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Genome-Wide Analysis Identifies Genetic Effects on Reproductive Success and Ongoing Natural Selection at the Fads Locus Publisher Pubmed



Mathieson I1 ; Day FR2 ; Barban N3 ; Tropf FC4, 5, 6 ; Brazel DM4, 7 ; Van Heemst D47 ; Vaez A8, 9 ; Van Zuydam N10 ; Bitarello BD1 ; Gardner EJ2 ; Akimova ET4, 7 ; Azad A11 ; Bergmann S12, 13, 14 ; Bielak LF15 Show All Authors
Authors
  1. Mathieson I1
  2. Day FR2
  3. Barban N3
  4. Tropf FC4, 5, 6
  5. Brazel DM4, 7
  6. Van Heemst D47
  7. Vaez A8, 9
  8. Van Zuydam N10
  9. Bitarello BD1
  10. Gardner EJ2
  11. Akimova ET4, 7
  12. Azad A11
  13. Bergmann S12, 13, 14
  14. Bielak LF15
  15. Boomsma DI16, 17
  16. Bosak K18
  17. Brumat M19
  18. Buring JE20, 21
  19. Cesarini D22, 23, 24
  20. Chasman DI20, 21
  21. Chavarro JE25, 26, 27
  22. Cocca M28
  23. Concas MP28
  24. Davey Smith G29
  25. Davies G30
  26. Deary IJ30
  27. Esko T31, 32
  28. Faul JD33
  29. Franco O34, 35
  30. Ganna A36, 37
  31. Gaskins AJ38
  32. Gelemanovic A39
  33. De Geus EJC16
  34. Gieger C40
  35. Girotto G19, 28
  36. Gopinath B41
  37. Grabe HJ42
  38. Gunderson EP43
  39. Hayward C44
  40. He C45, 46
  41. Hill WD30
  42. Hoffmann ER11
  43. Homuth G48
  44. Hottenga JJ16
  45. Huang H25
  46. Hyppnen E49, 50
  47. Ikram MA34
  48. Jansen R51
  49. Johannesson M52
  50. Kamali Z8, 9
  51. Kardia SLR15
  52. Kavousi M34
  53. Kifley A41
  54. Kiiskinen T36, 53
  55. Kraft P25, 54
  56. Kuhnel B40
  57. Langenberg C2
  58. Liew G41
  59. Van Der Most PJ8
  60. Lind PA55
  61. Luan J2
  62. Magi R31
  63. Magnusson PKE56
  64. Mahajan A57, 58
  65. Martin NG59
  66. Mbarek H16, 60
  67. Mccarthy MI57, 58
  68. Mcmahon G61
  69. Medland SE55
  70. Meitinger T62
  71. Metspalu A31, 63
  72. Mihailov E31
  73. Milani L31
  74. Missmer SA25, 64, 65
  75. Mitchell P41
  76. Mollegaard S66
  77. Mookkanamori DO67, 68
  78. Morgan A28
  79. De Mutsert R67
  80. Nauck M69
  81. Nolte IM8
  82. Noordam R47
  83. Penninx BWJH70
  84. Peters A71
  85. Peyser PA15
  86. Polasek O39, 72
  87. Power C73
  88. Pribisalic A39
  89. Redmond P30
  90. Richedwards JW25, 27, 74
  91. Ridker PM20, 21
  92. Rietveld CA75, 76
  93. Ring SM29
  94. Rose LM20
  95. Rueedi R12, 13
  96. Shukla V11
  97. Smith JA15, 33
  98. Stankovic S2
  99. Stefansson K77
  100. Stockl D71
  101. Strauch K78, 79, 80
  102. Swertz MA81
  103. Teumer A82
  104. Thorleifsson G77
  105. Thorsteinsdottir U77
  106. Thurik AR75, 76, 83
  107. Timpson NJ29
  108. Turman C25
  109. Uitterlinden AG75, 84
  110. Waldenberger M40, 71
  111. Wareham NJ2
  112. Weir DR33
  113. Willemsen G16
  114. Zhao JH2
  115. Zhao W15
  116. Zhao Y2
  117. Snieder H8
  118. Den Hoed M10
  119. Ong KK2
  120. Mills MC4, 7, 81, 85
  121. Perry JRB2
Show Affiliations
Authors Affiliations
  1. 1. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
  2. 2. MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
  3. 3. Alma Mater Studiorum University of Bologna, Bologna, Italy
  4. 4. Nuffield College, University of Oxford, Oxford, United Kingdom
  5. 5. Ecole Nationale de la Statistique et de L’administration Economique (ENSAE), Paris, France
  6. 6. Center for Research in Economics and Statistics (CREST), Paris, France
  7. 7. Leverhulme Centre for Demographic Science, University of Oxford, Oxford, United Kingdom
  8. 8. Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
  9. 9. Department of Bioinformatics, Isfahan University of Medical Sciences, Isfahan, Iran
  10. 10. Beijer Laboratory and Department of Immunology, Genetics and Pathology, Uppsala University and SciLifeLab, Uppsala, Sweden
  11. 11. DNRF Center for Chromosome Stability, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  12. 12. Department of Computational Biology, University of Lausanne, Lausanne, Switzerland
  13. 13. Swiss Institute of Bioinformatics, Lausanne, Switzerland
  14. 14. Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa
  15. 15. Department of Epidemiology, University of Michigan, Ann Arbor, MI, United States
  16. 16. Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
  17. 17. Amsterdam Reproduction and Development (AR&D) Research Institute, Amsterdam, Netherlands
  18. 18. Psychiatric Hospital ‘Sveti Ivan’, Zagreb, Croatia
  19. 19. Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
  20. 20. Brigham and Women’s Hospital, Boston, MA, United States
  21. 21. Harvard Medical School, Boston, MA, United States
  22. 22. Department of Economics, New York University, New York, NY, United States
  23. 23. Research Institute for Industrial Economics, Stockholm, Sweden
  24. 24. National Bureau of Economic Research, Cambridge, MA, United States
  25. 25. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States
  26. 26. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, United States
  27. 27. Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
  28. 28. Institute for Maternal and Child Health, IRCCS ‘Burlo Garofolo’, Trieste, Italy
  29. 29. MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
  30. 30. Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom
  31. 31. Estonian Genome Center, University of Tartu, Tartu, Estonia
  32. 32. Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA, United States
  33. 33. Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, United States
  34. 34. Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
  35. 35. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
  36. 36. Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
  37. 37. Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States
  38. 38. Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, United States
  39. 39. University of Split School of Medicine, Split, Croatia
  40. 40. Research Unit of Molecular Epidemiology, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Neuherberg, Germany
  41. 41. Centre for Vision Research, Westmead Institute for Medical Research and Department of Ophthalmology, University of Sydney, Sydney, NSW, Australia
  42. 42. Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
  43. 43. Division of Research, Kaiser Permanente Northern California, Oakland, CA, United States
  44. 44. Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
  45. 45. Markey Cancer Center, University of Kentucky, Lexington, KY, United States
  46. 46. Department of Internal Medicine, Division of Medical Oncology, University of Kentucky College of Medicine, Lexington, KY, United States
  47. 47. Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, Netherlands
  48. 48. Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany
  49. 49. Australian Centre for Precision Health, University of South Australia Cancer Research Institute, Adelaide, SA, Australia
  50. 50. South Australian Health and Medical Research Institute, Adelaide, SA, Australia
  51. 51. Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit, Amsterdam, Netherlands
  52. 52. Department of Economics, Stockholm School of Economics, Stockholm, Sweden
  53. 53. National Institute for Health and Welfare, Helsinki, Finland
  54. 54. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, United States
  55. 55. Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
  56. 56. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  57. 57. Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
  58. 58. Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
  59. 59. Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
  60. 60. Qatar Genome Programme, Qatar Foundation Research, Development and Innovation, Qatar Foundation, Doha, Qatar
  61. 61. School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom
  62. 62. Institute of Human Genetics, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Neuherberg, Germany
  63. 63. Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
  64. 64. Division of Adolescent and Young Adult Medicine, Department of Medicine, Boston Children’s Hospital and Harvard Medical School, Boston, MA, United States
  65. 65. Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States
  66. 66. Department of Sociology, University of Copenhagen, Copenhagen, Denmark
  67. 67. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands
  68. 68. Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, Netherlands
  69. 69. Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
  70. 70. Department of Psychiatry, VU University Medical Center/GGZ inGeest, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, Amsterdam, Netherlands
  71. 71. Institute of Epidemiology, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Neuherberg, Germany
  72. 72. Algebra University College, Zagreb, Croatia
  73. 73. Population, Policy and Practice Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
  74. 74. Division of Women’s Health, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
  75. 75. Erasmus University Rotterdam Institute for Behavior and Biology, Rotterdam, Netherlands
  76. 76. Department of Applied Economics, Erasmus School of Economics, Rotterdam, Netherlands
  77. 77. deCODE Genetics/Amgen Inc., Reykjavik, Iceland
  78. 78. Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg University, Mainz, Germany
  79. 79. Institute of Genetic Epidemiology, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Neuherberg, Germany
  80. 80. Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU, Munich, Germany
  81. 81. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
  82. 82. Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
  83. 83. Montpellier Business School, Montpellier, France
  84. 84. Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
  85. 85. Department of Economics, Econometrics and Finance, University of Groningen, Groningen, Netherlands

Source: Nature Human Behaviour Published:2023


Abstract

Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success. © 2023, The Author(s), under exclusive licence to Springer Nature Limited.
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