☆ 4.7 Article

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

NATURE NEUROSCIENCE (2016)

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NATURE NEUROSCIENCE
Volume 19, Issue 12, Pages 1569-1582

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NATURE PUBLISHING GROUP
DOI: 10.1038/nn.4398

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Neurosciences

Funding

  1. National Heart, Lung and Blood Institute [HL105756]
  2. National Institute on Aging [AG033193]
  3. NIH Institute, NIBIB [U54 EB020403]
  4. NIH Institute, NCI [U54 EB020403]
  5. NIH [N01-AG-1-2100, 271201200022C, R01MH62873, K99MH102357, R01 HD050735, P30AG10161, RF1AG15819, R01AG17917, R01AG30146, R01AG40039, 5R01AG037212]
  6. NIA Intramural Research Program
  7. Hjartavernd (the Icelandic Heart Association)
  8. Althingi (the Icelandic Parliament)
  9. ADNI (National Institutes of Health Grant) [U01 AG024904]
  10. DOD ADNI (Department of Defense) [W81XWH-12-2-0012]
  11. National Institute on Aging
  12. National Institute of Biomedical Imaging and Bioengineering
  13. lzheimer's Association
  14. Alzheimer's Drug Discovery Foundation
  15. BioClinica, Inc.
  16. Biogen Idec Inc.
  17. Bristol-Myers Squibb Company
  18. Eisai Inc.
  19. Elan Pharmaceuticals, Inc.
  20. Eli Lilly and Company
  21. F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.
  22. GE Healthcare
  23. Innogenetics, N.V.
  24. IXICO Ltd.
  25. Janssen Alzheimer Immunotherapy Research & Development, LLC.
  26. Johnson & Johnson Pharmaceutical Research & Development LLC.
  27. Medpace, Inc.
  28. Merck Co., Inc.
  29. Meso Scale Diagnostics, LLC.
  30. NeuroRx Research
  31. Novartis Pharmaceuticals Corporation
  32. Pfizer Inc.
  33. Piramal Imaging
  34. Servier
  35. Synarc Inc.
  36. Takeda Pharmaceutical Company
  37. Canadian Institutes of Health Research
  38. EU
  39. Kuopio University Hospital
  40. National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HSN268201100006C, HSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL70825, R01HL087641, R01HL59367, R01HL086694]
  41. National Human Genome Research Institute [U01HG004402]
  42. National Institutes of Health (NIH) [HHSN268200625226C, R01D0042157-01A, MH081802, 1RC2 MH089951, 1RC2 MH089995]
  43. component of the NIH and NIH Roadmap for Medical Research [UL1RR025005]
  44. NIH R01 grant [NS087541]
  45. Austrian Science Fund (FWF) [1904]
  46. Medical University of Graz
  47. Steiermarkische Krankenanstalten Gesellschaft
  48. Knut and Alice Wallenberg (KAW) foundation
  49. Torsten and Ragnar Soderbergs Foundation
  50. HelseVest RHF [911554]
  51. Brain Research Imaging Centre Edinburgh, a center in the Scottish Funding Council Scottish Imaging Network-A Platform for Scientific Excellence (SINAPSE) Collaboration
  52. National Alliance for Research on Schizophrenia and Depression (NARSAD) Independent Investigator Award
  53. Health Foundation Clinician Scientist Fellowship
  54. European Community [602450, 278948, 602805, 643051]
  55. Biobanking and Biomolecular Resources Research Infrastructure (Netherlands) (BBMRI-NL)
  56. Hersenstichting Nederland
  57. Netherlands Organization for Scientific Research (NWO)
  58. NWO Gravitation grant 'Language in Interaction'
  59. ERC [268800-NEUROSCHEMA]
  60. ENIGMA Consortium from the BD2K Initiative of a cross-NIH partnership [U54 EB020403]
  61. Center for Brain Science Neuroinformatics Research Group
  62. Athinoula A. Martinos Center for Biomedical Imaging
  63. Center for Human Genetic Research
  64. NIMH [K99 MH101367, R01-MH079799, K24MH094614, K01MH099232]
  65. National Institute of Health [AG033193, AG011101, AG030146, AG008122, AG054076, AG049607, AG010129, NS017950, U01AG49505]
  66. International Alzheimer's Association [NIRP-14-302587]
  67. National Medical Research Council, Singapore [0796/2003, IRG07nov013, IRG09nov014, STaR/0003/2008, CG/SERI/2010]
  68. Biomedical Research Council, Singapore [09/1/35/19/616]
  69. National Medical Research Council, Singapore (NMRC/CG/NUHS) [R-184-006-184-511]
  70. Singapore Ministry of Health's National Medical Research Council [NMRC/CSA/038/2013]
  71. Wellcome Trust [084730, 082604/2/07/Z]
  72. University College London (UCL)/University College London Hospitals (UCLH) NIHR Biomedical Research Centre/Specialist Biomedical Research Centres (CBRC/SBRC) [114]
  73. European Union Marie Curie Reintegration
  74. UK NIHR [08-08-SCC]
  75. Comprehensive Local Research Network (CLRN) Flexibility and Sustainability Funding (FSF) [CEL1300]
  76. Big Lottery Fund
  77. Wolfson Trust
  78. Epilepsy Society
  79. UK Department of Health's NIHR Biomedical Research Centres funding scheme
  80. Science Foundation Ireland [08/RFP/GEN1538]
  81. Netherlands Organization for Scientific Research NWO [MW904-61-193, 400-07-080, MagW 480-04-004, 51.02.060, 668.772]
  82. European Research Council [ERC-230374]
  83. High Potential Grant Utrecht University
  84. NWO Brain and Cognition [433-09-220]
  85. Neuroscience Campus Amsterdam
  86. NHLBI [HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, R01HL130114, R01 HL105756]
  87. National Institute on Aging (NIA) [R01AG023629, R01AG15928, R01AG20098, R01AG027002, R01AG05133, R01AG027058]
  88. National Center for Advancing Translational Sciences, CTSI grant [UL1TR000124]
  89. National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]
  90. Brainwave-the Irish Epilepsy Association
  91. Epilepsy Research UK [F1206]
  92. European Commission [018947 (LSHG-CT-2006-01947), 223004]
  93. European Community's Seventh Framework Programme (FP7) by the European Commission under the programme Quality of Life and Management of the Living Resources of 5th Framework Programme [HEALTH-F4-2007-201413, QLG2-CT-2002-01254]
  94. Netherlands Organization for Scientific Research
  95. Russian Foundation for Basic Research [NWO-RFBR 047.017.043]
  96. Netherlands Brain Foundation [F2013(1)-28, 15F07[2]27]
  97. National Heart, Lung and Blood Institute's Framingham Heart Study [HHSN2682015000011]
  98. ZonMw [TOP 40-00812-98-11021, 916.13.054]
  99. National Institute of Neurological Disorders and Stroke [R01NS062059]
  100. National Heart, Lung, and Blood Institute [U01 HL72518, HL097698]
  101. National Institutes of Health/National Center for Research Resources [M01-RR000052]
  102. National Institute of Mental Health [MH0708143, MH078111, MH083824]
  103. Research Facilities Improvement Program from the National Center for Research Resources, NIH [C06 RR13556, C06 RR017515]
  104. Swedish Research Council [K2007-62X-15077-04-1, K2008-62P-20597-01-3, K2010-62X-15078-07-2, K2012-61X-15078-09-3]
  105. Stockholm County Council
  106. Karolinska Institutet
  107. Knut and Alice Wallenberg Foundation
  108. HUBIN project
  109. Swedish Research Council
  110. European Union [602450, LSHM-CT-2007-037286, 603016]
  111. Innovative Medicine Initiative Project EU-AIMS [115300-2]
  112. Medical Research Council Programme Grant Developmental pathways into adolescent substance abuse [93558]
  113. NIHR-biomedical Research Center Mental Health: Swedish Research Council FORMAS
  114. German Federal Ministry for Education and Research BMBF (Forschungsnetz AERIAL) [eMED SysAlc 01ZX1311A, 1EV0711]
  115. US National Institutes of Health (Axon)
  116. US National Institutes of Health (Testosterone)
  117. US National Institutes of Health (Mental Health during Adolescence)
  118. US National Institutes of Health [MH085772-01A1]
  119. French MILDECA
  120. Fondation pour la Recherche Medicale
  121. Brain & Cognition Excellence Program of the Netherlands Organization for Scientific Research (NWO) [433-09-229]
  122. Netherlands Organization for Scientific Research (NWO) [016.130.669]
  123. Research into Ageing programme grant
  124. Age UK-Disconnected Mind project
  125. UK Medical Research Council (MRC)
  126. Scottish Funding Council through the SINAPSE Collaboration
  127. Row Fogo Charitable Trust
  128. UK Biotechnology and Biological Sciences Research Council (BBSRC) [MRC MR/K026992/1]
  129. UK MRC
  130. BBSRC [BB/F019394/1]
  131. Innovation-Oriented Research Program on Genomics (SenterNovem) [IGE05007]
  132. Netherlands Consortium for Healthy Ageing [050-060-810]
  133. Department of Energy [DE-FG02-08ER64581]
  134. German Federal Ministry of Education and Research (BMBF) through the Integrated Genome Research Network (IG) MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia) unde (NGFNplus) [01GS08144, 01GS08147, 01GS08148]
  135. German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders) under e:Med Programme [01ZX1314A, 01ZX1314C, 01ZX1314G]
  136. Exzellenz-Stiftung of the Max Planck Society
  137. Federal Ministry of Education and Research (BMBF) [FKZ 01GS0481]
  138. Bergen Research Foundation
  139. University of Bergen
  140. Dr. Einar Martens Fund
  141. K.G. Jebsen Foundation
  142. Research Council of Norway
  143. Netherlands Organization for Scientific Research [10-000-1002]
  144. Center for Medical Systems Biology (CSMB, NWO Genomics)
  145. Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL)
  146. VU University's Institutes for Health and Care Research (EMGO+)
  147. University Medical Center Groningen
  148. Leiden University Medical Center
  149. Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health
  150. BiG Grid
  151. Dutch e-Science Grid - NWO
  152. NWO Large Investment Grant [1750102007010]
  153. Radboud University Nijmegen Medical Center
  154. University Medical Center Groningen and Accare
  155. VU University Amsterdam
  156. NIMH Intramural Research Program [ZIAMH002810, Z01MH002792, Z01MH002790]
  157. Intramural Research Program of the NIH, National Institute on Aging
  158. NHMRC/Australian Research Council Strategic Award [401162]
  159. NHMRC [R01 HD050735, 1045325, 310667, 401184, 525453, 568940, 389875, 486682, 1009064, 1061457]
  160. Commonwealth Scientific and Industrial Research Organisation Flagship Collaboration Fund Grant
  161. Australian Government - Dementia Collaborative Research Centre (DCRC), UNSW
  162. Alzheimer's Australia Dementia Research Foundation
  163. Japanese Ministry of Health, Labor and Welfare
  164. Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT) KAKENHI
  165. Scientific Research on Innovative Areas (Comprehensive Brain Science Network)
  166. Brain Sciences Project of the Center for Novel Science Initiatives (CNSI)
  167. National Institutes of Natural Sciences (NINS)
  168. Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) from Japan Agency for Medical Research and development, AMED
  169. Instituto de Salud Carlos III [FIS00/3095, 01/3129, PI020499, PI060507, PI10/00183, PI14/00639]
  170. SENY Fundacio Research Grant [CI 2005-0308007]
  171. Fundacion Marques de Valdecilla [API07/011]
  172. Carlos III Health Institute [CA12/00312]
  173. Bristol-Myers Squibb
  174. Netherlands Heart Foundation [2001 D 032]
  175. Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging) [050-060-810]
  176. Autism Speaks
  177. Australian Research Council [FT0991634]
  178. National Health and Medical Research Council (NHMRC), Australia [1103623, 619667]
  179. Translational Genomics Research Institute
  180. Netherlands Organisation of Scientific Research NWO [175.010.2005.011, 911-03-012]
  181. Research Institute for Diseases in the Elderly [014-93-015, RIDE2]
  182. Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) [050-060-810]
  183. Erasmus Medical Center
  184. Erasmus University, Rotterdam
  185. Netherlands Organization for the Health Research and Development (ZonMw)
  186. Research Institute for Diseases in the Elderly (RIDE)
  187. Ministry of Education, Culture and Science
  188. Ministry for Health, Welfare and Sports
  189. European Commission (DG XII)
  190. Municipality of Rotterdam
  191. Dutch Technology Foundation STW, NWO
  192. Ministry of Economic Affairs
  193. European Research Council (ERC) under the European Union's Horizon research and innovation programme [678543]
  194. Joint Programme - Neurodegenerative Disease Research working group on High-Dimensional Research in Alzheimer's Disease (ZonMW) [733051031]
  195. Van Leersum Grant of the Royal Netherlands Academy of Arts and Sciences
  196. Heart and Stroke Foundation of Quebec
  197. Canadian Foundation for Innovation
  198. Tanenbaum Chair in Population Neuroscience at the Rotman Research Institute, University of Toronto
  199. German Federal Ministry of Education and Research
  200. German Ministry of Cultural Affairs
  201. Social Ministry of the Federal State of Mecklenburg-West Pomerania [01ZZ9603, 01ZZ0103, 01ZZ0403]
  202. network 'Greifswald Approach to Individualized Medicine (GANI_MED)' - Federal Ministry of Education and Research [03IS2061A]
  203. Federal Ministry of Education and Research [03ZIK012]
  204. Siemens Healthcare, Erlangen, Germany
  205. Federal State of Mecklenburg-West Pomerania
  206. Australian National Health and Medical Research Council (NHMRC) Program [350833, 568969]
  207. National Health and Medical Research Council of Australia (NHMRC) [403000, 491109, 606543]
  208. Wicking Dementia Education and Research Centre
  209. Heart Foundation Future Leader Fellowship [100089]
  210. Caisse Nationale Maladie des Travailleurs Salaries
  211. Direction Generale de la Sante
  212. Mutuelle Generale de l'Education Nationale (MGEN)
  213. Institut de la Longevite
  214. Conseil Regionaux of Aquitaine
  215. Conseil Regionaux of Bourgogne
  216. Fondation de France
  217. Ministry of Research INSEAM Programme Cohortes et collections de donnees biologiques
  218. Fondation Leducq
  219. Research Council of Norway [213837, 223273, 229129]
  220. South-East Norway Health Authority [2013-123]
  221. KG Jebsen Foundation
  222. Netherlands Organization for Health Research and Development ZonMW [917.46.370, 908-02-123]
  223. French National Foundation on Alzheimer's disease and related disorders
  224. LABEX (laboratory of excellence program investment for the future) DISTALZ grant
  225. Inserm
  226. Institut Pasteur de Lille
  227. University de Lille 2
  228. Lille University Hospital
  229. Medical Research Council [503480]
  230. Alzheimer's Research UK [503176]
  231. German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) [01G10102, 01G10711, 01G10420]
  232. NIH/NIA grant [R01 AG033193, U01 AG032984, U24 AG021886, U01 AG016976]
  233. NIA [AG081220]
  234. AGES [N01-AG-12100]
  235. Icelandic Heart Association
  236. Erasmus University
  237. Alzheimer's Association [ADGC-10-196728]
  238. [NWO/SPI 56-464-14192]
  239. [MH59490]
  240. Science Foundation Ireland (SFI) [08/RFP/GEN1538] Funding Source: Science Foundation Ireland (SFI)
  241. BBSRC [BB/F019394/1] Funding Source: UKRI
  242. MRC [MR/K01417X/1, MR/N008324/1, G0802462, G0901858, MC_UU_12013/1, G0901254, G0701075, MC_UU_12013/2, MR/L016400/1] Funding Source: UKRI
  243. Biotechnology and Biological Sciences Research Council [BB/F019394/1] Funding Source: researchfish
  244. Epilepsy Research UK [F1206] Funding Source: researchfish
  245. Lundbeck Foundation [R155-2014-1724] Funding Source: researchfish
  246. Medical Research Council [G0901858, MR/L016400/1, MR/K026992/1, MR/N008324/1, MR/K01417X/1, MC_UU_12013/1, G0802462, MC_UU_12013/2] Funding Source: researchfish
  247. National Institute for Health Research [ACF-2012-17-017] Funding Source: researchfish
  248. Parkinson's UK [J-0901, J-1403] Funding Source: researchfish
  249. Wellcome Trust [100309/A/12/Z] Funding Source: researchfish
  250. National Health and Medical Research Council of Australia [1061457, 1103623] Funding Source: NHMRC

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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 (rho(genetic) = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (N-combined = 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.

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