Article open access publication

Novel genetic loci underlying human intracranial volume identified through genome-wide association

Nature Neuroscience, Springer Nature, ISSN 1546-1726

Volume 19, 12, 2016

DOI:10.1038/nn.4398, Dimensions: pub.1040794888, PMC: PMC5227112, PMID: 27694991,

Authors

Chouraki, Vincent (3) (4) (5)
Stein, Jason L (2) (6)
Seshadri, Sudha (4) (5)
Alhusaini, Saud (17) (18)
Athanasiu, Lavinia (26) (27)
Beiser, Alexa (4) (5) (29)
Bralten, Janita (10) (11)
Ehrlich, Stefan (40) (41)
Filippi, Irina (42) (43)
Ge, Tian (40) (44) (45)
Giddaluru, Sudheer (46) (47)
Greven, Corina U (10) (12) (48)
Guadalupe, Tulio (51) (52)
Haukvik, Unn K (27) (53)
Hilal, Saima (54) (55)
Holmes, Avram J (40) (58)
Hoogman, Martine (10) (11)
Kasperaviciute, Dalia (59) (60) (61)
Klein, Marieke (10) (11)
Lee, Phil H (40) (44) (45) (64)
Matarin, Mar (60) (61)
Mattheisen, Manuel (66) (67)
McKay, David R (58) (69)
Muetzel, Ryan L (1) (32)
Papmeyer, Martina (23) (74)
Pappa, Irene (1) (75)
Ramasamy, Adaikalavan (12) (61) (76)
Richards, Jennifer S (10) (11) (48)
Rommelse, Nanda (10) (11) (48)
Schmaal, Lianne (39) (80) (81)
Schork, Andrew J (82) (83)
Shen, Li (62)
Shin, Jean (30)
Shumskaya, Elena (10) (11)
Smith, Albert V (84) (85)
Sprooten, Emma (23) (58) (69) (86)
Trabzuni, Daniah (61) (91)
Van Rooij, Daan (10) (11) (92)
Westlye, Lars T (26) (94)
Wolfers, Thomas (10) (11)
Xu, Bing (12)
Agartz, Ingrid (27) (53) (97)
Almasy, Laura (98) (99) (100)
Ames, David (81) (101)
Andreassen, Ole A (26) (27)
van Bokhoven, Hans (10) (11)
Brunner, Han G (10) (11) (104)
Buckner, Randy L (40) (44)
Buitelaar, Jan K (10) (11) (48)
Calhoun, Vince D (106) (107)
Cannon, Dara M (72) (108)
Chen, Christopher (54) (55)
Cheng, Ching-Y U (54) (65) (109)
Cichon, Sven (110) (111) (112)
Davies, Gareth E (44) (45) (113) (114)
De Jager, Philip L (44) (45)
Delanty, Norman (17) (116)
Djurovic, Srdjan (26) (47)
Donohoe, Gary (108) (118)
Drevets, Wayne C (72) (119)
Erk, Susanne (120)
Espeseth, Thomas (26) (94)
Fisher, Simon E (11) (52)
Ford, Ian (122)
Fox, Peter T (123)
Francks, Clyde (11) (52)
Gibbs, J Raphael (61) (102)
Glahn, David C (58) (69)
Gollub, Randy L (40) (44)
Green, Robert C (44) (114)
Hernandez, Dena G (61) (102) (126)
Hoffmann, Wolfgang (14) (15)
Holsboer, Florian (57) (128)
Ikram, M Kamran (1) (54) (55) (65) (109)
Jönsson, Erik G (27) (76)
Kanai, Ryota (61) (132) (133)
Kwok, John B (25) (135)
Lemaitre, Herve S (42) (43)
Liu, Xinmin (33) (72)
Longo, Dan L (121)
Lovestone, Simon (12) (76)
Martinot, Jean-Luc (42) (43)
Melle, Ingrid (26) (27)
Morris, Derek W (108) (118)
Mühleisen, Thomas W (108) (111)
Müller-Myhsok, Bertram (57) (138) (139)
Nauck, Matthias (15) (140)
Nichols, Thomas E (76) (141)
Niessen, Wiro J (1) (142)
Ophoff, Roel A (16) (38)
Paus, Tomas (30) (143)
Psaty, Bruce M (31) (145)
Reppermund, Simone (25) (146)
Ryten, Mina (12) (61)
Schofield, Peter R (25) (135)
Sisodiya, Sanjay M (60) (61)
Smoller, Jordan W (40) (44) (45)
Soininen, Hilkka (149) (150)
Steen, Vidar M (46) (47)
Wen, Wei (25)
White, Tonya (1) (32)
Wong, Tien Y (54) (65) (105)
Franke, Barbara (10) (11)
Debette, Stéphanie (5) (37) (157)

* Corresponding author

Affiliations

Organisations

  1. (1) Erasmus University Medical Center, grid.5645.2
  2. (2) University of Southern California, grid.42505.36
  3. (3) Centre Hospitalier Regional et Universitaire de Lille, grid.410463.4
  4. (4) Framingham Heart Study, Framingham, Massachusetts, USA
  5. (5) Boston University School of Medicine, grid.475010.7
  6. (6) University of North Carolina System, grid.410711.2
  7. (7) Johns Hopkins University, grid.21107.35
  8. (8) QIMR Berghofer Medical Research Institute, grid.1049.c
  9. (9) Leiden University Medical Center, grid.10419.3d
  10. (10) Radboud University Nijmegen Medical Centre, grid.10417.33
  11. (11) Radboud University Nijmegen, grid.5590.9
  12. (12) King's College London, grid.13097.3c
  13. (13) University of Miami, grid.26790.3a
  14. (14) German Center for Neurodegenerative Diseases (DZNE) Rostock/Greifswald, Greifswald, Germany
  15. (15) University of Greifswald, grid.5603.0
  16. (16) University Medical Center Utrecht, grid.7692.a
  17. (17) Royal College of Surgeons in Ireland, grid.4912.e
  18. (18) McGill University, grid.14709.3b
  19. (19) Umeå University, grid.12650.30
  20. (20) Illinois Institute of Technology, grid.62813.3e
  21. (21) Rush University Medical Center, grid.240684.c
  22. (22) Lagos State University, grid.411276.7
  23. (23) University of Edinburgh, grid.4305.2
  24. (24) Murdoch University, grid.1025.6
  25. (25) UNSW Sydney, grid.1005.4
  26. (26) Oslo University Hospital, grid.55325.34
  27. (27) NORMENT - KG Jebsen Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
  28. (28) Uppsala University, grid.8993.b
  29. (29) Boston University, grid.189504.1
  30. (30) University of Toronto, grid.17063.33
  31. (31) University of Washington, grid.34477.33
  32. (32) Sophia Children's Hospital, grid.416135.4
  33. (33) Columbia University Medical Center, grid.239585.0
  34. (34) Pennington Biomedical Research Center, grid.250514.7
  35. (35) Douglas Mental Health University Institute, grid.412078.8
  36. (36) University of Bordeaux, grid.412041.2
  37. (37) Lieber Institute for Brain Development, grid.429552.d
  38. (38) University of California, Los Angeles, grid.19006.3e
  39. (39) Amsterdam Neuroscience, grid.484519.5
  40. (40) Massachusetts General Hospital, grid.32224.35
  41. (41) TU Dresden, grid.4488.0
  42. (42) Hôpital Cochin, grid.411784.f
  43. (43) Paris Descartes University, grid.10992.33
  44. (44) Harvard University, grid.38142.3c
  45. (45) Broad Institute, grid.66859.34
  46. (46) Haukeland University Hospital, grid.412008.f
  47. (47) University of Bergen, grid.7914.b
  48. (48) Karakter Child and Adolescent Psychiatry University Center, Nijmegen, the Netherlands
  49. (49) Central Institute of Mental Health, grid.413757.3
  50. (50) University of Mississippi Medical Center, grid.410721.1
  51. (51) International Max Planck Research School for Language Sciences, Nijmegen, the Netherlands
  52. (52) Max Planck Institute for Psycholinguistics, grid.419550.c
  53. (53) Diakonhjemmet Hospital, grid.413684.c
  54. (54) National University of Singapore, grid.4280.e
  55. (55) National University Health System, grid.410759.e
  56. (56) Medical University of Graz, grid.11598.34
  57. (57) Max Planck Institute of Psychiatry, grid.419548.5
  58. (58) Yale University, grid.47100.32
  59. (59) Imperial College London, grid.7445.2
  60. (60) Epilepsy Society, grid.452379.e
  61. (61) University College London, grid.83440.3b
  62. (62) Indiana University – Purdue University Indianapolis, grid.257413.6
  63. (63) Heidelberg University, grid.7700.0
  64. (64) Lurie Center for Autism, Massachusetts General Hospital, Harvard Medical School, Lexington, Massachusetts, USA
  65. (65) Singapore National Eye Center, grid.419272.b
  66. (66) Aarhus University, grid.7048.b, AU
  67. (67) Lundbeck Foundation, grid.452548.a
  68. (68) French National Centre for Scientific Research, grid.4444.0
  69. (69) Olin Neuropsychiatric Research Center, Hartford, Connecticut, USA
  70. (70) University of Tasmania, grid.1009.8
  71. (71) Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands
  72. (72) National Institute of Mental Health, grid.416868.5
  73. (73) VU Amsterdam, grid.12380.38
  74. (74) Division of Systems Neuroscience of Psychopathology, Translational Research Center, University Hospital of Psychiatry, University of Bern, Switzerland
  75. (75) Erasmus University Rotterdam, grid.6906.9
  76. (76) University of Oxford, grid.4991.5
  77. (77) CIBERSAM (Centro Investigación Biomédica en Red Salud Mental), Santander, Spain
  78. (78) Marqués de Valdecilla University Hospital, grid.411325.0
  79. (79) Department of Psychiatry and Trinity Translational Medicine Institute, Psychosis Research Group, Trinity College Dublin
  80. (80) Orygen, grid.488501.0
  81. (81) University of Melbourne, grid.1008.9
  82. (82) Department of Cognitive Sciences, University of California, San Diego, USA
  83. (83) University of California, San Diego, grid.266100.3
  84. (84) University of Iceland, grid.14013.37
  85. (85) Icelandic Heart Association, grid.420802.c
  86. (86) Icahn School of Medicine at Mount Sinai, grid.59734.3c
  87. (87) University of Queensland, grid.1003.2
  88. (88) Western Sydney University, grid.1029.a
  89. (89) Instituto de Investigación Marqués de Valdecilla, grid.484299.a
  90. (90) Institut Pasteur, grid.428999.7
  91. (91) King Faisal Specialist Hospital & Research Centre, grid.415310.2
  92. (92) University Medical Center Groningen, grid.4494.d
  93. (93) University of California, Irvine, grid.266093.8
  94. (94) Department of Psychology, NORMENT - KG Jebsen Centre, University of Oslo, Oslo, Norway
  95. (95) University of Würzburg, grid.8379.5
  96. (96) Biospective Inc, Montreal, Quebec, Canada, Montréal, Québec, Canada
  97. (97) Karolinska Institute, grid.4714.6
  98. (98) Children's Hospital of Philadelphia, grid.239552.a
  99. (99) University of Pennsylvania, grid.25879.31
  100. (100) The University of Texas Rio Grande Valley, grid.449717.8
  101. (101) Royal Melbourne Hospital, grid.416153.4
  102. (102) National Institutes of Health, grid.94365.3d
  103. (103) University of Pittsburgh, grid.21925.3d
  104. (104) Maastricht University Medical Centre, grid.412966.e
  105. (105) Dagestan State University, grid.445702.0
  106. (106) Mind Research Network, grid.280503.c
  107. (107) University of New Mexico, grid.266832.b
  108. (108) National University of Ireland, Galway, grid.6142.1
  109. (109) Duke NUS Graduate Medical School, grid.428397.3
  110. (110) University of Basel, grid.6612.3
  111. (111) Forschungszentrum Jülich, grid.8385.6
  112. (112) University of Bonn, grid.10388.32
  113. (113) Avera Institute for Human Genetics, Sioux Falls, South Dakota, USA
  114. (114) Brigham and Women's Hospital, grid.62560.37
  115. (115) Queensland University of Technology, grid.1024.7
  116. (116) Beaumont Hospital, grid.414315.6
  117. (117) Department of Neurology, Hopital Erasme, Universite Libre de Bruxelles, Brussels, Belgium
  118. (118) Trinity College Dublin, grid.8217.c
  119. (119) Janssen (United States), grid.497530.c
  120. (120) Charité, grid.6363.0
  121. (121) National Institute on Aging, grid.419475.a
  122. (122) University of Glasgow, grid.8756.c
  123. (123) The University of Texas Health Science Center at San Antonio, grid.267309.9
  124. (124) National Institute for Physiological Sciences, grid.467811.d
  125. (125) Osaka University, grid.136593.b
  126. (126) German Center for Neurodegenerative Diseases, grid.424247.3
  127. (127) University of Iowa, grid.214572.7
  128. (128) HolsboerMaschmeyer NeuroChemie (Germany), grid.476381.f
  129. (129) Fujita Health University, grid.256115.4
  130. (130) Mayo Clinic, grid.66875.3a
  131. (131) University of Maryland, Baltimore, grid.411024.2
  132. (132) Department of Neuroinformatics, Araya Brain Imaging, Tokyo, Japan
  133. (133) University of Sussex, grid.12082.39
  134. (134) Medical University of Lodz, grid.8267.b
  135. (135) Neuroscience Research Australia, grid.250407.4
  136. (136) University of California, Davis, grid.27860.3b
  137. (137) University of Perugia, grid.9027.c
  138. (138) Munich Cluster for Systems Neurology, grid.452617.3
  139. (139) University of Liverpool, grid.10025.36
  140. (140) German Centre for Cardiovascular Research, grid.452396.f
  141. (141) University of Warwick, grid.7372.1
  142. (142) Delft University of Technology, grid.5292.c
  143. (143) Child Mind Institute, grid.428122.f
  144. (144) University of Calgary, grid.22072.35
  145. (145) Group Health Cooperative, grid.280243.f
  146. (146) Department of Developmental Disability Neuropsychiatry, School of Psychiatry, UNSW Medicine, Australia
  147. (147) Harbor–UCLA Medical Center, grid.239844.0
  148. (148) Prince of Wales Hospital, grid.415193.b
  149. (149) Kuopio University Hospital, grid.410705.7
  150. (150) University of Eastern Finland, grid.9668.1
  151. (151) Monash University, grid.1002.3
  152. (152) Georgia State University, grid.256304.6
  153. (153) Institute for Neurodegenerative Disorders, UMR 5293, CEA, CNRS, Université de Bordeaux, France
  154. (154) Roche (United States), grid.418158.1
  155. (155) Center for Imaging of Neurodegenerative Disease, San Francisco VA Medical Center, University of California, San Francisco, California, USA
  156. (156) The University of Texas Health Science Center at Houston, grid.267308.8
  157. (157) Centre Hospitalier Universitaire de Bordeaux, grid.42399.35

Description

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.

Funders

Funders and Grants

Research Categories

Main Subject Area

Fields of Research

Links & Metrics

NORA University Profiles

Aarhus University

Danish Open Access Indicator

2016: Unused

Research area: Medicine

Dimensions Citation Indicators

Times Cited: 126

Field Citation Ratio (FCR): 33.23

Relative Citation ratio (RCR): 5.6

Open Access Info

Green, Published