan
  46. Centre for Prevention and Health Services Research, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.

    • Alet H Wijga
  47. Division of Human Genetics, The Children's Hospital of Philadelphia, Pennsylvania, USA.

    • Jianhua Zhao,
    • Struan F A Grant &
    • Hakon Hakonarson
  48. Department of Obstetrics and Gynecology, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Eric A P Steegers
  49. Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland.

    • Johan G Eriksson
  50. Department of General Practice, University of Helsinki, Helsinki, Finland.

    • Johan G Eriksson
  51. Folkhälsan Research Centre, Helsinki, Finland.

    • Johan G Eriksson
  52. National Institute for Health and Welfare, Helsinki, Finland.

    • Johan G Eriksson
  53. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Leena Peltonen
  54. Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

    • Struan F A Grant &
    • Hakon Hakonarson
  55. Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University Medical Center, University of Groningen, Groningen, The Netherlands.

    • Gerard H Koppelman
  56. Obesity Prevention Program, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts, USA.

    • Matthew W Gillman
  57. Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK.

    • Mark I McCarthy
  58. A complete list of members is available in a Supplementary Note.

    • The Genetic Investigation of ANthropometric Traits (GIANT) Consortium,
    • The Meta-Analyses of Glucose and Insulin-related traits Consortium &
    • The Wellcome Trust Case Control Consortium
  59. Deceased.

    • Leena Peltonen

Consortia

  1. The Genetic Investigation of ANthropometric Traits (GIANT) Consortium

  2. The Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC)

  3. The Wellcome Trust Case Control Consortium (WTCCC)

  4. the Early Growth Genetics (EGG) Consortium

    • Mark I McCarthy

Contributions

Project design: R.M.F., U.S., N.J.T., E.W., M. Kerkhof, H.N.L., L.S.A., J.B.B., E.J.C.d.G., A.-L.H., J.N.H., A.H., E.H., J.L., D.S.P., A.P., A.T., A.H.W., G.W., J.F.W., E.A.P.S., A.T.H., L.P., K.L.M., S.F.A.G., H.H., G.H.K., G.V.D., J.H., M.W.G., L.J.P., T.M.F., D.I.B., G.D.S., C.P., V.W.V.J., M.-R.J., M.I.M.

Sample collection and phenotyping: D.O.M.-K., U.S., D.J.B., M. Kaakinen, M. Kerkhof, L.S.A., A.J.B., J.B.B., P.E., A.-L.H., E.H., S.K., B.A.K., J.L., W.L.M., C.E.P., D.S.P., A.P., F.R., B.M.S., D.P.S., A.T., A.G.U., A.H.W., G.W., J.F.W., A.T.H., J.G.E., S.F.A.G., H.H., G.H.K., G.V.D., J.H., M.W.G., L.J.P., G.D.S., C.P., V.W.V.J., M.-R.J.

Genotyping: R.M.F., J.J.H., M. Kerkhof, H.N.L., A.J.B., N.B.-N., E.J.C.d.G., P.D., P.E., P.F., C.J.G., N.H., J.N.H., W.L.M., D.S.P., S.M.R., F.R., A.G.U., A.H.W., J.F.W., L.P., S.F.A.G., H.H., G.H.K., D.I.B., M.-R.J.

Statistical analysis: R.M.F., D.O.M.K., U.S., I.P., N.J.T., D.J.B., N.M.W., E.W., J.J.H., M. Kaakinen, L.A.L., J.P.B., M. Kerkhof, J.A.M., R.M., C.-M.C., H.N.L., M. Kirin, Y.S.A., P.C., L.J.M.C., D.L.C., D.M.E., B.G., C.M.L., P.F.O., D.S.P., A.R., N.W.R, B.M.S., I.S., C.T., C.M.v.D., A.H.W., J.Z., H.Z., G.H.K., M.W.G., L.J.P.

Writing: R.M.F., D.O.M.K., U.S., I.P., N.J.T., D.J.B., J.M.P.H., A.T.H., L.J.P., T.M.F., V.W.V.J., M.-R.J., M.I.M.

Competing financial interests

The authors declare no competing financial interests.

Author details

Supplementary information

PDF files

  1. Supplementary Text and Figures (4M)

    Supplementary Tables 1–5, Supplementary Figures 1–5 and Supplementary Note.

Excel files

  1. Supplementary Table 1 (100K)

    Basic characteristics, exclusions, genotyping, quality control and imputation in discovery studies

  2. Supplementary Table 2 (116K)

    Basic characteristics, exclusions, genotyping, quality control and imputation in European replication studies and non-European/admixed studies

Additional data