Genetic architecture of subcortical brain structures in 38,851 individuals

Claudia L Satizabal, Hieab H H Adams, Derrek P Hibar, Charles C White, Maria J Knol, Jason L Stein, Markus Scholz, Muralidharan Sargurupremraj, Neda Jahanshad, Gennady V Roshchupkin, Albert V Smith, Joshua C Bis, Xueqiu Jian, Michelle Luciano, Edith Hofer, Alexander Teumer, Sven J van der Lee, Jingyun Yang, Lisa R Yanek, Tom V LeeShuo Li, Yanhui Hu, Jia Yu Koh, John D Eicher, Sylvane Desrivières, Alejandro Arias-Vasquez, Ganesh Chauhan, Lavinia Athanasiu, Miguel E Rentería, Sungeun Kim, David Hoehn, Nicola J Armstrong, Qiang Chen, Avram J Holmes, Anouk den Braber, Iwona Kloszewska, Micael Andersson, Thomas Espeseth, Oliver Grimm, Lucija Abramovic, Saud Alhusaini, Yuri Milaneschi, Martina Papmeyer, Tomas Axelsson, Stefan Ehrlich, Roberto Roiz-Santiañez, Bernd Kraemer, Asta K Håberg, Hannah J Jones, G Bruce Pike, Dan J Stein, Allison Stevens, Janita Bralten, Meike W Vernooij, Tamara B Harris, Irina Filippi, A Veronica Witte, Tulio Guadalupe, Katharina Wittfeld, Thomas H Mosley, James T Becker, Nhat Trung Doan, Saskia P Hagenaars, Yasaman Saba, Gabriel Cuellar-Partida, Najaf Amin, Saima Hilal, Kwangsik Nho, Nazanin Mirza-Schreiber, Konstantinos Arfanakis, Diane M Becker, David Ames, Aaron L Goldman, Phil H Lee, Dorret I Boomsma, Simon Lovestone, Sudheer Giddaluru, Stephanie Le Hellard, Manuel Mattheisen, Marc M Bohlken, Dalia Kasperaviciute, Lianne Schmaal, Stephen M Lawrie, Ingrid Agartz, Esther Walton, Diana Tordesillas-Gutierrez, Gareth E Davies, Jean Shin, Jonathan C Ipser, Louis N Vinke, Martine Hoogman, Tianye Jia, Ralph Burkhardt, Marieke Klein, Fabrice Crivello, Deborah Janowitz, Owen Carmichael, Unn K Haukvik, Benjamin S Aribisala, Helena Schmidt, Lachlan T Strike, Ching-Yu Cheng, Shannon L Risacher, Benno Pütz, Debra A Fleischman, Amelia A Assareh, Venkata S Mattay, Randy L Buckner, Patrizia Mecocci, Anders M Dale, Sven Cichon, Marco P Boks, Mar Matarin, Brenda W J H Penninx, Vince D Calhoun, M Mallar Chakravarty, Andre F Marquand, Christine Macare, Shahrzad Kharabian Masouleh, Jaap Oosterlaan, Philippe Amouyel, Katrin Hegenscheid, Jerome I Rotter, Andrew J Schork, David C M Liewald, Greig I de Zubicaray, Tien Yin Wong, Li Shen, Philipp G Sämann, Henry Brodaty, Joshua L Roffman, Eco J C de Geus, Magda Tsolaki, Susanne Erk, Kristel R van Eijk, Gianpiero L Cavalleri, Nic J A van der Wee, Andrew M McIntosh, Randy L Gollub, Kazima B Bulayeva, Manon Bernard, Jennifer S Richards, Jayandra J Himali, Markus Loeffler, Nanda Rommelse, Wolfgang Hoffmann, Lars T Westlye, Maria C Valdés Hernández, Narelle K Hansell, Theo G M van Erp, Christiane Wolf, John B J Kwok, Bruno Vellas, Andreas Heinz, Loes M Olde Loohuis, Norman Delanty, Beng-Choon Ho, Christopher R K Ching, Elena Shumskaya, Baljeet Singh, Albert Hofman, Dennis van der Meer, Georg Homuth, Bruce M Psaty, Mark E Bastin, Grant W Montgomery, Tatiana M Foroud, Simone Reppermund, Jouke-Jan Hottenga, Andrew Simmons, Andreas Meyer-Lindenberg, Wiepke Cahn, Christopher D Whelan, Marjolein M J van Donkelaar, Qiong Yang, Norbert Hosten, Robert C Green, Anbupalam Thalamuthu, Sebastian Mohnke, Hilleke E Hulshoff Pol, Honghuang Lin, Clifford R Jack, Peter R Schofield, Thomas W Mühleisen, Pauline Maillard, Steven G Potkin, Wei Wen, Evan Fletcher, Arthur W Toga, Oliver Gruber, Matthew Huentelman, George Davey Smith, Lenore J Launer, Lars Nyberg, Erik G Jönsson, Benedicto Crespo-Facorro, Nastassja Koen, Douglas N Greve, André G Uitterlinden, Daniel R Weinberger, Vidar M Steen, Iryna O Fedko, Nynke A Groenewold, Wiro J Niessen, Roberto Toro, Christophe Tzourio, William T Longstreth, M Kamran Ikram, Jordan W Smoller, Marie-Jose van Tol, Jessika E Sussmann, Tomas Paus, Hervé Lemaître, Matthias L Schroeter, Bernard Mazoyer, Ole A Andreassen, Florian Holsboer, Chantal Depondt, Dick J Veltman, Jessica A Turner, Zdenka Pausova, Gunter Schumann, Daan van Rooij, Srdjan Djurovic, Ian J Deary, Katie L McMahon, Bertram Müller-Myhsok, Rachel M Brouwer, Hilkka Soininen, Massimo Pandolfo, Thomas H Wassink, Joshua W Cheung, Thomas Wolfers, Jean-Luc Martinot, Marcel P Zwiers, Matthias Nauck, Ingrid Melle, Nicholas G Martin, Ryota Kanai, Eric Westman, René S Kahn, Sanjay M Sisodiya, Tonya White, Arvin Saremi, Hans van Bokhoven, Han G Brunner, Henry Völzke, Margaret J Wright, Dennis van 't Ent, Markus M Nöthen, Roel A Ophoff, Jan K Buitelaar, Guillén Fernández, Perminder S Sachdev, Marcella Rietschel, Neeltje E M van Haren, Simon E Fisher, Alexa S Beiser, Clyde Francks, Andrew J Saykin, Karen A Mather, Nina Romanczuk-Seiferth, Catharina A Hartman, Anita L DeStefano, Dirk J Heslenfeld, Michael W Weiner, Henrik Walter, Pieter J Hoekstra, Paul A Nyquist, Barbara Franke, David A Bennett, Hans J Grabe, Andrew D Johnson, Christopher Chen, Cornelia M van Duijn, Oscar L Lopez, Myriam Fornage, Joanna M Wardlaw, Reinhold Schmidt, Charles DeCarli, Philip L De Jager, Arno Villringer, Stéphanie Debette, Vilmundur Gudnason, Sarah E Medland, Joshua M Shulman, Paul M Thompson, Sudha Seshadri, M Arfan Ikram

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Abstract

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

Original languageEnglish
Pages (from-to)1624-1636
Number of pages13
JournalNature Genetics
Volume51
Issue number11
Early online date21 Oct 2019
DOIs
Publication statusPublished - Nov 2019

Funding

D.P.H. is currently an employee at Genentech. D.J. has received travel and speaker’s honoraria from Janssen–Cilag, as well as research funding from DFG. R.L.B. is a consultant for Pfizer and Roche. P.A. is a scientific adviser for Genoscreen. T.Y.W. is a consultant and advisory board member for Allergan, Bayer, Boehringer–Ingelheim, Genentech, Merck, Novartis, Oxurion (formerly ThromboGenics) and Roche, and is a co-founder of Plano and EyRiS. A.M.M. has received grant support from Eli Lilly, Janssen, Pfizer and the Sackler Trust. B.M.P. serves on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson. A.M.-L. is a member of the advisory board for the Lundbeck International Neuroscience Foundation and Brainsway, a member of the editorial board for the American Association for the Advancement of Science and Elsevier, a faculty member of the Lundbeck International Neuroscience Foundation and a consultant for Boehringer Ingelheim. W.J.N. is the founder and scientific lead of Quantib BV, in addition to being a shareholder. M.M.N. is a shareholder of Life & Brain, receives a salary from Life & Brain, has received support from Shire for attending conferences and has received financial remuneration from the Lundbeck Foundation, Robert Bosch Foundation and Deutsches Ärzteblatt for participation in scientific advisory boards. B.F. has received educational speaking fees from Shire and Medice. H.J.G. has received travel grants and speaker’s honoraria from Fresenius Medical Care, Neuraxpharm and Janssen– Cilag, as well as research funding from Fresenius Medical Care.

FundersFunder number
Fresenius Medical Care
Sackler Trust
National Institute of Mental Health5R01MH094524, K99MH102357, R01MH117601, R01MH111671, K99MH116115, P20GM103472
National Institute on AgingK01 AG049050, R01AG033193, P30 AG010133, U01AG046161, R01AG053960, AG047866, R01 AG019771, R01AG059874, R01AG050631, R03 AG054936, RF1 AG041915, R56 AG058854, U01 AG024904, P01 AG026572, R01 AG061788
National Center for Research ResourcesNIH 1 U24 RR021992, NIH 1 U24 RR025736-01, C06RR029965
Burroughs Wellcome Fund
Michael J. Fox Foundation for Parkinson's Research14848
Alzheimer's AssociationAARF-17-532877
Eli Lilly and Company
Pfizer
Janssen Biotech
National Center for Advancing Translational SciencesUL1TR000153
Mrs Gladys Row Fogo Charitable TrustBROD.FID3668413
National Health and Medical Research CouncilAPP1095127, 1037196, 1102821
South African Medical Research Council
National Medical Research CouncilCSA-SI/0012/2017
Deutsche ForschungsgemeinschaftWI 3342/3-1
Fonds De La Recherche Scientifique - FNRS
Canadian HIV Trials Network, Canadian Institutes of Health Research
Nederlandse Organisatie voor Wetenschappelijk OnderzoekVeni grant 91619115
Instituto de Salud Carlos IIIPI14/00918
Norges forskningsråd223273, 248778, 262656, 275054
Medical Research FoundationMC_UU_00011/1

    Cohort Studies

    • Netherlands Twin Register (NTR)

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