Abstract
Subcortical brain structures are integral to motion, consciousness, emotions, and learning. We identified common genetic variation related to the volumes of nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen, and thalamus, using genome-wide association analyses in over 40,000 individuals from CHARGE, ENIGMA and the UK-Biobank. We show that variability in subcortical volumes is heritable, and identify 25 significantly associated loci (20 novel). Annotation of these loci utilizing gene expression, methylation, and neuropathological data identified 62 candidate genes implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, 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 (US) |
|---|---|
| Journal | Unknown Journal |
| DOIs | |
| State | Published - Aug 28 2017 |
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Agricultural and Biological Sciences(all)
- Immunology and Microbiology(all)
- Neuroscience(all)
- Pharmacology, Toxicology and Pharmaceutics(all)
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Genetic Architecture of Subcortical Brain Structures in Over 40,000 Individuals Worldwide. / Satizabal, Claudia L.; Adams, Hieab H.H.; Hibar, Derrek P.; White, Charles C.; Stein, Jason L.; Scholz, Markus; Sargurupremraj, Murali; Jahanshad, Neda; 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; Renteria, Miguel E.; Kim, Sungeun; Höhn, David; Armstrong, Nicola J.; Chen, Qiang; Holmes, Avram J.; Braber, Anouk den; 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; Karbalai, 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; Knol, Maria J.; 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 WJH; Calhoun, Vince D.; Chakravarty, M. Mallar; Marquand, Andre; Macare, Christine; Masouleh, Shahrzad Kharabian; 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; Loohuis, Loes M.Olde; Delanty, Norman; Ho, Beng Choon; Ching, Christopher R.K.; Shumskaya, Elena; Hofman, Albert; Van der Meer, Dennis; Homuth, Georg; Psaty, Bruce M.; Bastin, Mark; 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; Pol, Hilleke E.Hulshoff; 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; Smith, George Davey; Launer, Lenore J.; Nyberg, Lars; Jönsson, Erik G.; Crespo-Facorro, Benedicto; Koen, Nastassja; Greve, Douglas; 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; Mazoyer, Bernard; Andreassen, Ole A.; Holsboer, Florian; 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 A.; 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: Unknown Journal, 28.08.2017.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Genetic Architecture of Subcortical Brain Structures in Over 40,000 Individuals Worldwide
AU - Satizabal, Claudia L.
AU - Adams, Hieab H.H.
AU - Hibar, Derrek P.
AU - White, Charles C.
AU - Stein, Jason L.
AU - Scholz, Markus
AU - Sargurupremraj, Murali
AU - Jahanshad, Neda
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 - Renteria, Miguel E.
AU - Kim, Sungeun
AU - Höhn, David
AU - Armstrong, Nicola J.
AU - Chen, Qiang
AU - Holmes, Avram J.
AU - Braber, Anouk den
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 - Karbalai, 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 - Knol, Maria J.
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 WJH
AU - Calhoun, Vince D.
AU - Chakravarty, M. Mallar
AU - Marquand, Andre
AU - Macare, Christine
AU - Masouleh, Shahrzad Kharabian
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 - Loohuis, Loes M.Olde
AU - Delanty, Norman
AU - Ho, Beng Choon
AU - Ching, Christopher R.K.
AU - Shumskaya, Elena
AU - Hofman, Albert
AU - Van der Meer, Dennis
AU - Homuth, Georg
AU - Psaty, Bruce M.
AU - Bastin, Mark
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 - Pol, Hilleke E.Hulshoff
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 - Smith, George Davey
AU - Launer, Lenore J.
AU - Nyberg, Lars
AU - Jönsson, Erik G.
AU - Crespo-Facorro, Benedicto
AU - Koen, Nastassja
AU - Greve, Douglas
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 - Mazoyer, Bernard
AU - Andreassen, Ole A.
AU - Holsboer, Florian
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 A.
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
N1 - Publisher Copyright: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2017/8/28
Y1 - 2017/8/28
N2 - Subcortical brain structures are integral to motion, consciousness, emotions, and learning. We identified common genetic variation related to the volumes of nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen, and thalamus, using genome-wide association analyses in over 40,000 individuals from CHARGE, ENIGMA and the UK-Biobank. We show that variability in subcortical volumes is heritable, and identify 25 significantly associated loci (20 novel). Annotation of these loci utilizing gene expression, methylation, and neuropathological data identified 62 candidate genes implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, 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 nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen, and thalamus, using genome-wide association analyses in over 40,000 individuals from CHARGE, ENIGMA and the UK-Biobank. We show that variability in subcortical volumes is heritable, and identify 25 significantly associated loci (20 novel). Annotation of these loci utilizing gene expression, methylation, and neuropathological data identified 62 candidate genes implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, 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=85095649894&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85095649894&partnerID=8YFLogxK
U2 - 10.1101/173831
DO - 10.1101/173831
M3 - Article
AN - SCOPUS:85095649894
JO - Advances in Water Resources
JF - Advances in Water Resources
SN - 0309-1708
ER -