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 | |
| Publication status | Published - Nov 2019 |
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- Genetic architecture of subcortical brain structures in 38851 individualsFinal published version, 4.73 MBLicence: Article 25fa Dutch Copyright Act
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Genetic architecture of subcortical brain structures in 38,851 individuals. / Satizabal, Claudia L; Adams, Hieab H H; Hibar, Derrek P; White, Charles C; Knol, Maria J; Stein, Jason L; Scholz, Markus; Sargurupremraj, Muralidharan; Jahanshad, Neda; Roshchupkin, Gennady V; Smith, Albert V; Bis, Joshua C; Jian, Xueqiu; Luciano, Michelle; Hofer, Edith; Teumer, Alexander; van der Lee, Sven J; Yang, Jingyun; Yanek, Lisa R; Lee, Tom V; Li, Shuo; Hu, Yanhui; Koh, Jia Yu; Eicher, John D; Desrivières, Sylvane; Arias-Vasquez, Alejandro; Chauhan, Ganesh; Athanasiu, Lavinia; Rentería, Miguel E; Kim, Sungeun; Hoehn, David; Armstrong, Nicola J; Chen, Qiang; Holmes, Avram J; den Braber, Anouk; Kloszewska, Iwona; Andersson, Micael; Espeseth, Thomas; Grimm, Oliver; Abramovic, Lucija; Alhusaini, Saud; Milaneschi, Yuri; Papmeyer, Martina; Axelsson, Tomas; Ehrlich, Stefan; Roiz-Santiañez, Roberto; Kraemer, Bernd; Håberg, Asta K; Jones, Hannah J; Pike, G Bruce; Stein, Dan J; Stevens, Allison; Bralten, Janita; Vernooij, Meike W; Harris, Tamara B; Filippi, Irina; Witte, A Veronica; Guadalupe, Tulio; Wittfeld, Katharina; Mosley, Thomas H; Becker, James T; Doan, Nhat Trung; Hagenaars, Saskia P; Saba, Yasaman; Cuellar-Partida, Gabriel; Amin, Najaf; Hilal, Saima; Nho, Kwangsik; Mirza-Schreiber, Nazanin; Arfanakis, Konstantinos; Becker, Diane M; Ames, David; Goldman, Aaron L; Lee, Phil H; Boomsma, Dorret I; Lovestone, Simon; Giddaluru, Sudheer; Le Hellard, Stephanie; Mattheisen, Manuel; Bohlken, Marc M; Kasperaviciute, Dalia; Schmaal, Lianne; Lawrie, Stephen M; Agartz, Ingrid; Walton, Esther; Tordesillas-Gutierrez, Diana; Davies, Gareth E; Shin, Jean; Ipser, Jonathan C; Vinke, Louis N; Hoogman, Martine; Jia, Tianye; Burkhardt, Ralph; Klein, Marieke; Crivello, Fabrice; Janowitz, Deborah; Carmichael, Owen; Haukvik, Unn K; Aribisala, Benjamin S; Schmidt, Helena; Strike, Lachlan T; Cheng, Ching-Yu; Risacher, Shannon L; Pütz, Benno; Fleischman, Debra A; Assareh, Amelia A; Mattay, Venkata S; Buckner, Randy L; Mecocci, Patrizia; Dale, Anders M; Cichon, Sven; Boks, Marco P; Matarin, Mar; Penninx, Brenda W J H; Calhoun, Vince D; Chakravarty, M Mallar; Marquand, Andre F; Macare, Christine; Kharabian Masouleh, Shahrzad; Oosterlaan, Jaap; Amouyel, Philippe; Hegenscheid, Katrin; Rotter, Jerome I; Schork, Andrew J; Liewald, David C M; de Zubicaray, Greig I; Wong, Tien Yin; Shen, Li; Sämann, Philipp G; Brodaty, Henry; Roffman, Joshua L; de Geus, Eco J C; Tsolaki, Magda; Erk, Susanne; van Eijk, Kristel R; Cavalleri, Gianpiero L; van der Wee, Nic J A; McIntosh, Andrew M; Gollub, Randy L; Bulayeva, Kazima B; Bernard, Manon; Richards, Jennifer S; Himali, Jayandra J; Loeffler, Markus; Rommelse, Nanda; Hoffmann, Wolfgang; Westlye, Lars T; Valdés Hernández, Maria C; Hansell, Narelle K; van Erp, Theo G M; Wolf, Christiane; Kwok, John B J; Vellas, Bruno; Heinz, Andreas; Olde Loohuis, Loes M; Delanty, Norman; Ho, Beng-Choon; Ching, Christopher R K; Shumskaya, Elena; Singh, Baljeet; Hofman, Albert; van der Meer, Dennis; Homuth, Georg; Psaty, Bruce M; Bastin, Mark E; Montgomery, Grant W; Foroud, Tatiana M; Reppermund, Simone; Hottenga, Jouke-Jan; Simmons, Andrew; Meyer-Lindenberg, Andreas; Cahn, Wiepke; Whelan, Christopher D; van Donkelaar, Marjolein M J; Yang, Qiong; Hosten, Norbert; Green, Robert C; Thalamuthu, Anbupalam; Mohnke, Sebastian; Hulshoff Pol, Hilleke E; Lin, Honghuang; Jack, Clifford R; Schofield, Peter R; Mühleisen, Thomas W; Maillard, Pauline; Potkin, Steven G; Wen, Wei; Fletcher, Evan; Toga, Arthur W; Gruber, Oliver; Huentelman, Matthew; Davey Smith, George; Launer, Lenore J; Nyberg, Lars; Jönsson, Erik G; Crespo-Facorro, Benedicto; Koen, Nastassja; Greve, Douglas N; Uitterlinden, André G; Weinberger, Daniel R; Steen, Vidar M; Fedko, Iryna O; Groenewold, Nynke A; Niessen, Wiro J; Toro, Roberto; Tzourio, Christophe; Longstreth, William T; Ikram, M Kamran; Smoller, Jordan W; van Tol, Marie-Jose; Sussmann, Jessika E; Paus, Tomas; Lemaître, Hervé; Schroeter, Matthias L; Mazoyer, Bernard; Andreassen, Ole A; Holsboer, Florian; Depondt, Chantal; Veltman, Dick J; Turner, Jessica A; Pausova, Zdenka; Schumann, Gunter; van Rooij, Daan; Djurovic, Srdjan; Deary, Ian J; McMahon, Katie L; Müller-Myhsok, Bertram; Brouwer, Rachel M; Soininen, Hilkka; Pandolfo, Massimo; Wassink, Thomas H; Cheung, Joshua W; Wolfers, Thomas; Martinot, Jean-Luc; Zwiers, Marcel P; Nauck, Matthias; Melle, Ingrid; Martin, Nicholas G; Kanai, Ryota; Westman, Eric; Kahn, René S; Sisodiya, Sanjay M; White, Tonya; Saremi, Arvin; van Bokhoven, Hans; Brunner, Han G; Völzke, Henry; Wright, Margaret J; van 't Ent, Dennis; Nöthen, Markus M; Ophoff, Roel A; Buitelaar, Jan K; Fernández, Guillén; Sachdev, Perminder S; Rietschel, Marcella; van Haren, Neeltje E M; Fisher, Simon E; Beiser, Alexa S; Francks, Clyde; Saykin, Andrew J; Mather, Karen A; Romanczuk-Seiferth, Nina; Hartman, Catharina A; DeStefano, Anita L; Heslenfeld, Dirk J; Weiner, Michael W; Walter, Henrik; Hoekstra, Pieter J; Nyquist, Paul A; Franke, Barbara; Bennett, David A; Grabe, Hans J; Johnson, Andrew D; Chen, Christopher; van Duijn, Cornelia M; Lopez, Oscar L; Fornage, Myriam; Wardlaw, Joanna M; Schmidt, Reinhold; DeCarli, Charles; De Jager, Philip L; Villringer, Arno; Debette, Stéphanie; Gudnason, Vilmundur; Medland, Sarah E; Shulman, Joshua M; Thompson, Paul M; Seshadri, Sudha; Ikram, M Arfan.
In: Nature Genetics, Vol. 51, No. 11, 11.2019, p. 1624-1636.Research output: Contribution to Journal › Article › Academic › peer-review
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
VL - 51
SP - 1624
EP - 1636
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 11
ER -