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 Lee; Shuo 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

doi:10.1038/s41588-019-0511-y

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 language	English
Pages (from-to)	1624-1636
Number of pages	13
Journal	Nature Genetics
Volume	51
Issue number	11
Early online date	21 Oct 2019
DOIs	https://doi.org/10.1038/s41588-019-0511-y
Publication status	Published - 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.

Funders	Funder number
Fresenius Medical Care
Sackler Trust
National Institute of Mental Health	5R01MH094524, K99MH102357, R01MH117601, R01MH111671, K99MH116115, P20GM103472
National Institute on Aging	K01 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 Resources	NIH 1 U24 RR021992, NIH 1 U24 RR025736-01, C06RR029965
Burroughs Wellcome Fund
Michael J. Fox Foundation for Parkinson's Research	14848
Alzheimer's Association	AARF-17-532877
Eli Lilly and Company
Pfizer
Janssen Biotech
National Center for Advancing Translational Sciences	UL1TR000153
Mrs Gladys Row Fogo Charitable Trust	BROD.FID3668413
National Health and Medical Research Council	APP1095127, 1037196, 1102821
South African Medical Research Council
National Medical Research Council	CSA-SI/0012/2017
Deutsche Forschungsgemeinschaft	WI 3342/3-1
Fonds De La Recherche Scientifique - FNRS
Canadian HIV Trials Network, Canadian Institutes of Health Research
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	Veni grant 91619115
Instituto de Salud Carlos III	PI14/00918
Norges forskningsråd	223273, 248778, 262656, 275054
Medical Research Foundation	MC_UU_00011/1

Cohort Studies

Netherlands Twin Register (NTR)

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41588-019-0511-y

Genetic architecture of subcortical brain structures in 38851 individualsFinal published version, 4.73 MBLicence: Article 25fa Dutch Copyright Act

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Cite this

Satizabal, C. L., Adams, H. H. H., Hibar, D. P., White, C. C., Knol, M. J., Stein, J. L., Scholz, M., Sargurupremraj, M., Jahanshad, N., Roshchupkin, G. V., Smith, A. V., Bis, J. C., Jian, X., Luciano, M., Hofer, E., Teumer, A., van der Lee, S. J., Yang, J., Yanek, L. R., ... Ikram, M. A. (2019). Genetic architecture of subcortical brain structures in 38,851 individuals. Nature Genetics, 51(11), 1624-1636. https://doi.org/10.1038/s41588-019-0511-y

@article{78126867921a42a49782e8522f6ba4d4,

title = "Genetic architecture of subcortical brain structures in 38,851 individuals",

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.",

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

year = "2019",

month = nov,

doi = "10.1038/s41588-019-0511-y",

language = "English",

volume = "51",

pages = "1624--1636",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "11",

}

Satizabal, CL, Adams, HHH, Hibar, DP, White, CC, Knol, MJ, Stein, JL, Scholz, M, Sargurupremraj, M, Jahanshad, N, Roshchupkin, GV, Smith, AV, Bis, JC, Jian, X, Luciano, M, Hofer, E, Teumer, A, van der Lee, SJ, Yang, J, Yanek, LR, Lee, TV, Li, S, Hu, Y, Koh, JY, Eicher, JD, Desrivières, S, Arias-Vasquez, A, Chauhan, G, Athanasiu, L, Rentería, ME, Kim, S, Hoehn, D, Armstrong, NJ, Chen, Q, Holmes, AJ, den Braber, A, Kloszewska, I, Andersson, M, Espeseth, T, Grimm, O, Abramovic, L, Alhusaini, S, Milaneschi, Y, Papmeyer, M, Axelsson, T, Ehrlich, S, Roiz-Santiañez, R, Kraemer, B, Håberg, AK, Jones, HJ, Pike, GB, Stein, DJ, Stevens, A, Bralten, J, Vernooij, MW, Harris, TB, Filippi, I, Witte, AV, Guadalupe, T, Wittfeld, K, Mosley, TH, Becker, JT, Doan, NT, Hagenaars, SP, Saba, Y, Cuellar-Partida, G, Amin, N, Hilal, S, Nho, K, Mirza-Schreiber, N, Arfanakis, K, Becker, DM, Ames, D, Goldman, AL, Lee, PH, Boomsma, DI, Lovestone, S, Giddaluru, S, Le Hellard, S, Mattheisen, M, Bohlken, MM, Kasperaviciute, D, Schmaal, L, Lawrie, SM, Agartz, I, Walton, E, Tordesillas-Gutierrez, D, Davies, GE, Shin, J, Ipser, JC, Vinke, LN, Hoogman, M, Jia, T, Burkhardt, R, Klein, M, Crivello, F, Janowitz, D, Carmichael, O, Haukvik, UK, Aribisala, BS, Schmidt, H, Strike, LT, Cheng, C-Y, Risacher, SL, Pütz, B, Fleischman, DA, Assareh, AA, Mattay, VS, Buckner, RL, Mecocci, P, Dale, AM, Cichon, S, Boks, MP, Matarin, M, Penninx, BWJH, Calhoun, VD, Chakravarty, MM, Marquand, AF, Macare, C, Kharabian Masouleh, S, Oosterlaan, J, Amouyel, P, Hegenscheid, K, Rotter, JI, Schork, AJ, Liewald, DCM, de Zubicaray, GI, Wong, TY, Shen, L, Sämann, PG, Brodaty, H, Roffman, JL, de Geus, EJC, Tsolaki, M, Erk, S, van Eijk, KR, Cavalleri, GL, van der Wee, NJA, McIntosh, AM, Gollub, RL, Bulayeva, KB, Bernard, M, Richards, JS, Himali, JJ, Loeffler, M, Rommelse, N, Hoffmann, W, Westlye, LT, Valdés Hernández, MC, Hansell, NK, van Erp, TGM, Wolf, C, Kwok, JBJ, Vellas, B, Heinz, A, Olde Loohuis, LM, Delanty, N, Ho, B-C, Ching, CRK, Shumskaya, E, Singh, B, Hofman, A, van der Meer, D, Homuth, G, Psaty, BM, Bastin, ME, Montgomery, GW, Foroud, TM, Reppermund, S, Hottenga, J-J, Simmons, A, Meyer-Lindenberg, A, Cahn, W, Whelan, CD, van Donkelaar, MMJ, Yang, Q, Hosten, N, Green, RC, Thalamuthu, A, Mohnke, S, Hulshoff Pol, HE, Lin, H, Jack, CR, Schofield, PR, Mühleisen, TW, Maillard, P, Potkin, SG, Wen, W, Fletcher, E, Toga, AW, Gruber, O, Huentelman, M, Davey Smith, G, Launer, LJ, Nyberg, L, Jönsson, EG, Crespo-Facorro, B, Koen, N, Greve, DN, Uitterlinden, AG, Weinberger, DR, Steen, VM, Fedko, IO, Groenewold, NA, Niessen, WJ, Toro, R, Tzourio, C, Longstreth, WT, Ikram, MK, Smoller, JW, van Tol, M-J, Sussmann, JE, Paus, T, Lemaître, H, Schroeter, ML, Mazoyer, B, Andreassen, OA, Holsboer, F, Depondt, C, Veltman, DJ, Turner, JA, Pausova, Z, Schumann, G, van Rooij, D, Djurovic, S, Deary, IJ, McMahon, KL, Müller-Myhsok, B, Brouwer, RM, Soininen, H, Pandolfo, M, Wassink, TH, Cheung, JW, Wolfers, T, Martinot, J-L, Zwiers, MP, Nauck, M, Melle, I, Martin, NG, Kanai, R, Westman, E, Kahn, RS, Sisodiya, SM, White, T, Saremi, A, van Bokhoven, H, Brunner, HG, Völzke, H, Wright, MJ, van 't Ent, D, Nöthen, MM, Ophoff, RA, Buitelaar, JK, Fernández, G, Sachdev, PS, Rietschel, M, van Haren, NEM, Fisher, SE, Beiser, AS, Francks, C, Saykin, AJ, Mather, KA, Romanczuk-Seiferth, N, Hartman, CA, DeStefano, AL, Heslenfeld, DJ, Weiner, MW, Walter, H, Hoekstra, PJ, Nyquist, PA, Franke, B, Bennett, DA, Grabe, HJ, Johnson, AD, Chen, C, van Duijn, CM, Lopez, OL, Fornage, M, Wardlaw, JM, Schmidt, R, DeCarli, C, De Jager, PL, Villringer, A, Debette, S, Gudnason, V, Medland, SE, Shulman, JM, Thompson, PM, Seshadri, S & Ikram, MA 2019, 'Genetic architecture of subcortical brain structures in 38,851 individuals', Nature Genetics, vol. 51, no. 11, pp. 1624-1636. https://doi.org/10.1038/s41588-019-0511-y

TY - JOUR

T1 - Genetic architecture of subcortical brain structures in 38,851 individuals

AU - Satizabal, Claudia L

AU - Adams, Hieab H H

AU - Hibar, Derrek P

AU - White, Charles C

AU - Knol, Maria J

AU - Stein, Jason L

AU - Scholz, Markus

AU - Sargurupremraj, Muralidharan

AU - Jahanshad, Neda

AU - Roshchupkin, Gennady V

AU - Smith, Albert V

AU - Bis, Joshua C

AU - Jian, Xueqiu

AU - Luciano, Michelle

AU - Hofer, Edith

AU - Teumer, Alexander

AU - van der Lee, Sven J

AU - Yang, Jingyun

AU - Yanek, Lisa R

AU - Lee, Tom V

AU - Li, Shuo

AU - Hu, Yanhui

AU - Koh, Jia Yu

AU - Eicher, John D

AU - Desrivières, Sylvane

AU - Arias-Vasquez, Alejandro

AU - Chauhan, Ganesh

AU - Athanasiu, Lavinia

AU - Rentería, Miguel E

AU - Kim, Sungeun

AU - Hoehn, David

AU - Armstrong, Nicola J

AU - Chen, Qiang

AU - Holmes, Avram J

AU - den Braber, Anouk

AU - Kloszewska, Iwona

AU - Andersson, Micael

AU - Espeseth, Thomas

AU - Grimm, Oliver

AU - Abramovic, Lucija

AU - Alhusaini, Saud

AU - Milaneschi, Yuri

AU - Papmeyer, Martina

AU - Axelsson, Tomas

AU - Ehrlich, Stefan

AU - Roiz-Santiañez, Roberto

AU - Kraemer, Bernd

AU - Håberg, Asta K

AU - Jones, Hannah J

AU - Pike, G Bruce

AU - Stein, Dan J

AU - Stevens, Allison

AU - Bralten, Janita

AU - Vernooij, Meike W

AU - Harris, Tamara B

AU - Filippi, Irina

AU - Witte, A Veronica

AU - Guadalupe, Tulio

AU - Wittfeld, Katharina

AU - Mosley, Thomas H

AU - Becker, James T

AU - Doan, Nhat Trung

AU - Hagenaars, Saskia P

AU - Saba, Yasaman

AU - Cuellar-Partida, Gabriel

AU - Amin, Najaf

AU - Hilal, Saima

AU - Nho, Kwangsik

AU - Mirza-Schreiber, Nazanin

AU - Arfanakis, Konstantinos

AU - Becker, Diane M

AU - Ames, David

AU - Goldman, Aaron L

AU - Lee, Phil H

AU - Boomsma, Dorret I

AU - Lovestone, Simon

AU - Giddaluru, Sudheer

AU - Le Hellard, Stephanie

AU - Mattheisen, Manuel

AU - Bohlken, Marc M

AU - Kasperaviciute, Dalia

AU - Schmaal, Lianne

AU - Lawrie, Stephen M

AU - Agartz, Ingrid

AU - Walton, Esther

AU - Tordesillas-Gutierrez, Diana

AU - Davies, Gareth E

AU - Shin, Jean

AU - Ipser, Jonathan C

AU - Vinke, Louis N

AU - Hoogman, Martine

AU - Jia, Tianye

AU - Burkhardt, Ralph

AU - Klein, Marieke

AU - Crivello, Fabrice

AU - Janowitz, Deborah

AU - Carmichael, Owen

AU - Haukvik, Unn K

AU - Aribisala, Benjamin S

AU - Schmidt, Helena

AU - Strike, Lachlan T

AU - Cheng, Ching-Yu

AU - Risacher, Shannon L

AU - Pütz, Benno

AU - Fleischman, Debra A

AU - Assareh, Amelia A

AU - Mattay, Venkata S

AU - Buckner, Randy L

AU - Mecocci, Patrizia

AU - Dale, Anders M

AU - Cichon, Sven

AU - Boks, Marco P

AU - Matarin, Mar

AU - Penninx, Brenda W J H

AU - Calhoun, Vince D

AU - Chakravarty, M Mallar

AU - Marquand, Andre F

AU - Macare, Christine

AU - Kharabian Masouleh, Shahrzad

AU - Oosterlaan, Jaap

AU - Amouyel, Philippe

AU - Hegenscheid, Katrin

AU - Rotter, Jerome I

AU - Schork, Andrew J

AU - Liewald, David C M

AU - de Zubicaray, Greig I

AU - Wong, Tien Yin

AU - Shen, Li

AU - Sämann, Philipp G

AU - Brodaty, Henry

AU - Roffman, Joshua L

AU - de Geus, Eco J C

AU - Tsolaki, Magda

AU - Erk, Susanne

AU - van Eijk, Kristel R

AU - Cavalleri, Gianpiero L

AU - van der Wee, Nic J A

AU - McIntosh, Andrew M

AU - Gollub, Randy L

AU - Bulayeva, Kazima B

AU - Bernard, Manon

AU - Richards, Jennifer S

AU - Himali, Jayandra J

AU - Loeffler, Markus

AU - Rommelse, Nanda

AU - Hoffmann, Wolfgang

AU - Westlye, Lars T

AU - Valdés Hernández, Maria C

AU - Hansell, Narelle K

AU - van Erp, Theo G M

AU - Wolf, Christiane

AU - Kwok, John B J

AU - Vellas, Bruno

AU - Heinz, Andreas

AU - Olde Loohuis, Loes M

AU - Delanty, Norman

AU - Ho, Beng-Choon

AU - Ching, Christopher R K

AU - Shumskaya, Elena

AU - Singh, Baljeet

AU - Hofman, Albert

AU - van der Meer, Dennis

AU - Homuth, Georg

AU - Psaty, Bruce M

AU - Bastin, Mark E

AU - Montgomery, Grant W

AU - Foroud, Tatiana M

AU - Reppermund, Simone

AU - Hottenga, Jouke-Jan

AU - Simmons, Andrew

AU - Meyer-Lindenberg, Andreas

AU - Cahn, Wiepke

AU - Whelan, Christopher D

AU - van Donkelaar, Marjolein M J

AU - Yang, Qiong

AU - Hosten, Norbert

AU - Green, Robert C

AU - Thalamuthu, Anbupalam

AU - Mohnke, Sebastian

AU - Hulshoff Pol, Hilleke E

AU - Lin, Honghuang

AU - Jack, Clifford R

AU - Schofield, Peter R

AU - Mühleisen, Thomas W

AU - Maillard, Pauline

AU - Potkin, Steven G

AU - Wen, Wei

AU - Fletcher, Evan

AU - Toga, Arthur W

AU - Gruber, Oliver

AU - Huentelman, Matthew

AU - Davey Smith, George

AU - Launer, Lenore J

AU - Nyberg, Lars

AU - Jönsson, Erik G

AU - Crespo-Facorro, Benedicto

AU - Koen, Nastassja

AU - Greve, Douglas N

AU - Uitterlinden, André G

AU - Weinberger, Daniel R

AU - Steen, Vidar M

AU - Fedko, Iryna O

AU - Groenewold, Nynke A

AU - Niessen, Wiro J

AU - Toro, Roberto

AU - Tzourio, Christophe

AU - Longstreth, William T

AU - Ikram, M Kamran

AU - Smoller, Jordan W

AU - van Tol, Marie-Jose

AU - Sussmann, Jessika E

AU - Paus, Tomas

AU - Lemaître, Hervé

AU - Schroeter, Matthias L

AU - Mazoyer, Bernard

AU - Andreassen, Ole A

AU - Holsboer, Florian

AU - Depondt, Chantal

AU - Veltman, Dick J

AU - Turner, Jessica A

AU - Pausova, Zdenka

AU - Schumann, Gunter

AU - van Rooij, Daan

AU - Djurovic, Srdjan

AU - Deary, Ian J

AU - McMahon, Katie L

AU - Müller-Myhsok, Bertram

AU - Brouwer, Rachel M

AU - Soininen, Hilkka

AU - Pandolfo, Massimo

AU - Wassink, Thomas H

AU - Cheung, Joshua W

AU - Wolfers, Thomas

AU - Martinot, Jean-Luc

AU - Zwiers, Marcel P

AU - Nauck, Matthias

AU - Melle, Ingrid

AU - Martin, Nicholas G

AU - Kanai, Ryota

AU - Westman, Eric

AU - Kahn, René S

AU - Sisodiya, Sanjay M

AU - White, Tonya

AU - Saremi, Arvin

AU - van Bokhoven, Hans

AU - Brunner, Han G

AU - Völzke, Henry

AU - Wright, Margaret J

AU - van 't Ent, Dennis

AU - Nöthen, Markus M

AU - Ophoff, Roel A

AU - Buitelaar, Jan K

AU - Fernández, Guillén

AU - Sachdev, Perminder S

AU - Rietschel, Marcella

AU - van Haren, Neeltje E M

AU - Fisher, Simon E

AU - Beiser, Alexa S

AU - Francks, Clyde

AU - Saykin, Andrew J

AU - Mather, Karen A

AU - Romanczuk-Seiferth, Nina

AU - Hartman, Catharina A

AU - DeStefano, Anita L

AU - Heslenfeld, Dirk J

AU - Weiner, Michael W

AU - Walter, Henrik

AU - Hoekstra, Pieter J

AU - Nyquist, Paul A

AU - Franke, Barbara

AU - Bennett, David A

AU - Grabe, Hans J

AU - Johnson, Andrew D

AU - Chen, Christopher

AU - van Duijn, Cornelia M

AU - Lopez, Oscar L

AU - Fornage, Myriam

AU - Wardlaw, Joanna M

AU - Schmidt, Reinhold

AU - DeCarli, Charles

AU - De Jager, Philip L

AU - Villringer, Arno

AU - Debette, Stéphanie

AU - Gudnason, Vilmundur

AU - Medland, Sarah E

AU - Shulman, Joshua M

AU - Thompson, Paul M

AU - Seshadri, Sudha

AU - Ikram, M Arfan

PY - 2019/11

Y1 - 2019/11

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85074320860&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85074320860&partnerID=8YFLogxK

U2 - 10.1038/s41588-019-0511-y

DO - 10.1038/s41588-019-0511-y

M3 - Article

C2 - 31636452

SN - 1061-4036

VL - 51

SP - 1624

EP - 1636

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -

Genetic architecture of subcortical brain structures in 38,851 individuals

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