Common genetic variants influence human subcortical brain structures

Derrek P. Hibar; Jason L. Stein; Miguel E. Renteria; Alejandro Arias-Vasquez; Sylvane Desrivieres; Neda Jahanshad; Roberto Toro; Katharina Wittfeld; Lucija Abramovic; Micael Andersson; Benjamin S. Aribisala; Nicola J. Armstrong; Manon Bernard; Marc M. Bohlken; Marco P. Boks; Janita Bralten; Andrew A. Brown; M. Mallar Chakravarty; Qiang Chen; Christopher R. K. Ching; Gabriel Cuellar-Partida; Anouk den Braber; Sudheer Giddaluru; Aaron L. Goldman; Oliver Grimm; Tulio Guadalupe; Johanna Hass; Girma Woldehawariat; Avram J. Holmes; Martine Hoogman; Deborah Janowitz; Tianye Jia; Sungeun Kim; Marieke Klein; Bernd Kraemer; Phil H. Lee; Loes M. Olde Loohuis; Michelle Luciano; Christine Macare; Karen A. Mather; Manuel Mattheisen; Yuri Milaneschi; Kwangsik Nho; Martina Papmeyer; Adaikalavan Ramasamy; Shannon L. Risacher; Roberto Roiz-Santianez; Emma J. Rose; Alireza Salami; Philipp G. Saemann; Lianne Schmaal; Andrew J. Schork; Jean Shin; Lachlan T. Strike; Alexander Teumer; Marjolein M. J. van Donkelaar; Kristel R. van Eijk; Raymond K. Walters; Lars T. Westlye; Christopher D. Whelan; Anderson M. Winkler; Marcel P. Zwiers; Saud Alhusaini; Lavinia Athanasiu; Stefan Ehrlich; Marina M. H. Hakobjan; Cecilie B. Hartberg; Unn K. Haukvik; Angelien J. G. A. M. Heister; David Hoehn; Dalia Kasperaviciute; David C. M. Liewald; Lorna M. Lopez; Remco R. R. Makkinje; Mar Matarin; Marlies A. M. Naber; D. Reese McKay; Margaret Needham; Allison C. Nugent; Benno Puetz; Natalie A. Royle; Li Shen; Emma Sprooten; Daniah Trabzuni; Saskia S. L. van der Marel; Kimm J. E. van Hulzen; Esther Walton; Christiane Wolf; Laura Almasy; David Ames; Sampath Arepalli; Amelia A. Assareh; Mark E. Bastin; Henry Brodaty; Kazima B. Bulayeva; Melanie A. Carless; Sven Cichon; Aiden Corvin; Joanne E. Curran; Michael Czisch; Greig I. de Zubicaray; Allissa Dillman; Ravi Duggirala; Thomas D. Dyer; Susanne Erk; Iryna O. Fedko; Luigi Ferrucci; Tatiana M. Foroud; Peter T. Fox; Masaki Fukunaga; J. Raphael Gibbs; Harald H. H. Goering; Robert C. Green; Sebastian Guelfi; Narelle K. Hansell; Catharina A. Hartman; Katrin Hegenscheid; Andreas Heinz; Dena G. Hernandez; Dirk J. Heslenfeld; Pieter J. Hoekstra; Florian Holsboer; Georg Homuth; Jouke-Jan Hottenga; Masashi Ikeda; Clifford R., Jr. Jack; Mark Jenkinson; Robert Johnson; Ryota Kanai; Maria Keil; Jack W., Jr. Kent; Peter Kochunov; John B. Kwok; Stephen M. Lawrie; Xinmin Liu; Dan L. Longo; Katie L. McMahon; Eva Meisenzah; Ingrid Melle; Sebastian Mahnke; Grant W. Montgomery; Jeanette C. Mostert; Thomas W. Muehleisen; Michael A. Nalls; Thomas E. Nichols; Lars G. Nilsson; Markus M. Noethen; Kazutaka Ohi; Rene L. Olvera; Rocio Perez-Iglesias; G. Bruce Pike; Steven G. Potkin; Ivar Reinvang; Simone Reppermund; Marcella Rietschel; Nina Romanczuk-Seiferth; Glenn D. Rosen; Dan Rujescu; Knut Schnell; Peter R. Schofield; Colin Smith; Vidar M. Steen; Jessika E. Sussmann; Anbupalam Thalamuthu; Arthur W. Toga; Bryan J. Traynor; Juan Troncoso; Jessica A. Turner; Maria C. Valdes Hernandez; Dennis van't Ent; Marcel van der Brug; Nic J. A. van der Wee; Marie-Jose van Tol; Dick J. Veltman; Thomas H. Wassink; Eric Westman; Ronald H. Zielke; Alan B. Zonderman; David G. Ashbrook; Reinmar Hager; Lu Lu; Francis J. McMahon; Derek W. Morris; Robert W. Williams; Han G. Brunner; Randy L. Buckner; Jan K. Buitelaar; Wiepke Cahn; Vince D. Calhoun; Gianpiero L. Cavalleri; Benedicto Crespo-Facorro; Anders M. Dale; Gareth E. Davies; Norman Delanty; Chantal Depondt; Srdjan Djurovic; Wayne C. Drevets; Thomas Espeseth; Randy L. Gollub; Beng-Choon Ho; Wolfgang Hoffman; Norbert Hosten; Rene S. Kahn; Stephanie Le Hellard; Andreas Meyer-Lindenberg; Bertram Mueller-Myhsok; Matthias Nauck; Lars Nyberg; Massimo Pandolfo; Brenda W. J. H. Penninx; Joshua L. Roffman; Sanjay M. Sisodiya; Jordan W. Smoller; Hans van Bokhoven; Neeltje E. M. van Haren; Henry Voelzke; Henrik Walter; Michael W. Weiner; Wei Wen; Tonya White; Ingrid Agartz; Ole A. Andreassen; John Blangero; Dorret I. Boomsma; Rachel M. Brouwer; Dara M. Cannon; Mark R. Cookson; Eco J. C. de Geus; Ian J. Deary; Gary Donohoe; Guillen Fernandez; Simon E. Fisher; Clyde Francks; David C. Glahn; Hans J. Grabe; Oliver Gruber; John Hardy; Ryota Hashimoto; Hilleke E. Hulshoff Pol; Erik G. Jönsson; Iwona Kloszewska; Simon Lovestone; Venkata S. Mattay; Patrizia Mecocci; Colm McDonald; Andrew M. McIntosh; Roel A. Ophoff; Tomas Paus; Zdenka Pausova; Mina Ryten; Perminder S. Sachdev; Andrew J. Saykin; Andy Simmons; Andrew Singleton; Hilkka Soininen; Joanna M. Wardlaw; Michael E. Weale; Daniel R. Weinberger; Hieab H. H. Adams; Lenore J. Launer; Stephan Seiler; Reinhold Schmidt; Ganesh Chauhan; Claudia L. Satizabal; James T. Becker; Lisa Yanek; Sven J. van der Lee; Maritza Ebling; Bruce Fischl; W. T., Jr. Longstreth; Douglas Greve; Helena Schmidt; Paul Nyquist; Louis N. Vinke; Cornelia M. van Duijn; Luting Xue; Bernard Mazoyer; Joshua C. Bis; Vilmundur Gudnason; Sudha Seshadri; M. Arfan Ikram; Nicholas G. Martin; Margaret J. Wright; Gunter Schumann; Barbara Franke; Paul M., Jr. Thompson; Sarah E. Medland

doi:10.1038/nature14101

Common genetic variants influence human subcortical brain structures

Derrek P. Hibar, Jason L. Stein, Miguel E. Renteria, Alejandro Arias-Vasquez, Sylvane Desrivieres, Neda Jahanshad, Roberto Toro, Katharina Wittfeld, Lucija Abramovic, Micael Andersson, Benjamin S. Aribisala, Nicola J. Armstrong, Manon Bernard, Marc M. Bohlken, Marco P. Boks, Janita Bralten, Andrew A. Brown, M. Mallar Chakravarty, Qiang Chen, Christopher R. K. ChingGabriel Cuellar-Partida, Anouk den Braber, Sudheer Giddaluru, Aaron L. Goldman, Oliver Grimm, Tulio Guadalupe, Johanna Hass, Girma Woldehawariat, Avram J. Holmes, Martine Hoogman, Deborah Janowitz, Tianye Jia, Sungeun Kim, Marieke Klein, Bernd Kraemer, Phil H. Lee, Loes M. Olde Loohuis, Michelle Luciano, Christine Macare, Karen A. Mather, Manuel Mattheisen, Yuri Milaneschi, Kwangsik Nho, Martina Papmeyer, Adaikalavan Ramasamy, Shannon L. Risacher, Roberto Roiz-Santianez, Emma J. Rose, Alireza Salami, Philipp G. Saemann, Lianne Schmaal, Andrew J. Schork, Jean Shin, Lachlan T. Strike, Alexander Teumer, Marjolein M. J. van Donkelaar, Kristel R. van Eijk, Raymond K. Walters, Lars T. Westlye, Christopher D. Whelan, Anderson M. Winkler, Marcel P. Zwiers, Saud Alhusaini, Lavinia Athanasiu, Stefan Ehrlich, Marina M. H. Hakobjan, Cecilie B. Hartberg, Unn K. Haukvik, Angelien J. G. A. M. Heister, David Hoehn, Dalia Kasperaviciute, David C. M. Liewald, Lorna M. Lopez, Remco R. R. Makkinje, Mar Matarin, Marlies A. M. Naber, D. Reese McKay, Margaret Needham, Allison C. Nugent, Benno Puetz, Natalie A. Royle, Li Shen, Emma Sprooten, Daniah Trabzuni, Saskia S. L. van der Marel, Kimm J. E. van Hulzen, Esther Walton, Christiane Wolf, Laura Almasy, David Ames, Sampath Arepalli, Amelia A. Assareh, Mark E. Bastin, Henry Brodaty, Kazima B. Bulayeva, Melanie A. Carless, Sven Cichon, Aiden Corvin, Joanne E. Curran, Michael Czisch, Greig I. de Zubicaray, Allissa Dillman, Ravi Duggirala, Thomas D. Dyer, Susanne Erk, Iryna O. Fedko, Luigi Ferrucci, Tatiana M. Foroud, Peter T. Fox, Masaki Fukunaga, J. Raphael Gibbs, Harald H. H. Goering, Robert C. Green, Sebastian Guelfi, Narelle K. Hansell, Catharina A. Hartman, Katrin Hegenscheid, Andreas Heinz, Dena G. Hernandez, Dirk J. Heslenfeld, Pieter J. Hoekstra, Florian Holsboer, Georg Homuth, Jouke-Jan Hottenga, Masashi Ikeda, Clifford R., Jr. Jack, Mark Jenkinson, Robert Johnson, Ryota Kanai, Maria Keil, Jack W., Jr. Kent, Peter Kochunov, John B. Kwok, Stephen M. Lawrie, Xinmin Liu, Dan L. Longo, Katie L. McMahon, Eva Meisenzah, Ingrid Melle, Sebastian Mahnke, Grant W. Montgomery, Jeanette C. Mostert, Thomas W. Muehleisen, Michael A. Nalls, Thomas E. Nichols, Lars G. Nilsson, Markus M. Noethen, Kazutaka Ohi, Rene L. Olvera, Rocio Perez-Iglesias, G. Bruce Pike, Steven G. Potkin, Ivar Reinvang, Simone Reppermund, Marcella Rietschel, Nina Romanczuk-Seiferth, Glenn D. Rosen, Dan Rujescu, Knut Schnell, Peter R. Schofield, Colin Smith, Vidar M. Steen, Jessika E. Sussmann, Anbupalam Thalamuthu, Arthur W. Toga, Bryan J. Traynor, Juan Troncoso, Jessica A. Turner, Maria C. Valdes Hernandez, Dennis van't Ent, Marcel van der Brug, Nic J. A. van der Wee, Marie-Jose van Tol, Dick J. Veltman, Thomas H. Wassink, Eric Westman, Ronald H. Zielke, Alan B. Zonderman, David G. Ashbrook, Reinmar Hager, Lu Lu, Francis J. McMahon, Derek W. Morris, Robert W. Williams, Han G. Brunner, Randy L. Buckner, Jan K. Buitelaar, Wiepke Cahn, Vince D. Calhoun, Gianpiero L. Cavalleri, Benedicto Crespo-Facorro, Anders M. Dale, Gareth E. Davies, Norman Delanty, Chantal Depondt, Srdjan Djurovic, Wayne C. Drevets, Thomas Espeseth, Randy L. Gollub, Beng-Choon Ho, Wolfgang Hoffman, Norbert Hosten, Rene S. Kahn, Stephanie Le Hellard, Andreas Meyer-Lindenberg, Bertram Mueller-Myhsok, Matthias Nauck, Lars Nyberg, Massimo Pandolfo, Brenda W. J. H. Penninx, Joshua L. Roffman, Sanjay M. Sisodiya, Jordan W. Smoller, Hans van Bokhoven, Neeltje E. M. van Haren, Henry Voelzke, Henrik Walter, Michael W. Weiner, Wei Wen, Tonya White, Ingrid Agartz, Ole A. Andreassen, John Blangero, Dorret I. Boomsma, Rachel M. Brouwer, Dara M. Cannon, Mark R. Cookson, Eco J. C. de Geus, Ian J. Deary, Gary Donohoe, Guillen Fernandez, Simon E. Fisher, Clyde Francks, David C. Glahn, Hans J. Grabe, Oliver Gruber, John Hardy, Ryota Hashimoto, Hilleke E. Hulshoff Pol, Erik G. Jönsson, Iwona Kloszewska, Simon Lovestone, Venkata S. Mattay, Patrizia Mecocci, Colm McDonald, Andrew M. McIntosh, Roel A. Ophoff, Tomas Paus, Zdenka Pausova, Mina Ryten, Perminder S. Sachdev, Andrew J. Saykin, Andy Simmons, Andrew Singleton, Hilkka Soininen, Joanna M. Wardlaw, Michael E. Weale, Daniel R. Weinberger, Hieab H. H. Adams, Lenore J. Launer, Stephan Seiler, Reinhold Schmidt, Ganesh Chauhan, Claudia L. Satizabal, James T. Becker, Lisa Yanek, Sven J. van der Lee, Maritza Ebling, Bruce Fischl, W. T., Jr. Longstreth, Douglas Greve, Helena Schmidt, Paul Nyquist, Louis N. Vinke, Cornelia M. van Duijn, Luting Xue, Bernard Mazoyer, Joshua C. Bis, Vilmundur Gudnason, Sudha Seshadri, M. Arfan Ikram, Nicholas G. Martin, Margaret J. Wright, Gunter Schumann, Barbara Franke, Paul M., Jr. Thompson^*, Sarah E. Medland

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

478 Citations (Web of Science)

Abstract

The highly complex structure of the human brain is strongly shaped by genetic influences(1). Subcortical brain regions form circuits with cortical areas to coordinate movement(2), learning, memory(3) and motivation(4), and altered circuits can lead to abnormal behaviour and disease(5). To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume(5) and intracranial volume(6). These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 X 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

Original language	English
Pages (from-to)	224-U216
Journal	Nature
Volume	520
Issue number	7546
DOIs	https://doi.org/10.1038/nature14101
Publication status	Published - 9 Apr 2015

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10.1038/nature14101

Cite this

Hibar, D. P., Stein, J. L., Renteria, M. E., Arias-Vasquez, A., Desrivieres, S., Jahanshad, N., Toro, R., Wittfeld, K., Abramovic, L., Andersson, M., Aribisala, B. S., Armstrong, N. J., Bernard, M., Bohlken, M. M., Boks, M. P., Bralten, J., Brown, A. A., Chakravarty, M. M., Chen, Q., ... Medland, S. E. (2015). Common genetic variants influence human subcortical brain structures. Nature, 520(7546), 224-U216. https://doi.org/10.1038/nature14101

@article{02e6c9295e6a4be7bf2e808146433afb,

title = "Common genetic variants influence human subcortical brain structures",

abstract = "The highly complex structure of the human brain is strongly shaped by genetic influences(1). Subcortical brain regions form circuits with cortical areas to coordinate movement(2), learning, memory(3) and motivation(4), and altered circuits can lead to abnormal behaviour and disease(5). To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume(5) and intracranial volume(6). These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 X 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.",

author = "Hibar, {Derrek P.} and Stein, {Jason L.} and Renteria, {Miguel E.} and Alejandro Arias-Vasquez and Sylvane Desrivieres and Neda Jahanshad and Roberto Toro and Katharina Wittfeld and Lucija Abramovic and Micael Andersson and Aribisala, {Benjamin S.} and Armstrong, {Nicola J.} and Manon Bernard and Bohlken, {Marc M.} and Boks, {Marco P.} and Janita Bralten and Brown, {Andrew A.} and Chakravarty, {M. Mallar} and Qiang Chen and Ching, {Christopher R. K.} and Gabriel Cuellar-Partida and {den Braber}, Anouk and Sudheer Giddaluru and Goldman, {Aaron L.} and Oliver Grimm and Tulio Guadalupe and Johanna Hass and Girma Woldehawariat and Holmes, {Avram J.} and Martine Hoogman and Deborah Janowitz and Tianye Jia and Sungeun Kim and Marieke Klein and Bernd Kraemer and Lee, {Phil H.} and Loohuis, {Loes M. Olde} and Michelle Luciano and Christine Macare and Mather, {Karen A.} and Manuel Mattheisen and Yuri Milaneschi and Kwangsik Nho and Martina Papmeyer and Adaikalavan Ramasamy and Risacher, {Shannon L.} and Roberto Roiz-Santianez and Rose, {Emma J.} and Alireza Salami and Saemann, {Philipp G.} and Lianne Schmaal and Schork, {Andrew J.} and Jean Shin and Strike, {Lachlan T.} and Alexander Teumer and {van Donkelaar}, {Marjolein M. J.} and {van Eijk}, {Kristel R.} and Walters, {Raymond K.} and Westlye, {Lars T.} and Whelan, {Christopher D.} and Winkler, {Anderson M.} and Zwiers, {Marcel P.} and Saud Alhusaini and Lavinia Athanasiu and Stefan Ehrlich and Hakobjan, {Marina M. H.} and Hartberg, {Cecilie B.} and Haukvik, {Unn K.} and Heister, {Angelien J. G. A. M.} and David Hoehn and Dalia Kasperaviciute and Liewald, {David C. M.} and Lopez, {Lorna M.} and Makkinje, {Remco R. R.} and Mar Matarin and Naber, {Marlies A. M.} and McKay, {D. Reese} and Margaret Needham and Nugent, {Allison C.} and Benno Puetz and Royle, {Natalie A.} and Li Shen and Emma Sprooten and Daniah Trabzuni and {van der Marel}, {Saskia S. L.} and {van Hulzen}, {Kimm J. E.} and Esther Walton and Christiane Wolf and Laura Almasy and David Ames and Sampath Arepalli and Assareh, {Amelia A.} and Bastin, {Mark E.} and Henry Brodaty and Bulayeva, {Kazima B.} and Carless, {Melanie A.} and Sven Cichon and Aiden Corvin and Curran, {Joanne E.} and Michael Czisch and {de Zubicaray}, {Greig I.} and Allissa Dillman and Ravi Duggirala and Dyer, {Thomas D.} and Susanne Erk and Fedko, {Iryna O.} and Luigi Ferrucci and Foroud, {Tatiana M.} and Fox, {Peter T.} and Masaki Fukunaga and Gibbs, {J. Raphael} and Goering, {Harald H. H.} and Green, {Robert C.} and Sebastian Guelfi and Hansell, {Narelle K.} and Hartman, {Catharina A.} and Katrin Hegenscheid and Andreas Heinz and Hernandez, {Dena G.} and Heslenfeld, {Dirk J.} and Hoekstra, {Pieter J.} and Florian Holsboer and Georg Homuth and Jouke-Jan Hottenga and Masashi Ikeda and Jack, {Clifford R., Jr.} and Mark Jenkinson and Robert Johnson and Ryota Kanai and Maria Keil and Kent, {Jack W., Jr.} and Peter Kochunov and Kwok, {John B.} and Lawrie, {Stephen M.} and Xinmin Liu and Longo, {Dan L.} and McMahon, {Katie L.} and Eva Meisenzah and Ingrid Melle and Sebastian Mahnke and Montgomery, {Grant W.} and Mostert, {Jeanette C.} and Muehleisen, {Thomas W.} and Nalls, {Michael A.} and Nichols, {Thomas E.} and Nilsson, {Lars G.} and Noethen, {Markus M.} and Kazutaka Ohi and Olvera, {Rene L.} and Rocio Perez-Iglesias and Pike, {G. Bruce} and Potkin, {Steven G.} and Ivar Reinvang and Simone Reppermund and Marcella Rietschel and Nina Romanczuk-Seiferth and Rosen, {Glenn D.} and Dan Rujescu and Knut Schnell and Schofield, {Peter R.} and Colin Smith and Steen, {Vidar M.} and Sussmann, {Jessika E.} and Anbupalam Thalamuthu and Toga, {Arthur W.} and Traynor, {Bryan J.} and Juan Troncoso and Turner, {Jessica A.} and {Valdes Hernandez}, {Maria C.} and {van't Ent}, Dennis and {van der Brug}, Marcel and {van der Wee}, {Nic J. A.} and {van Tol}, Marie-Jose and Veltman, {Dick J.} and Wassink, {Thomas H.} and Eric Westman and Zielke, {Ronald H.} and Zonderman, {Alan B.} and Ashbrook, {David G.} and Reinmar Hager and Lu Lu and McMahon, {Francis J.} and Morris, {Derek W.} and Williams, {Robert W.} and Brunner, {Han G.} and Buckner, {Randy L.} and Buitelaar, {Jan K.} and Wiepke Cahn and Calhoun, {Vince D.} and Cavalleri, {Gianpiero L.} and Benedicto Crespo-Facorro and Dale, {Anders M.} and Davies, {Gareth E.} and Norman Delanty and Chantal Depondt and Srdjan Djurovic and Drevets, {Wayne C.} and Thomas Espeseth and Gollub, {Randy L.} and Beng-Choon Ho and Wolfgang Hoffman and Norbert Hosten and Kahn, {Rene S.} and {Le Hellard}, Stephanie and Andreas Meyer-Lindenberg and Bertram Mueller-Myhsok and Matthias Nauck and Lars Nyberg and Massimo Pandolfo and Penninx, {Brenda W. J. H.} and Roffman, {Joshua L.} and Sisodiya, {Sanjay M.} and Smoller, {Jordan W.} and {van Bokhoven}, Hans and {van Haren}, {Neeltje E. M.} and Henry Voelzke and Henrik Walter and Weiner, {Michael W.} and Wei Wen and Tonya White and Ingrid Agartz and Andreassen, {Ole A.} and John Blangero and Boomsma, {Dorret I.} and Brouwer, {Rachel M.} and Cannon, {Dara M.} and Cookson, {Mark R.} and {de Geus}, {Eco J. C.} and Deary, {Ian J.} and Gary Donohoe and Guillen Fernandez and Fisher, {Simon E.} and Clyde Francks and Glahn, {David C.} and Grabe, {Hans J.} and Oliver Gruber and John Hardy and Ryota Hashimoto and Pol, {Hilleke E. Hulshoff} and J{\"o}nsson, {Erik G.} and Iwona Kloszewska and Simon Lovestone and Mattay, {Venkata S.} and Patrizia Mecocci and Colm McDonald and McIntosh, {Andrew M.} and Ophoff, {Roel A.} and Tomas Paus and Zdenka Pausova and Mina Ryten and Sachdev, {Perminder S.} and Saykin, {Andrew J.} and Andy Simmons and Andrew Singleton and Hilkka Soininen and Wardlaw, {Joanna M.} and Weale, {Michael E.} and Weinberger, {Daniel R.} and Adams, {Hieab H. H.} and Launer, {Lenore J.} and Stephan Seiler and Reinhold Schmidt and Ganesh Chauhan and Satizabal, {Claudia L.} and Becker, {James T.} and Lisa Yanek and {van der Lee}, {Sven J.} and Maritza Ebling and Bruce Fischl and Longstreth, {W. T., Jr.} and Douglas Greve and Helena Schmidt and Paul Nyquist and Vinke, {Louis N.} and {van Duijn}, {Cornelia M.} and Luting Xue and Bernard Mazoyer and Bis, {Joshua C.} and Vilmundur Gudnason and Sudha Seshadri and Ikram, {M. Arfan} and Martin, {Nicholas G.} and Wright, {Margaret J.} and Gunter Schumann and Barbara Franke and Thompson, {Paul M., Jr.} and Medland, {Sarah E.}",

year = "2015",

month = apr,

day = "9",

doi = "10.1038/nature14101",

language = "English",

volume = "520",

pages = "224--U216",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7546",

}

Hibar, DP, Stein, JL, Renteria, ME, Arias-Vasquez, A, Desrivieres, S, Jahanshad, N, Toro, R, Wittfeld, K, Abramovic, L, Andersson, M, Aribisala, BS, Armstrong, NJ, Bernard, M, Bohlken, MM, Boks, MP, Bralten, J, Brown, AA, Chakravarty, MM, Chen, Q, Ching, CRK, Cuellar-Partida, G, den Braber, A, Giddaluru, S, Goldman, AL, Grimm, O, Guadalupe, T, Hass, J, Woldehawariat, G, Holmes, AJ, Hoogman, M, Janowitz, D, Jia, T, Kim, S, Klein, M, Kraemer, B, Lee, PH, Loohuis, LMO, Luciano, M, Macare, C, Mather, KA, Mattheisen, M, Milaneschi, Y, Nho, K, Papmeyer, M, Ramasamy, A, Risacher, SL, Roiz-Santianez, R, Rose, EJ, Salami, A, Saemann, PG, Schmaal, L, Schork, AJ, Shin, J, Strike, LT, Teumer, A, van Donkelaar, MMJ, van Eijk, KR, Walters, RK, Westlye, LT, Whelan, CD, Winkler, AM, Zwiers, MP, Alhusaini, S, Athanasiu, L, Ehrlich, S, Hakobjan, MMH, Hartberg, CB, Haukvik, UK, Heister, AJGAM, Hoehn, D, Kasperaviciute, D, Liewald, DCM, Lopez, LM, Makkinje, RRR, Matarin, M, Naber, MAM, McKay, DR, Needham, M, Nugent, AC, Puetz, B, Royle, NA, Shen, L, Sprooten, E, Trabzuni, D, van der Marel, SSL, van Hulzen, KJE, Walton, E, Wolf, C, Almasy, L, Ames, D, Arepalli, S, Assareh, AA, Bastin, ME, Brodaty, H, Bulayeva, KB, Carless, MA, Cichon, S, Corvin, A, Curran, JE, Czisch, M, de Zubicaray, GI, Dillman, A, Duggirala, R, Dyer, TD, Erk, S, Fedko, IO, Ferrucci, L, Foroud, TM, Fox, PT, Fukunaga, M, Gibbs, JR, Goering, HHH, Green, RC, Guelfi, S, Hansell, NK, Hartman, CA, Hegenscheid, K, Heinz, A, Hernandez, DG, Heslenfeld, DJ, Hoekstra, PJ, Holsboer, F, Homuth, G, Hottenga, J-J, Ikeda, M, Jack, CRJ, Jenkinson, M, Johnson, R, Kanai, R, Keil, M, Kent, JWJ, Kochunov, P, Kwok, JB, Lawrie, SM, Liu, X, Longo, DL, McMahon, KL, Meisenzah, E, Melle, I, Mahnke, S, Montgomery, GW, Mostert, JC, Muehleisen, TW, Nalls, MA, Nichols, TE, Nilsson, LG, Noethen, MM, Ohi, K, Olvera, RL, Perez-Iglesias, R, Pike, GB, Potkin, SG, Reinvang, I, Reppermund, S, Rietschel, M, Romanczuk-Seiferth, N, Rosen, GD, Rujescu, D, Schnell, K, Schofield, PR, Smith, C, Steen, VM, Sussmann, JE, Thalamuthu, A, Toga, AW, Traynor, BJ, Troncoso, J, Turner, JA, Valdes Hernandez, MC, van't Ent, D, van der Brug, M, van der Wee, NJA, van Tol, M-J, Veltman, DJ, Wassink, TH, Westman, E, Zielke, RH, Zonderman, AB, Ashbrook, DG, Hager, R, Lu, L, McMahon, FJ, Morris, DW, Williams, RW, Brunner, HG, Buckner, RL, Buitelaar, JK, Cahn, W, Calhoun, VD, Cavalleri, GL, Crespo-Facorro, B, Dale, AM, Davies, GE, Delanty, N, Depondt, C, Djurovic, S, Drevets, WC, Espeseth, T, Gollub, RL, Ho, B-C, Hoffman, W, Hosten, N, Kahn, RS, Le Hellard, S, Meyer-Lindenberg, A, Mueller-Myhsok, B, Nauck, M, Nyberg, L, Pandolfo, M, Penninx, BWJH, Roffman, JL, Sisodiya, SM, Smoller, JW, van Bokhoven, H, van Haren, NEM, Voelzke, H, Walter, H, Weiner, MW, Wen, W, White, T, Agartz, I, Andreassen, OA, Blangero, J, Boomsma, DI, Brouwer, RM, Cannon, DM, Cookson, MR, de Geus, EJC, Deary, IJ, Donohoe, G, Fernandez, G, Fisher, SE, Francks, C, Glahn, DC, Grabe, HJ, Gruber, O, Hardy, J, Hashimoto, R, Pol, HEH, Jönsson, EG, Kloszewska, I, Lovestone, S, Mattay, VS, Mecocci, P, McDonald, C, McIntosh, AM, Ophoff, RA, Paus, T, Pausova, Z, Ryten, M, Sachdev, PS, Saykin, AJ, Simmons, A, Singleton, A, Soininen, H, Wardlaw, JM, Weale, ME, Weinberger, DR, Adams, HHH, Launer, LJ, Seiler, S, Schmidt, R, Chauhan, G, Satizabal, CL, Becker, JT, Yanek, L, van der Lee, SJ, Ebling, M, Fischl, B, Longstreth, WTJ, Greve, D, Schmidt, H, Nyquist, P, Vinke, LN, van Duijn, CM, Xue, L, Mazoyer, B, Bis, JC, Gudnason, V, Seshadri, S, Ikram, MA, Martin, NG, Wright, MJ, Schumann, G, Franke, B, Thompson, PMJ & Medland, SE 2015, 'Common genetic variants influence human subcortical brain structures', Nature, vol. 520, no. 7546, pp. 224-U216. https://doi.org/10.1038/nature14101

TY - JOUR

T1 - Common genetic variants influence human subcortical brain structures

AU - Hibar, Derrek P.

AU - Stein, Jason L.

AU - Renteria, Miguel E.

AU - Arias-Vasquez, Alejandro

AU - Desrivieres, Sylvane

AU - Jahanshad, Neda

AU - Toro, Roberto

AU - Wittfeld, Katharina

AU - Abramovic, Lucija

AU - Andersson, Micael

AU - Aribisala, Benjamin S.

AU - Armstrong, Nicola J.

AU - Bernard, Manon

AU - Bohlken, Marc M.

AU - Boks, Marco P.

AU - Bralten, Janita

AU - Brown, Andrew A.

AU - Chakravarty, M. Mallar

AU - Chen, Qiang

AU - Ching, Christopher R. K.

AU - Cuellar-Partida, Gabriel

AU - den Braber, Anouk

AU - Giddaluru, Sudheer

AU - Goldman, Aaron L.

AU - Grimm, Oliver

AU - Guadalupe, Tulio

AU - Hass, Johanna

AU - Woldehawariat, Girma

AU - Holmes, Avram J.

AU - Hoogman, Martine

AU - Janowitz, Deborah

AU - Jia, Tianye

AU - Kim, Sungeun

AU - Klein, Marieke

AU - Kraemer, Bernd

AU - Lee, Phil H.

AU - Loohuis, Loes M. Olde

AU - Luciano, Michelle

AU - Macare, Christine

AU - Mather, Karen A.

AU - Mattheisen, Manuel

AU - Milaneschi, Yuri

AU - Nho, Kwangsik

AU - Papmeyer, Martina

AU - Ramasamy, Adaikalavan

AU - Risacher, Shannon L.

AU - Roiz-Santianez, Roberto

AU - Rose, Emma J.

AU - Salami, Alireza

AU - Saemann, Philipp G.

AU - Schmaal, Lianne

AU - Schork, Andrew J.

AU - Shin, Jean

AU - Strike, Lachlan T.

AU - Teumer, Alexander

AU - van Donkelaar, Marjolein M. J.

AU - van Eijk, Kristel R.

AU - Walters, Raymond K.

AU - Westlye, Lars T.

AU - Whelan, Christopher D.

AU - Winkler, Anderson M.

AU - Zwiers, Marcel P.

AU - Alhusaini, Saud

AU - Athanasiu, Lavinia

AU - Ehrlich, Stefan

AU - Hakobjan, Marina M. H.

AU - Hartberg, Cecilie B.

AU - Haukvik, Unn K.

AU - Heister, Angelien J. G. A. M.

AU - Hoehn, David

AU - Kasperaviciute, Dalia

AU - Liewald, David C. M.

AU - Lopez, Lorna M.

AU - Makkinje, Remco R. R.

AU - Matarin, Mar

AU - Naber, Marlies A. M.

AU - McKay, D. Reese

AU - Needham, Margaret

AU - Nugent, Allison C.

AU - Puetz, Benno

AU - Royle, Natalie A.

AU - Shen, Li

AU - Sprooten, Emma

AU - Trabzuni, Daniah

AU - van der Marel, Saskia S. L.

AU - van Hulzen, Kimm J. E.

AU - Walton, Esther

AU - Wolf, Christiane

AU - Almasy, Laura

AU - Ames, David

AU - Arepalli, Sampath

AU - Assareh, Amelia A.

AU - Bastin, Mark E.

AU - Brodaty, Henry

AU - Bulayeva, Kazima B.

AU - Carless, Melanie A.

AU - Cichon, Sven

AU - Corvin, Aiden

AU - Curran, Joanne E.

AU - Czisch, Michael

AU - de Zubicaray, Greig I.

AU - Dillman, Allissa

AU - Duggirala, Ravi

AU - Dyer, Thomas D.

AU - Erk, Susanne

AU - Fedko, Iryna O.

AU - Ferrucci, Luigi

AU - Foroud, Tatiana M.

AU - Fox, Peter T.

AU - Fukunaga, Masaki

AU - Gibbs, J. Raphael

AU - Goering, Harald H. H.

AU - Green, Robert C.

AU - Guelfi, Sebastian

AU - Hansell, Narelle K.

AU - Hartman, Catharina A.

AU - Hegenscheid, Katrin

AU - Heinz, Andreas

AU - Hernandez, Dena G.

AU - Heslenfeld, Dirk J.

AU - Hoekstra, Pieter J.

AU - Holsboer, Florian

AU - Homuth, Georg

AU - Hottenga, Jouke-Jan

AU - Ikeda, Masashi

AU - Jack, Clifford R., Jr.

AU - Jenkinson, Mark

AU - Johnson, Robert

AU - Kanai, Ryota

AU - Keil, Maria

AU - Kent, Jack W., Jr.

AU - Kochunov, Peter

AU - Kwok, John B.

AU - Lawrie, Stephen M.

AU - Liu, Xinmin

AU - Longo, Dan L.

AU - McMahon, Katie L.

AU - Meisenzah, Eva

AU - Melle, Ingrid

AU - Mahnke, Sebastian

AU - Montgomery, Grant W.

AU - Mostert, Jeanette C.

AU - Muehleisen, Thomas W.

AU - Nalls, Michael A.

AU - Nichols, Thomas E.

AU - Nilsson, Lars G.

AU - Noethen, Markus M.

AU - Ohi, Kazutaka

AU - Olvera, Rene L.

AU - Perez-Iglesias, Rocio

AU - Pike, G. Bruce

AU - Potkin, Steven G.

AU - Reinvang, Ivar

AU - Reppermund, Simone

AU - Rietschel, Marcella

AU - Romanczuk-Seiferth, Nina

AU - Rosen, Glenn D.

AU - Rujescu, Dan

AU - Schnell, Knut

AU - Schofield, Peter R.

AU - Smith, Colin

AU - Steen, Vidar M.

AU - Sussmann, Jessika E.

AU - Thalamuthu, Anbupalam

AU - Toga, Arthur W.

AU - Traynor, Bryan J.

AU - Troncoso, Juan

AU - Turner, Jessica A.

AU - Valdes Hernandez, Maria C.

AU - van't Ent, Dennis

AU - van der Brug, Marcel

AU - van der Wee, Nic J. A.

AU - van Tol, Marie-Jose

AU - Veltman, Dick J.

AU - Wassink, Thomas H.

AU - Westman, Eric

AU - Zielke, Ronald H.

AU - Zonderman, Alan B.

AU - Ashbrook, David G.

AU - Hager, Reinmar

AU - Lu, Lu

AU - McMahon, Francis J.

AU - Morris, Derek W.

AU - Williams, Robert W.

AU - Brunner, Han G.

AU - Buckner, Randy L.

AU - Buitelaar, Jan K.

AU - Cahn, Wiepke

AU - Calhoun, Vince D.

AU - Cavalleri, Gianpiero L.

AU - Crespo-Facorro, Benedicto

AU - Dale, Anders M.

AU - Davies, Gareth E.

AU - Delanty, Norman

AU - Depondt, Chantal

AU - Djurovic, Srdjan

AU - Drevets, Wayne C.

AU - Espeseth, Thomas

AU - Gollub, Randy L.

AU - Ho, Beng-Choon

AU - Hoffman, Wolfgang

AU - Hosten, Norbert

AU - Kahn, Rene S.

AU - Le Hellard, Stephanie

AU - Meyer-Lindenberg, Andreas

AU - Mueller-Myhsok, Bertram

AU - Nauck, Matthias

AU - Nyberg, Lars

AU - Pandolfo, Massimo

AU - Penninx, Brenda W. J. H.

AU - Roffman, Joshua L.

AU - Sisodiya, Sanjay M.

AU - Smoller, Jordan W.

AU - van Bokhoven, Hans

AU - van Haren, Neeltje E. M.

AU - Voelzke, Henry

AU - Walter, Henrik

AU - Weiner, Michael W.

AU - Wen, Wei

AU - White, Tonya

AU - Agartz, Ingrid

AU - Andreassen, Ole A.

AU - Blangero, John

AU - Boomsma, Dorret I.

AU - Brouwer, Rachel M.

AU - Cannon, Dara M.

AU - Cookson, Mark R.

AU - de Geus, Eco J. C.

AU - Deary, Ian J.

AU - Donohoe, Gary

AU - Fernandez, Guillen

AU - Fisher, Simon E.

AU - Francks, Clyde

AU - Glahn, David C.

AU - Grabe, Hans J.

AU - Gruber, Oliver

AU - Hardy, John

AU - Hashimoto, Ryota

AU - Pol, Hilleke E. Hulshoff

AU - Jönsson, Erik G.

AU - Kloszewska, Iwona

AU - Lovestone, Simon

AU - Mattay, Venkata S.

AU - Mecocci, Patrizia

AU - McDonald, Colm

AU - McIntosh, Andrew M.

AU - Ophoff, Roel A.

AU - Paus, Tomas

AU - Pausova, Zdenka

AU - Ryten, Mina

AU - Sachdev, Perminder S.

AU - Saykin, Andrew J.

AU - Simmons, Andy

AU - Singleton, Andrew

AU - Soininen, Hilkka

AU - Wardlaw, Joanna M.

AU - Weale, Michael E.

AU - Weinberger, Daniel R.

AU - Adams, Hieab H. H.

AU - Launer, Lenore J.

AU - Seiler, Stephan

AU - Schmidt, Reinhold

AU - Chauhan, Ganesh

AU - Satizabal, Claudia L.

AU - Becker, James T.

AU - Yanek, Lisa

AU - van der Lee, Sven J.

AU - Ebling, Maritza

AU - Fischl, Bruce

AU - Longstreth, W. T., Jr.

AU - Greve, Douglas

AU - Schmidt, Helena

AU - Nyquist, Paul

AU - Vinke, Louis N.

AU - van Duijn, Cornelia M.

AU - Xue, Luting

AU - Mazoyer, Bernard

AU - Bis, Joshua C.

AU - Gudnason, Vilmundur

AU - Seshadri, Sudha

AU - Ikram, M. Arfan

AU - Martin, Nicholas G.

AU - Wright, Margaret J.

AU - Schumann, Gunter

AU - Franke, Barbara

AU - Thompson, Paul M., Jr.

AU - Medland, Sarah E.

PY - 2015/4/9

Y1 - 2015/4/9

N2 - The highly complex structure of the human brain is strongly shaped by genetic influences(1). Subcortical brain regions form circuits with cortical areas to coordinate movement(2), learning, memory(3) and motivation(4), and altered circuits can lead to abnormal behaviour and disease(5). To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume(5) and intracranial volume(6). These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 X 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

AB - The highly complex structure of the human brain is strongly shaped by genetic influences(1). Subcortical brain regions form circuits with cortical areas to coordinate movement(2), learning, memory(3) and motivation(4), and altered circuits can lead to abnormal behaviour and disease(5). To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume(5) and intracranial volume(6). These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 X 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

U2 - 10.1038/nature14101

DO - 10.1038/nature14101

M3 - Article

C2 - 25607358

VL - 520

SP - 224-U216

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7546

ER -