Preprint open access publication

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

bioRxiv, Cold Spring Harbor Laboratory,

2018

DOI:10.1101/442756, Dimensions: pub.1107687815,

Authors

Horikoshi, Momoko (3) (4) (5)
Helgeland, Øyvind (7) (8) (9)
Hao, Ke (12)
Mahajan, Anubha (4) (5)
Tyrrell, Jessica (2) (14)
Rayner, N William (4) (5) (15)
Chen, Jia (12)
Ahluwalia, Tarunveer S (20) (27) (28)
Rueedi, Rico (29) (30)
Cavadino, Alana (35) (36)
Cousminer, Diana L (24) (38)
Wu, Ying (39)
Lagou, Vasiliki (4) (50) (51)
Espinosa, Ana (52) (53) (54) (55)
Inskip, Hazel M (56) (57)
Santa-Marina, Loreto (52) (58) (59)
Estivill, Xavier (60) (61)
Ang, Wei (62)
Hocher, Berthold (64) (66)
Lunetta, Kathryn L (67) (68)
Murabito, Joanne M (67) (68)
Relton, Caroline L (10) (69)
Kogevinas, Manolis (52) (53) (54) (55)
Bouchard, Luigi (71) (72) (73)
Hivert, Marie-France (73) (74) (75)
Zhang, Ge (76) (77) (78)
Muglia, Louis J (76) (77) (78)
Gaulton, Kyle J (4) (82)
Kutalik, Zoltán (30) (83)
Willemsen, Gonneke (32) (33)
Mbarek, Hamdi (32) (33) (85)
Müller-Nurasyid, Martina (86) (87) (88)
Fonvig, Cilius E (20) (89) (90)
Trier, Caecilie (20) (90)
Murcia, Mario (52) (91)
Bustamante, Mariona (52) (54) (55)
Mercader, Josep M (74) (92) (93)
Linneberg, Allan (20) (94)
Bartels, Meike (32) (33)
Torrents, David (92) (97)
Prokopenko, Inga (4) (99)
Loh, Po-Ru (75) (93)
Lakka, Timo A (49) (101) (102)
Niinikoski, Harri (48) (103)
Pahkala, Katja (48) (104)
Raitakari, Olli T (48) (103)
Jacobsson, Bo (9) (11)
Saw, Seang-Mei (96) (106)
Vrijheid, Martine (52) (54) (55)
de Geus, Eco JCN (32) (33)
Heinrich, Joachim (41) (108)
Eriksson, Johan G (111) (112) (113)
Viikari, Jorma S (48) (103)
Boomsma, Dorret I (32) (33) (85)
Sebert, Sylvain (31) (99)
Melbye, Mads (13) (116)
Vaag, Allan A (20) (119)
Järvelin, Marjo-Riitta (31) (99) (120) (121)
Hyppönen, Elina (36) (122) (123)
Smith, George Davey (10) (124)
Morris, Andrew P (4) (125) (126)
Hakonarson, Hakon (24) (38)
Grant, Struan FA (24) (38)
Lawlor, Debbie A (10) (124)
McCarthy, Mark I (4) (5) (127)
Evans, David M * (1) (10)
Freathy, Rachel M * (2) (10)

* Corresponding author

Affiliations

Organisations

  1. (1) University of Queensland, grid.1003.2
  2. (2) Institute of Biomedical and Clinical Science, University of Exeter Medical School, University of Exeter, Royal Devon and Exeter Hospital, Exeter, UK
  3. (3) RIKEN, grid.7597.c
  4. (4) Wellcome Centre for Human Genetics, grid.270683.8
  5. (5) University of Oxford, grid.4991.5
  6. (6) University of Cambridge, grid.5335.0
  7. (7) University of Bergen, grid.7914.b
  8. (8) Haukeland University Hospital, grid.412008.f
  9. (9) Norwegian Institute of Public Health, grid.418193.6
  10. (10) University of Bristol, grid.5337.2
  11. (11) University of Gothenburg, grid.8761.8
  12. (12) Icahn School of Medicine at Mount Sinai, grid.59734.3c
  13. (13) State Serum Institute, grid.6203.7
  14. (14) University of Exeter, grid.8391.3
  15. (15) Wellcome Sanger Institute, grid.10306.34
  16. (16) Oslo University Hospital, grid.55325.34
  17. (17) University of Oslo, grid.5510.1
  18. (18) Emory University, grid.189967.8
  19. (19) Northwestern University, grid.16753.36
  20. (20) University of Copenhagen, grid.5254.6, KU
  21. (21) Department of Clinical Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, Academic Medical Center (AMC), University of Amsterdam, the Netherlands
  22. (22) Department of Public Health, Amsterdam Public Health Research Institute, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands
  23. (23) Quantinuum Research LLC, San Diego, USA
  24. (24) Children's Hospital of Philadelphia, grid.239552.a
  25. (25) Erasmus University Medical Center, grid.5645.2
  26. (26) Leiden University Medical Center, grid.10419.3d
  27. (27) Steno Diabetes Center, grid.419658.7, Capital Region
  28. (28) COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
  29. (29) University of Lausanne, grid.9851.5
  30. (30) Swiss Institute of Bioinformatics, grid.419765.8
  31. (31) University of Oulu, grid.10858.34
  32. (32) VU Amsterdam, grid.12380.38
  33. (33) VU University Medical Center, grid.16872.3a
  34. (34) Tampere University, grid.502801.e
  35. (35) University of Auckland, grid.9654.e
  36. (36) University College London, grid.83440.3b
  37. (37) King's College London, grid.13097.3c
  38. (38) University of Pennsylvania, grid.25879.31
  39. (39) University of North Carolina at Chapel Hill, grid.10698.36
  40. (40) Klinikum der Universität München, grid.411095.8
  41. (41) Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
  42. (42) University of Newcastle Australia, grid.266842.c
  43. (43) Barcelonabeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain
  44. (44) Centre for Genomic Regulation, grid.11478.3b
  45. (45) University of Edinburgh, grid.4305.2
  46. (46) QIMR Berghofer Medical Research Institute, Locked Bag 2000, Royal Brisbane Hospital, Herston, Australia
  47. (47) Queen Mary University of London, grid.4868.2
  48. (48) University of Turku, grid.1374.1
  49. (49) University of Eastern Finland, grid.9668.1
  50. (50) KU Leuven, grid.5596.f
  51. (51) VIB Center for Brain and Disease Research, Leuven, Belgium
  52. (52) Institute of Health Carlos III, grid.413448.e
  53. (53) Hospital Del Mar, grid.411142.3
  54. (54) Barcelona Institute for Global Health, grid.434607.2
  55. (55) Pompeu Fabra University, grid.5612.0
  56. (56) University of Southampton, grid.5491.9
  57. (57) University Hospital Southampton NHS Foundation Trust, grid.430506.4
  58. (58) Biodonostia, grid.432380.e
  59. (59) Subdirección de Salud Pública y Adicciones de Gipuzkoa, Donostia/San Sebastián, Spain
  60. (60) Genomics Unit, Dexeus Woman’s Health, Barcelona, Spain
  61. (61) Sidra Medicine Research, Sidra Medicine, Doha, Qatar
  62. (62) University of Western Australia, grid.1012.2
  63. (63) Charité, grid.6363.0
  64. (64) University of Potsdam, grid.11348.3f
  65. (65) University of Ferrara, grid.8484.0
  66. (66) First Affiliated Hospital of Jinan University, grid.412601.0
  67. (67) Boston University, grid.189504.1
  68. (68) Framingham Heart Study, Framingham, USA
  69. (69) Newcastle University, grid.1006.7
  70. (70) University of Southern California, grid.42505.36
  71. (71) Centre Hospitalier Universitaire de Sherbrooke, grid.411172.0
  72. (72) ECOGENE-21 and Lipid Clinic, Chicoutimi Hospital, Saguenay, Canada
  73. (73) Université de Sherbrooke, grid.86715.3d
  74. (74) Massachusetts General Hospital, grid.32224.35
  75. (75) Harvard University, grid.38142.3c
  76. (76) Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, USA
  77. (77) Cincinnati Children's Hospital Medical Center, grid.239573.9
  78. (78) March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati, USA
  79. (79) University of Helsinki, grid.7737.4
  80. (80) University of Amsterdam, grid.7177.6
  81. (81) Bioinformatics Laboratory, Clinical Epidemiology, Biostatistics and Bioinformatics (KEBB), Amsterdam Public Health Research Institute, Academic Medical Center / University of Amsterdam, Amsterdam, the Netherlands
  82. (82) University of California, San Diego, grid.266100.3
  83. (83) Institute of Social and Preventive Medicine, grid.482968.9
  84. (84) University Hospital of Lausanne, grid.8515.9
  85. (85) Amsterdam Reproduction and Development, Amsterdam, the Netherlands
  86. (86) German Centre for Cardiovascular Research, grid.452396.f
  87. (87) Helmholtz Zentrum München, grid.4567.0
  88. (88) Ludwig Maximilian University of Munich, grid.5252.0
  89. (89) Odense University Hospital, grid.7143.1, Southern Denmark Region
  90. (90) The Children's Obesity Clinic, Department of Pediatrics, Copenhagen University Hospital Holbæk, Holbæk, Denmark
  91. (91) FISABIO–Universitat Jaume I–Universitat de València, Joint Research Unit of Epidemiology and Environmental Health, Valencia, Spain
  92. (92) Barcelona Supercomputing Center, grid.10097.3f
  93. (93) Broad Institute, grid.66859.34
  94. (94) Bispebjerg Hospital, grid.411702.1, Capital Region
  95. (95) NIHR Exeter Clinical Research Facility, grid.477603.1
  96. (96) National University of Singapore, grid.4280.e
  97. (97) Catalan Institution for Research and Advanced Studies, grid.425902.8
  98. (98) Leipzig University, grid.9647.c
  99. (99) Imperial College London, grid.7445.2
  100. (100) Genetics of Complex Traits, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter, UK
  101. (101) Kuopio University Hospital, grid.410705.7
  102. (102) Kuopion Liikuntalääketieteen Tutkimuslaitos, grid.419013.e
  103. (103) Turku University Hospital, grid.410552.7
  104. (104) Paavo Nurmi Centre, Sports and Exercise Medicine Unit, Department of Physical Activity and Health, Turku, Finland
  105. (105) Harokopio University, grid.15823.3d
  106. (106) Singapore Eye Research Institute, grid.272555.2
  107. (107) Technical University of Denmark, grid.5170.3, DTU
  108. (108) Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Inner City Clinic, University Hospital Munich, Ludwig Maximilian University of Munich, Munich, Germany
  109. (109) University of North Carolina System, grid.410711.2
  110. (110) University of San Carlos, grid.267101.3
  111. (111) Folkhälsans Forskningscentrum, grid.428673.c
  112. (112) Helsinki University Central Hospital, grid.15485.3d
  113. (113) National Institute for Health and Welfare, grid.14758.3f
  114. (114) Department of Clinical Physiology, Tampere University Hospital, and Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland
  115. (115) University of Iowa, grid.214572.7
  116. (116) Stanford University, grid.168010.e
  117. (117) University of Southern Denmark, grid.10825.3e, SDU
  118. (118) Research Center for Prevention and Health Capital Region, Center for Sundhed, Rigshospitalet – Glostrup, Copenhagen University, Glostrup, Denmark
  119. (119) AstraZeneca (Sweden), grid.418151.8
  120. (120) Brunel University London, grid.7728.a
  121. (121) Oulu University Hospital, grid.412326.0
  122. (122) Australian Centre for Precision Health, University of South Australia Cancer Research Institute, Adelaide, Australia
  123. (123) South Australian Health and Medical Research Institute, grid.430453.5
  124. (124) Bristol NIHR Biomedical Research Centre, Bristol, UK
  125. (125) University of Liverpool, grid.10025.36
  126. (126) University of Tartu, grid.10939.32
  127. (127) Churchill Hospital, grid.415719.f

Description

Abstract Birth weight (BW) variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. These associations have been proposed to reflect the lifelong consequences of an adverse intrauterine environment. In earlier work, we demonstrated that much of the negative correlation between BW and adult cardio-metabolic traits could instead be attributable to shared genetic effects. However, that work and other previous studies did not systematically distinguish the direct effects of an individual’s own genotype on BW and subsequent disease risk from indirect effects of their mother’s correlated genotype, mediated by the intrauterine environment. Here, we describe expanded genome-wide association analyses of own BW (n=321,223) and offspring BW (n=230,069 mothers), which identified 278 independent association signals influencing BW (214 novel). We used structural equation modelling to decompose the contributions of direct fetal and indirect maternal genetic influences on BW, implicating fetal- and maternal-specific mechanisms. We used Mendelian randomization to explore the causal relationships between factors influencing BW through fetal or maternal routes, for example, glycemic traits and blood pressure. Direct fetal genotype effects dominate the shared genetic contribution to the association between lower BW and higher type 2 diabetes risk, whereas the relationship between lower BW and higher later blood pressure (BP) is driven by a combination of indirect maternal and direct fetal genetic effects: indirect effects of maternal BP-raising genotypes act to reduce offspring BW, but only direct fetal genotype effects (once inherited) increase the offspring’s later BP. Instrumental variable analysis using maternal BW-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring BP. In successfully separating fetal from maternal genetic effects, this work represents an important advance in genetic studies of perinatal outcomes, and shows that the association between lower BW and higher adult BP is attributable to genetic effects, and not to intrauterine programming.

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