Article open access publication

Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics.

Human Molecular Genetics, Oxford University Press (OUP), ISSN 1460-2083

Volume 27, 4, 2018

DOI:10.1093/hmg/ddx429, Dimensions: pub.1100179793, PMC: PMC5886200, PMID: 29309628,

Authors

Richmond, Rebecca C (10) (11) (12)
Lunetta, Kathryn L (18) (19)
Espinosa, Ana (25) (26) (27)
Zhang, Ge (30) (31)
Ang, Wei (28)
Bouchard, Luigi (23) (33) (34)
Hakonarson, Hakon (13) (35)
Helgeland, Øyvind (37) (38)
Hocher, Berthold (39) (40)
Inskip, Hazel M (24) (41)
Kogevinas, Manolis (25) (26) (27)
Njølstad, Pål R (38) (44)
Ring, Susan M (10) (12)
Santa-Marina, Loreto (26) (47) (48)
Sebert, Sylvain (16) (49)
Willemsen, Gonneke (21) (22)
Muglia, Louis J (30) (31)
Bartels, Meike (21) (22)
Relton, Caroline L (10) (12) (29)
Estivill, Xavier (26) (27)
Boomsma, Dorret I (21) (22)
Murabito, Joanne M (19) (52)
Järvelin, Marjo-Ritta (16) (49) (53) (54)
Bisgaard, Hans (14) (15)
Grant, Struan F A (13) (35)
Jacobsson, Bo (9) (50)
Melbye, Mads (8) (55)
McCarthy, Mark I (6) (7) (56)
Hivert, Marie-France (34) (57) (58)
Hyppönen, Elina (32) (59) (60)
Evans, David M (2) (10) (12)
Lawlor, Debbie A (10) (12)

Affiliations

Organisations

  1. (1) Institute of Biomedical and Clinical Science, University of Exeter Medical School, University of Exeter, Royal Devon and Exeter Hospital, Exeter EX2 5DW, UK
  2. (2) University of Queensland, grid.1003.2
  3. (3) Queen Mary University of London, grid.4868.2
  4. (4) University of Exeter, grid.8391.3
  5. (5) Northwestern University, grid.16753.36
  6. (6) University of Oxford, grid.4991.5
  7. (7) Wellcome Centre for Human Genetics, grid.270683.8
  8. (8) State Serum Institute, grid.6203.7
  9. (9) Norwegian Institute of Public Health, grid.418193.6
  10. (10) Medical Research Council, grid.14105.31
  11. (11) Erasmus University Medical Center, grid.5645.2
  12. (12) University of Bristol, grid.5337.2
  13. (13) Children's Hospital of Philadelphia, grid.239552.a
  14. (14) Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark
  15. (15) University of Copenhagen, grid.5254.6, KU
  16. (16) University of Oulu, grid.10858.34
  17. (17) King's College London, grid.13097.3c
  18. (18) Boston University, grid.189504.1
  19. (19) Framingham Heart Study, Framingham, MA, USA
  20. (20) QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Herston, QLD 4029, Australia
  21. (21) EMGO Institute for Health and Care Research, grid.466632.3
  22. (22) VU Amsterdam, grid.12380.38
  23. (23) Centre Hospitalier Universitaire de Sherbrooke, grid.411172.0
  24. (24) University of Southampton, grid.5491.9
  25. (25) Hospital Del Mar, grid.411142.3
  26. (26) ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain
  27. (27) Pompeu Fabra University, grid.5612.0
  28. (28) University of Western Australia, grid.1012.2
  29. (29) Newcastle University, grid.1006.7
  30. (30) Cincinnati Children's Hospital Medical Center, grid.239573.9
  31. (31) March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati, OH, USA
  32. (32) University College London, grid.83440.3b
  33. (33) ECOGENE-21 and Lipid Clinic, Chicoutimi Hospital, Saguenay, QC, Canada
  34. (34) Université de Sherbrooke, grid.86715.3d
  35. (35) University of Pennsylvania, grid.25879.31
  36. (36) University of Helsinki, grid.7737.4
  37. (37) Department of Genetics and Bioinformatics, Domain of Health Data and Digitalisation, Institute of Public Health, Oslo, Norway
  38. (38) University of Bergen, grid.7914.b
  39. (39) First Affiliated Hospital of Jinan University, grid.412601.0
  40. (40) University of Potsdam, grid.11348.3f
  41. (41) University Hospital Southampton NHS Foundation Trust, grid.430506.4
  42. (42) University of Ferrara, grid.8484.0
  43. (43) University of Iowa, grid.214572.7
  44. (44) Haukeland University Hospital, grid.412008.f
  45. (45) University of Southern Denmark, grid.10825.3e, SDU
  46. (46) Charité, grid.6363.0
  47. (47) Biodonostia, grid.432380.e
  48. (48) Subdirección de Salud Pública y Adicciones de Gipuzkoa, Donostia/San Sebastián, Spain
  49. (49) Imperial College London, grid.7445.2
  50. (50) University of Gothenburg, grid.8761.8
  51. (51) University of Crete, grid.8127.c
  52. (52) Boston University School of Medicine, grid.475010.7
  53. (53) National Institute for Health and Welfare, grid.14758.3f
  54. (54) Oulu University Hospital, grid.412326.0
  55. (55) Stanford University, grid.168010.e
  56. (56) Churchill Hospital, grid.415719.f
  57. (57) Harvard University, grid.38142.3c
  58. (58) Massachusetts General Hospital, grid.32224.35
  59. (59) South Australian Health and Medical Research Institute, grid.430453.5
  60. (60) University of South Australia, grid.1026.5

Description

Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P < 5 × 10-8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.

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Times Cited: 68

Field Citation Ratio (FCR): 35.26

Relative Citation ratio (RCR): 9.74

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