Common genetic variants influence human subcortical brain structures

D.P. Hibar, J.L. Stein, M.E. Renteria, A. Arias-Vasquez, S. Desrivières, N. Jahanshad, R. Toro, K. Wittfeld, L. Abramovic, M. Andersson, B.S. Aribisala, N.J. Armstrong, M. Bernard, M.M. Bohlken, M.P. Biks, J. Bralten, A.A. Brown, M.M. Chakravarty, Q. Chen, C.R.K. Ching & 267 others G. Cuellar-Partida, A. den Braber, S. Giddaluru, A.L. Goldman, O. Grimm, T. Guadalupe, J. Hass, G. Woldehawariat, A.J. Holmes, M. Hoogman, D. Janowitz, T. Jia, S. Kim, M. Klein, B. Kraemer, P.H. Lee, L.M. Olde Loohuis, M. Luciano, C. Macare, K.A. Mather, M. Mattheisen, Y. Milaneschi, K. Nho, M. Papmeyer, A. Ramasamy, S.L. Risacher, R. Roiz-Santiañez, E.J. Rose, A. Salami, P.G. Sämann, L. Schmaal, A.J. Schork, J. Shin, L.T. Strike, A. Teumer, M.M.J. Donkelaar, K.R. van Eijk, R.K. Walters, L.T. Westlye, C.D. Welan, A.M. Winkler, M.P. Zwiers, S. Alhusaini, L. Athanasiu, S. Ehrlich, M.M.H. Hakobjan, C.B. Hartberg, U.K. Haukvik, A.J.G.A.M. Heister, D. Hoehn, D. Kasperaviciute, D.C.M. Liewald, L.M. Lopez, R.R. Makkinje, M. Matarin, M.A.M. Naber, D. Reese McKay, M. Needham, A.C. Nugent, B. Pütz, N.A. Royle, L. Shen, E. Sprooten, D. Trabzuni, S.S.L. van der Marel, K.J.E. van Hulzen, E. Walton, C. Wolf, L. Almasy, D. Ames, S. Arepalli, A.A. Assareh, M.E. Bastin, H. Brodaty, K.B. Bulayeva, M.A. Carless, S. Cichon, A. Corvin, J.E. Curran, M. Czisch, G.I. de Zubicaray, A. Dillman, R. Duggirala, T.D. Dyer, S. Erk, I.O. Fedko, L. Ferrucci, T.M. Foroud, P.T. Fox, M. Fukunaga, J.R. Gibbs, H.H.H. Göring, R.C. Green, S. Guelfi, N.K. Hansell, C.A. Hartman, K. Hegenscheid, A. Heinz, D.G. Hernandez, D.J. Heslenfeld, P.J. Hoekstra, F. Holsboer, G. Homuth, J.J. Hottenga, M. Ikeda, C.R., Jr. Jack, M. Jenkinson, R. Johnson, R. Kanai, M. Keil, J.W. Jr. Kent, P. Kochunov, J.B. Kwok, S.M. Lawrie, X. Liu, D.L. Longo, K.L. McMahon, E. Meisenzahl, I. Melle, S. Mohnke, G.W. Montgomery, J.C. Mostert, T.W. Mühleisen, M.A. Nalls, T.E. Nichols, L.G. Nilsson, M.M. Nöthen, K. Ohi, R.L. Olvera, R. Perez-Iglesias, G.B. Pike, S.G. Potkin, I. Reinvang, S. Reppermund, M. Rietschel, N. Romanczuk-Seiferth, G.D. Rosen, D. Rujescu, K. Schnell, P.R. Schofield, C. Smith, V.M. Steen, J.E. Sussmann, A. Thalamuthu, A.W. Toga, B.J. Traynor, J. Troncoso, J.A. Turner, M.C. Valdés Hernández, D. van t Ent, M. van der Brug, N.J.A. van der Wee, M.J. van Tol, D.J. Veltman, T.H. Wassink, E. Westmann, R.H. Zielke, A.B. Zonderman, D.G. Ashbrook, R. Hager, L. Lu, F.J. McMahon, D.W. Morris, R.W. Williams, H.G. Brunner, R.L. Buckner, J.K. Buitelaar, W. Cahn, V.D. Calhoun, G.L. Cavalleri, B. Crespo-Facorro, A.M. Dale, G.E. Davies, N. Delanty, C. Depondt, S. Djurovic, W.C. Drevets, T. Espeseth, R.L. Gollub, B.C. Ho, W. Hoffmann, N. Hosten, R.S. Kahn, S. Le Hellard, A. Meyer-Lindenberg, B. Müller-Myhsok, M. Nauck, L. Nyberg, M. Pandolfo, B.W.J.H. Penninx, J.L. Roffman, SM Sisodiya, J.W. Smoller, H. van Bokhoven, N.E.M. van Haren, H. Völzke, H. Walter, M.W. Weiner, W. Wen, T. White, I. Agartz, O.A. Andreassen, J. Blangero, D.I. Boomsma, R.M. Brouwer, D.M. Cannon, M.R. Cookson, E.J.C. de Geus, I.J. Deary, G. Donohoe, G. Fernandez, S.E. Fisher, C. Francks, D.C. Glahn, H.J. Grabe, O. Gruber, J. Hardy, R. Hashimoto, H.E. Hulshoff Pol, E.G. Jönsson, I. Kloszewska, S. Lovestone, V.S. Mattay, P. Mecocci, C. McDonald, A.M. McIntosh, R.A. Ophoff, T. Paus, Z. Pausova, M. Ryten, P.S. Sachdev, A.J. Saykin, A. Simmons, A. Singleton, H. Soininen, J.M. Wardlaw, M.E. Weale, D.R. Weinberger, H.H.H. Adams, L.J. Launer, S. Seiler, R. Schmidt, G. Chauhan, C.L. Satizabal, J.T. Becker, L. Yanek, S.J. van der Lee, M. Ebling, B. Fischl, Jr. W.T. Longstreth, D. Greve, H. Schmidt, P. Nyquist, L.N. Vinke, C.M. van Duijn, L. Xue, B. Mazoyer, J.C. Bis, V. Gudnason, S. Seshadri, M. Arfan Ikram, N.G. Martin, M.J. Wright, G. Schumann, B. Franke, P.M. Thompson, S.E. Medland

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. 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 and intracranial volume. 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 = 1.08×10 -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 languageEnglish
Pages (from-to)224-229
Number of pages6
JournalNature
Volume520
Issue number7546
DOIs
Publication statusPublished - 2015

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Putamen
Brain
Developmental Genes
Transport Vesicles
Caudate Nucleus
Genome-Wide Association Study
Human Development
Motivation
Magnetic Resonance Spectroscopy
Learning
Apoptosis
Gene Expression

Cite this

Hibar, D. P., Stein, J. L., Renteria, M. E., Arias-Vasquez, A., Desrivières, S., Jahanshad, N., ... Medland, S. E. (2015). Common genetic variants influence human subcortical brain structures. Nature, 520(7546), 224-229. https://doi.org/10.1038/nature14101
Hibar, D.P. ; Stein, J.L. ; Renteria, M.E. ; Arias-Vasquez, A. ; Desrivières, S. ; Jahanshad, N. ; Toro, R. ; Wittfeld, K. ; Abramovic, L. ; Andersson, M. ; Aribisala, B.S. ; Armstrong, N.J. ; Bernard, M. ; Bohlken, M.M. ; Biks, M.P. ; Bralten, J. ; Brown, A.A. ; Chakravarty, M.M. ; Chen, Q. ; Ching, C.R.K. ; Cuellar-Partida, G. ; den Braber, A. ; Giddaluru, S. ; Goldman, A.L. ; Grimm, O. ; Guadalupe, T. ; Hass, J. ; Woldehawariat, G. ; Holmes, A.J. ; Hoogman, M. ; Janowitz, D. ; Jia, T. ; Kim, S. ; Klein, M. ; Kraemer, B. ; Lee, P.H. ; Olde Loohuis, L.M. ; Luciano, M. ; Macare, C. ; Mather, K.A. ; Mattheisen, M. ; Milaneschi, Y. ; Nho, K. ; Papmeyer, M. ; Ramasamy, A. ; Risacher, S.L. ; Roiz-Santiañez, R. ; Rose, E.J. ; Salami, A. ; Sämann, P.G. ; Schmaal, L. ; Schork, A.J. ; Shin, J. ; Strike, L.T. ; Teumer, A. ; Donkelaar, M.M.J. ; van Eijk, K.R. ; Walters, R.K. ; Westlye, L.T. ; Welan, C.D. ; Winkler, A.M. ; Zwiers, M.P. ; Alhusaini, S. ; Athanasiu, L. ; Ehrlich, S. ; Hakobjan, M.M.H. ; Hartberg, C.B. ; Haukvik, U.K. ; Heister, A.J.G.A.M. ; Hoehn, D. ; Kasperaviciute, D. ; Liewald, D.C.M. ; Lopez, L.M. ; Makkinje, R.R. ; Matarin, M. ; Naber, M.A.M. ; Reese McKay, D. ; Needham, M. ; Nugent, A.C. ; Pütz, B. ; Royle, N.A. ; Shen, L. ; Sprooten, E. ; Trabzuni, D. ; van der Marel, S.S.L. ; van Hulzen, K.J.E. ; Walton, E. ; Wolf, C. ; Almasy, L. ; Ames, D. ; Arepalli, S. ; Assareh, A.A. ; Bastin, M.E. ; Brodaty, H. ; Bulayeva, K.B. ; Carless, M.A. ; Cichon, S. ; Corvin, A. ; Curran, J.E. ; Czisch, M. ; de Zubicaray, G.I. ; Dillman, A. ; Duggirala, R. ; Dyer, T.D. ; Erk, S. ; Fedko, I.O. ; Ferrucci, L. ; Foroud, T.M. ; Fox, P.T. ; Fukunaga, M. ; Gibbs, J.R. ; Göring, H.H.H. ; Green, R.C. ; Guelfi, S. ; Hansell, N.K. ; Hartman, C.A. ; Hegenscheid, K. ; Heinz, A. ; Hernandez, D.G. ; Heslenfeld, D.J. ; Hoekstra, P.J. ; Holsboer, F. ; Homuth, G. ; Hottenga, J.J. ; Ikeda, M. ; Jack, C.R., Jr. ; Jenkinson, M. ; Johnson, R. ; Kanai, R. ; Keil, M. ; Kent, J.W. Jr. ; Kochunov, P. ; Kwok, J.B. ; Lawrie, S.M. ; Liu, X. ; Longo, D.L. ; McMahon, K.L. ; Meisenzahl, E. ; Melle, I. ; Mohnke, S. ; Montgomery, G.W. ; Mostert, J.C. ; Mühleisen, T.W. ; Nalls, M.A. ; Nichols, T.E. ; Nilsson, L.G. ; Nöthen, M.M. ; Ohi, K. ; Olvera, R.L. ; Perez-Iglesias, R. ; Pike, G.B. ; Potkin, S.G. ; Reinvang, I. ; Reppermund, S. ; Rietschel, M. ; Romanczuk-Seiferth, N. ; Rosen, G.D. ; Rujescu, D. ; Schnell, K. ; Schofield, P.R. ; Smith, C. ; Steen, V.M. ; Sussmann, J.E. ; Thalamuthu, A. ; Toga, A.W. ; Traynor, B.J. ; Troncoso, J. ; Turner, J.A. ; Valdés Hernández, M.C. ; van t Ent, D. ; van der Brug, M. ; van der Wee, N.J.A. ; van Tol, M.J. ; Veltman, D.J. ; Wassink, T.H. ; Westmann, E. ; Zielke, R.H. ; Zonderman, A.B. ; Ashbrook, D.G. ; Hager, R. ; Lu, L. ; McMahon, F.J. ; Morris, D.W. ; Williams, R.W. ; Brunner, H.G. ; Buckner, R.L. ; Buitelaar, J.K. ; Cahn, W. ; Calhoun, V.D. ; Cavalleri, G.L. ; Crespo-Facorro, B. ; Dale, A.M. ; Davies, G.E. ; Delanty, N. ; Depondt, C. ; Djurovic, S. ; Drevets, W.C. ; Espeseth, T. ; Gollub, R.L. ; Ho, B.C. ; Hoffmann, W. ; Hosten, N. ; Kahn, R.S. ; Le Hellard, S. ; Meyer-Lindenberg, A. ; Müller-Myhsok, B. ; Nauck, M. ; Nyberg, L. ; Pandolfo, M. ; Penninx, B.W.J.H. ; Roffman, J.L. ; Sisodiya, SM ; Smoller, J.W. ; van Bokhoven, H. ; van Haren, N.E.M. ; Völzke, H. ; Walter, H. ; Weiner, M.W. ; Wen, W. ; White, T. ; Agartz, I. ; Andreassen, O.A. ; Blangero, J. ; Boomsma, D.I. ; Brouwer, R.M. ; Cannon, D.M. ; Cookson, M.R. ; de Geus, E.J.C. ; Deary, I.J. ; Donohoe, G. ; Fernandez, G. ; Fisher, S.E. ; Francks, C. ; Glahn, D.C. ; Grabe, H.J. ; Gruber, O. ; Hardy, J. ; Hashimoto, R. ; Hulshoff Pol, H.E. ; Jönsson, E.G. ; Kloszewska, I. ; Lovestone, S. ; Mattay, V.S. ; Mecocci, P. ; McDonald, C. ; McIntosh, A.M. ; Ophoff, R.A. ; Paus, T. ; Pausova, Z. ; Ryten, M. ; Sachdev, P.S. ; Saykin, A.J. ; Simmons, A. ; Singleton, A. ; Soininen, H. ; Wardlaw, J.M. ; Weale, M.E. ; Weinberger, D.R. ; Adams, H.H.H. ; Launer, L.J. ; Seiler, S. ; Schmidt, R. ; Chauhan, G. ; Satizabal, C.L. ; Becker, J.T. ; Yanek, L. ; van der Lee, S.J. ; Ebling, M. ; Fischl, B. ; Longstreth, Jr. W.T. ; Greve, D. ; Schmidt, H. ; Nyquist, P. ; Vinke, L.N. ; van Duijn, C.M. ; Xue, L. ; Mazoyer, B. ; Bis, J.C. ; Gudnason, V. ; Seshadri, S. ; Arfan Ikram, M. ; Martin, N.G. ; Wright, M.J. ; Schumann, G. ; Franke, B. ; Thompson, P.M. ; Medland, S.E. / Common genetic variants influence human subcortical brain structures. In: Nature. 2015 ; Vol. 520, No. 7546. pp. 224-229.
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title = "Common genetic variants influence human subcortical brain structures",
abstract = "The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. 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 and intracranial volume. 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 = 1.08×10 -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 = "D.P. Hibar and J.L. Stein and M.E. Renteria and A. Arias-Vasquez and S. Desrivi{\`e}res and N. Jahanshad and R. Toro and K. Wittfeld and L. Abramovic and M. Andersson and B.S. Aribisala and N.J. Armstrong and M. Bernard and M.M. Bohlken and M.P. Biks and J. Bralten and A.A. Brown and M.M. Chakravarty and Q. Chen and C.R.K. Ching and G. Cuellar-Partida and {den Braber}, A. and S. Giddaluru and A.L. Goldman and O. Grimm and T. Guadalupe and J. Hass and G. Woldehawariat and A.J. Holmes and M. Hoogman and D. Janowitz and T. Jia and S. Kim and M. Klein and B. Kraemer and P.H. Lee and {Olde Loohuis}, L.M. and M. Luciano and C. Macare and K.A. Mather and M. Mattheisen and Y. Milaneschi and K. Nho and M. Papmeyer and A. Ramasamy and S.L. Risacher and R. Roiz-Santia{\~n}ez and E.J. Rose and A. Salami and P.G. S{\"a}mann and L. Schmaal and A.J. Schork and J. Shin and L.T. Strike and A. Teumer and M.M.J. Donkelaar and {van Eijk}, K.R. and R.K. Walters and L.T. Westlye and C.D. Welan and A.M. Winkler and M.P. Zwiers and S. Alhusaini and L. Athanasiu and S. Ehrlich and M.M.H. Hakobjan and C.B. Hartberg and U.K. Haukvik and A.J.G.A.M. Heister and D. Hoehn and D. Kasperaviciute and D.C.M. Liewald and L.M. Lopez and R.R. Makkinje and M. Matarin and M.A.M. Naber and {Reese McKay}, D. and M. Needham and A.C. Nugent and B. P{\"u}tz and N.A. Royle and L. Shen and E. Sprooten and D. Trabzuni and {van der Marel}, S.S.L. and {van Hulzen}, K.J.E. and E. Walton and C. Wolf and L. Almasy and D. Ames and S. Arepalli and A.A. Assareh and M.E. Bastin and H. Brodaty and K.B. Bulayeva and M.A. Carless and S. Cichon and A. Corvin and J.E. Curran and M. Czisch and {de Zubicaray}, G.I. and A. Dillman and R. Duggirala and T.D. Dyer and S. Erk and I.O. Fedko and L. Ferrucci and T.M. Foroud and P.T. Fox and M. Fukunaga and J.R. Gibbs and H.H.H. G{\"o}ring and R.C. Green and S. Guelfi and N.K. Hansell and C.A. Hartman and K. Hegenscheid and A. Heinz and D.G. Hernandez and D.J. Heslenfeld and P.J. Hoekstra and F. Holsboer and G. Homuth and J.J. Hottenga and M. Ikeda and Jack, {C.R., Jr.} and M. Jenkinson and R. Johnson and R. Kanai and M. Keil and Kent, {J.W. Jr.} and P. Kochunov and J.B. Kwok and S.M. Lawrie and X. Liu and D.L. Longo and K.L. McMahon and E. Meisenzahl and I. Melle and S. Mohnke and G.W. Montgomery and J.C. Mostert and T.W. M{\"u}hleisen and M.A. Nalls and T.E. Nichols and L.G. Nilsson and M.M. N{\"o}then and K. Ohi and R.L. Olvera and R. Perez-Iglesias and G.B. Pike and S.G. Potkin and I. Reinvang and S. Reppermund and M. Rietschel and N. Romanczuk-Seiferth and G.D. Rosen and D. Rujescu and K. Schnell and P.R. Schofield and C. Smith and V.M. Steen and J.E. Sussmann and A. Thalamuthu and A.W. Toga and B.J. Traynor and J. Troncoso and J.A. Turner and {Vald{\'e}s Hern{\'a}ndez}, M.C. and {van t Ent}, D. and {van der Brug}, M. and {van der Wee}, N.J.A. and {van Tol}, M.J. and D.J. Veltman and T.H. Wassink and E. Westmann and R.H. Zielke and A.B. Zonderman and D.G. Ashbrook and R. Hager and L. Lu and F.J. McMahon and D.W. Morris and R.W. Williams and H.G. Brunner and R.L. Buckner and J.K. Buitelaar and W. Cahn and V.D. Calhoun and G.L. Cavalleri and B. Crespo-Facorro and A.M. Dale and G.E. Davies and N. Delanty and C. Depondt and S. Djurovic and W.C. Drevets and T. Espeseth and R.L. Gollub and B.C. Ho and W. Hoffmann and N. Hosten and R.S. Kahn and {Le Hellard}, S. and A. Meyer-Lindenberg and B. M{\"u}ller-Myhsok and M. Nauck and L. Nyberg and M. Pandolfo and B.W.J.H. Penninx and J.L. Roffman and SM Sisodiya and J.W. Smoller and {van Bokhoven}, H. and {van Haren}, N.E.M. and H. V{\"o}lzke and H. Walter and M.W. Weiner and W. Wen and T. White and I. Agartz and O.A. Andreassen and J. Blangero and D.I. Boomsma and R.M. Brouwer and D.M. Cannon and M.R. Cookson and {de Geus}, E.J.C. and I.J. Deary and G. Donohoe and G. Fernandez and S.E. Fisher and C. Francks and D.C. Glahn and H.J. Grabe and O. Gruber and J. Hardy and R. Hashimoto and {Hulshoff Pol}, H.E. and E.G. J{\"o}nsson and I. Kloszewska and S. Lovestone and V.S. Mattay and P. Mecocci and C. McDonald and A.M. McIntosh and R.A. Ophoff and T. Paus and Z. Pausova and M. Ryten and P.S. Sachdev and A.J. Saykin and A. Simmons and A. Singleton and H. Soininen and J.M. Wardlaw and M.E. Weale and D.R. Weinberger and H.H.H. Adams and L.J. Launer and S. Seiler and R. Schmidt and G. Chauhan and C.L. Satizabal and J.T. Becker and L. Yanek and {van der Lee}, S.J. and M. Ebling and B. Fischl and Longstreth, {Jr. W.T.} and D. Greve and H. Schmidt and P. Nyquist and L.N. Vinke and {van Duijn}, C.M. and L. Xue and B. Mazoyer and J.C. Bis and V. Gudnason and S. Seshadri and {Arfan Ikram}, M. and N.G. Martin and M.J. Wright and G. Schumann and B. Franke and P.M. Thompson and S.E. Medland",
year = "2015",
doi = "10.1038/nature14101",
language = "English",
volume = "520",
pages = "224--229",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7546",

}

Hibar, DP, Stein, JL, Renteria, ME, Arias-Vasquez, A, Desrivières, S, Jahanshad, N, Toro, R, Wittfeld, K, Abramovic, L, Andersson, M, Aribisala, BS, Armstrong, NJ, Bernard, M, Bohlken, MM, Biks, 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, Olde Loohuis, LM, Luciano, M, Macare, C, Mather, KA, Mattheisen, M, Milaneschi, Y, Nho, K, Papmeyer, M, Ramasamy, A, Risacher, SL, Roiz-Santiañez, R, Rose, EJ, Salami, A, Sämann, PG, Schmaal, L, Schork, AJ, Shin, J, Strike, LT, Teumer, A, Donkelaar, MMJ, van Eijk, KR, Walters, RK, Westlye, LT, Welan, 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, RR, Matarin, M, Naber, MAM, Reese McKay, D, Needham, M, Nugent, AC, Pütz, 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, Göring, HHH, Green, RC, Guelfi, S, Hansell, NK, Hartman, CA, Hegenscheid, K, Heinz, A, Hernandez, DG, Heslenfeld, DJ, Hoekstra, PJ, Holsboer, F, Homuth, G, Hottenga, JJ, 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, Meisenzahl, E, Melle, I, Mohnke, S, Montgomery, GW, Mostert, JC, Mühleisen, TW, Nalls, MA, Nichols, TE, Nilsson, LG, Nöthen, 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, Valdés Hernández, MC, van t Ent, D, van der Brug, M, van der Wee, NJA, van Tol, MJ, Veltman, DJ, Wassink, TH, Westmann, 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, BC, Hoffmann, W, Hosten, N, Kahn, RS, Le Hellard, S, Meyer-Lindenberg, A, Müller-Myhsok, B, Nauck, M, Nyberg, L, Pandolfo, M, Penninx, BWJH, Roffman, JL, Sisodiya, SM, Smoller, JW, van Bokhoven, H, van Haren, NEM, Völzke, 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, Hulshoff Pol, HE, 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, JWT, Greve, D, Schmidt, H, Nyquist, P, Vinke, LN, van Duijn, CM, Xue, L, Mazoyer, B, Bis, JC, Gudnason, V, Seshadri, S, Arfan Ikram, M, Martin, NG, Wright, MJ, Schumann, G, Franke, B, Thompson, PM & Medland, SE 2015, 'Common genetic variants influence human subcortical brain structures' Nature, vol. 520, no. 7546, pp. 224-229. https://doi.org/10.1038/nature14101

Common genetic variants influence human subcortical brain structures. / Hibar, D.P.; Stein, J.L.; Renteria, M.E.; Arias-Vasquez, A.; Desrivières, S.; Jahanshad, N.; Toro, R.; Wittfeld, K.; Abramovic, L.; Andersson, M.; Aribisala, B.S.; Armstrong, N.J.; Bernard, M.; Bohlken, M.M.; Biks, M.P.; Bralten, J.; Brown, A.A.; Chakravarty, M.M.; Chen, Q.; Ching, C.R.K.; Cuellar-Partida, G.; den Braber, A.; Giddaluru, S.; Goldman, A.L.; Grimm, O.; Guadalupe, T.; Hass, J.; Woldehawariat, G.; Holmes, A.J.; Hoogman, M.; Janowitz, D.; Jia, T.; Kim, S.; Klein, M.; Kraemer, B.; Lee, P.H.; Olde Loohuis, L.M.; Luciano, M.; Macare, C.; Mather, K.A.; Mattheisen, M.; Milaneschi, Y.; Nho, K.; Papmeyer, M.; Ramasamy, A.; Risacher, S.L.; Roiz-Santiañez, R.; Rose, E.J.; Salami, A.; Sämann, P.G.; Schmaal, L.; Schork, A.J.; Shin, J.; Strike, L.T.; Teumer, A.; Donkelaar, M.M.J.; van Eijk, K.R.; Walters, R.K.; Westlye, L.T.; Welan, C.D.; Winkler, A.M.; Zwiers, M.P.; Alhusaini, S.; Athanasiu, L.; Ehrlich, S.; Hakobjan, M.M.H.; Hartberg, C.B.; Haukvik, U.K.; Heister, A.J.G.A.M.; Hoehn, D.; Kasperaviciute, D.; Liewald, D.C.M.; Lopez, L.M.; Makkinje, R.R.; Matarin, M.; Naber, M.A.M.; Reese McKay, D.; Needham, M.; Nugent, A.C.; Pütz, B.; Royle, N.A.; Shen, L.; Sprooten, E.; Trabzuni, D.; van der Marel, S.S.L.; van Hulzen, K.J.E.; Walton, E.; Wolf, C.; Almasy, L.; Ames, D.; Arepalli, S.; Assareh, A.A.; Bastin, M.E.; Brodaty, H.; Bulayeva, K.B.; Carless, M.A.; Cichon, S.; Corvin, A.; Curran, J.E.; Czisch, M.; de Zubicaray, G.I.; Dillman, A.; Duggirala, R.; Dyer, T.D.; Erk, S.; Fedko, I.O.; Ferrucci, L.; Foroud, T.M.; Fox, P.T.; Fukunaga, M.; Gibbs, J.R.; Göring, H.H.H.; Green, R.C.; Guelfi, S.; Hansell, N.K.; Hartman, C.A.; Hegenscheid, K.; Heinz, A.; Hernandez, D.G.; Heslenfeld, D.J.; Hoekstra, P.J.; Holsboer, F.; Homuth, G.; Hottenga, J.J.; Ikeda, M.; Jack, C.R., Jr.; Jenkinson, M.; Johnson, R.; Kanai, R.; Keil, M.; Kent, J.W. Jr.; Kochunov, P.; Kwok, J.B.; Lawrie, S.M.; Liu, X.; Longo, D.L.; McMahon, K.L.; Meisenzahl, E.; Melle, I.; Mohnke, S.; Montgomery, G.W.; Mostert, J.C.; Mühleisen, T.W.; Nalls, M.A.; Nichols, T.E.; Nilsson, L.G.; Nöthen, M.M.; Ohi, K.; Olvera, R.L.; Perez-Iglesias, R.; Pike, G.B.; Potkin, S.G.; Reinvang, I.; Reppermund, S.; Rietschel, M.; Romanczuk-Seiferth, N.; Rosen, G.D.; Rujescu, D.; Schnell, K.; Schofield, P.R.; Smith, C.; Steen, V.M.; Sussmann, J.E.; Thalamuthu, A.; Toga, A.W.; Traynor, B.J.; Troncoso, J.; Turner, J.A.; Valdés Hernández, M.C.; van t Ent, D.; van der Brug, M.; van der Wee, N.J.A.; van Tol, M.J.; Veltman, D.J.; Wassink, T.H.; Westmann, E.; Zielke, R.H.; Zonderman, A.B.; Ashbrook, D.G.; Hager, R.; Lu, L.; McMahon, F.J.; Morris, D.W.; Williams, R.W.; Brunner, H.G.; Buckner, R.L.; Buitelaar, J.K.; Cahn, W.; Calhoun, V.D.; Cavalleri, G.L.; Crespo-Facorro, B.; Dale, A.M.; Davies, G.E.; Delanty, N.; Depondt, C.; Djurovic, S.; Drevets, W.C.; Espeseth, T.; Gollub, R.L.; Ho, B.C.; Hoffmann, W.; Hosten, N.; Kahn, R.S.; Le Hellard, S.; Meyer-Lindenberg, A.; Müller-Myhsok, B.; Nauck, M.; Nyberg, L.; Pandolfo, M.; Penninx, B.W.J.H.; Roffman, J.L.; Sisodiya, SM; Smoller, J.W.; van Bokhoven, H.; van Haren, N.E.M.; Völzke, H.; Walter, H.; Weiner, M.W.; Wen, W.; White, T.; Agartz, I.; Andreassen, O.A.; Blangero, J.; Boomsma, D.I.; Brouwer, R.M.; Cannon, D.M.; Cookson, M.R.; de Geus, E.J.C.; Deary, I.J.; Donohoe, G.; Fernandez, G.; Fisher, S.E.; Francks, C.; Glahn, D.C.; Grabe, H.J.; Gruber, O.; Hardy, J.; Hashimoto, R.; Hulshoff Pol, H.E.; Jönsson, E.G.; Kloszewska, I.; Lovestone, S.; Mattay, V.S.; Mecocci, P.; McDonald, C.; McIntosh, A.M.; Ophoff, R.A.; Paus, T.; Pausova, Z.; Ryten, M.; Sachdev, P.S.; Saykin, A.J.; Simmons, A.; Singleton, A.; Soininen, H.; Wardlaw, J.M.; Weale, M.E.; Weinberger, D.R.; Adams, H.H.H.; Launer, L.J.; Seiler, S.; Schmidt, R.; Chauhan, G.; Satizabal, C.L.; Becker, J.T.; Yanek, L.; van der Lee, S.J.; Ebling, M.; Fischl, B.; Longstreth, Jr. W.T.; Greve, D.; Schmidt, H.; Nyquist, P.; Vinke, L.N.; van Duijn, C.M.; Xue, L.; Mazoyer, B.; Bis, J.C.; Gudnason, V.; Seshadri, S.; Arfan Ikram, M.; Martin, N.G.; Wright, M.J.; Schumann, G.; Franke, B.; Thompson, P.M.; Medland, S.E.

In: Nature, Vol. 520, No. 7546, 2015, p. 224-229.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Common genetic variants influence human subcortical brain structures

AU - Hibar, D.P.

AU - Stein, J.L.

AU - Renteria, M.E.

AU - Arias-Vasquez, A.

AU - Desrivières, S.

AU - Jahanshad, N.

AU - Toro, R.

AU - Wittfeld, K.

AU - Abramovic, L.

AU - Andersson, M.

AU - Aribisala, B.S.

AU - Armstrong, N.J.

AU - Bernard, M.

AU - Bohlken, M.M.

AU - Biks, M.P.

AU - Bralten, J.

AU - Brown, A.A.

AU - Chakravarty, M.M.

AU - Chen, Q.

AU - Ching, C.R.K.

AU - Cuellar-Partida, G.

AU - den Braber, A.

AU - Giddaluru, S.

AU - Goldman, A.L.

AU - Grimm, O.

AU - Guadalupe, T.

AU - Hass, J.

AU - Woldehawariat, G.

AU - Holmes, A.J.

AU - Hoogman, M.

AU - Janowitz, D.

AU - Jia, T.

AU - Kim, S.

AU - Klein, M.

AU - Kraemer, B.

AU - Lee, P.H.

AU - Olde Loohuis, L.M.

AU - Luciano, M.

AU - Macare, C.

AU - Mather, K.A.

AU - Mattheisen, M.

AU - Milaneschi, Y.

AU - Nho, K.

AU - Papmeyer, M.

AU - Ramasamy, A.

AU - Risacher, S.L.

AU - Roiz-Santiañez, R.

AU - Rose, E.J.

AU - Salami, A.

AU - Sämann, P.G.

AU - Schmaal, L.

AU - Schork, A.J.

AU - Shin, J.

AU - Strike, L.T.

AU - Teumer, A.

AU - Donkelaar, M.M.J.

AU - van Eijk, K.R.

AU - Walters, R.K.

AU - Westlye, L.T.

AU - Welan, C.D.

AU - Winkler, A.M.

AU - Zwiers, M.P.

AU - Alhusaini, S.

AU - Athanasiu, L.

AU - Ehrlich, S.

AU - Hakobjan, M.M.H.

AU - Hartberg, C.B.

AU - Haukvik, U.K.

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

AU - Hoehn, D.

AU - Kasperaviciute, D.

AU - Liewald, D.C.M.

AU - Lopez, L.M.

AU - Makkinje, R.R.

AU - Matarin, M.

AU - Naber, M.A.M.

AU - Reese McKay, D.

AU - Needham, M.

AU - Nugent, A.C.

AU - Pütz, B.

AU - Royle, N.A.

AU - Shen, L.

AU - Sprooten, E.

AU - Trabzuni, D.

AU - van der Marel, S.S.L.

AU - van Hulzen, K.J.E.

AU - Walton, E.

AU - Wolf, C.

AU - Almasy, L.

AU - Ames, D.

AU - Arepalli, S.

AU - Assareh, A.A.

AU - Bastin, M.E.

AU - Brodaty, H.

AU - Bulayeva, K.B.

AU - Carless, M.A.

AU - Cichon, S.

AU - Corvin, A.

AU - Curran, J.E.

AU - Czisch, M.

AU - de Zubicaray, G.I.

AU - Dillman, A.

AU - Duggirala, R.

AU - Dyer, T.D.

AU - Erk, S.

AU - Fedko, I.O.

AU - Ferrucci, L.

AU - Foroud, T.M.

AU - Fox, P.T.

AU - Fukunaga, M.

AU - Gibbs, J.R.

AU - Göring, H.H.H.

AU - Green, R.C.

AU - Guelfi, S.

AU - Hansell, N.K.

AU - Hartman, C.A.

AU - Hegenscheid, K.

AU - Heinz, A.

AU - Hernandez, D.G.

AU - Heslenfeld, D.J.

AU - Hoekstra, P.J.

AU - Holsboer, F.

AU - Homuth, G.

AU - Hottenga, J.J.

AU - Ikeda, M.

AU - Jack, C.R., Jr.

AU - Jenkinson, M.

AU - Johnson, R.

AU - Kanai, R.

AU - Keil, M.

AU - Kent, J.W. Jr.

AU - Kochunov, P.

AU - Kwok, J.B.

AU - Lawrie, S.M.

AU - Liu, X.

AU - Longo, D.L.

AU - McMahon, K.L.

AU - Meisenzahl, E.

AU - Melle, I.

AU - Mohnke, S.

AU - Montgomery, G.W.

AU - Mostert, J.C.

AU - Mühleisen, T.W.

AU - Nalls, M.A.

AU - Nichols, T.E.

AU - Nilsson, L.G.

AU - Nöthen, M.M.

AU - Ohi, K.

AU - Olvera, R.L.

AU - Perez-Iglesias, R.

AU - Pike, G.B.

AU - Potkin, S.G.

AU - Reinvang, I.

AU - Reppermund, S.

AU - Rietschel, M.

AU - Romanczuk-Seiferth, N.

AU - Rosen, G.D.

AU - Rujescu, D.

AU - Schnell, K.

AU - Schofield, P.R.

AU - Smith, C.

AU - Steen, V.M.

AU - Sussmann, J.E.

AU - Thalamuthu, A.

AU - Toga, A.W.

AU - Traynor, B.J.

AU - Troncoso, J.

AU - Turner, J.A.

AU - Valdés Hernández, M.C.

AU - van t Ent, D.

AU - van der Brug, M.

AU - van der Wee, N.J.A.

AU - van Tol, M.J.

AU - Veltman, D.J.

AU - Wassink, T.H.

AU - Westmann, E.

AU - Zielke, R.H.

AU - Zonderman, A.B.

AU - Ashbrook, D.G.

AU - Hager, R.

AU - Lu, L.

AU - McMahon, F.J.

AU - Morris, D.W.

AU - Williams, R.W.

AU - Brunner, H.G.

AU - Buckner, R.L.

AU - Buitelaar, J.K.

AU - Cahn, W.

AU - Calhoun, V.D.

AU - Cavalleri, G.L.

AU - Crespo-Facorro, B.

AU - Dale, A.M.

AU - Davies, G.E.

AU - Delanty, N.

AU - Depondt, C.

AU - Djurovic, S.

AU - Drevets, W.C.

AU - Espeseth, T.

AU - Gollub, R.L.

AU - Ho, B.C.

AU - Hoffmann, W.

AU - Hosten, N.

AU - Kahn, R.S.

AU - Le Hellard, S.

AU - Meyer-Lindenberg, A.

AU - Müller-Myhsok, B.

AU - Nauck, M.

AU - Nyberg, L.

AU - Pandolfo, M.

AU - Penninx, B.W.J.H.

AU - Roffman, J.L.

AU - Sisodiya, SM

AU - Smoller, J.W.

AU - van Bokhoven, H.

AU - van Haren, N.E.M.

AU - Völzke, H.

AU - Walter, H.

AU - Weiner, M.W.

AU - Wen, W.

AU - White, T.

AU - Agartz, I.

AU - Andreassen, O.A.

AU - Blangero, J.

AU - Boomsma, D.I.

AU - Brouwer, R.M.

AU - Cannon, D.M.

AU - Cookson, M.R.

AU - de Geus, E.J.C.

AU - Deary, I.J.

AU - Donohoe, G.

AU - Fernandez, G.

AU - Fisher, S.E.

AU - Francks, C.

AU - Glahn, D.C.

AU - Grabe, H.J.

AU - Gruber, O.

AU - Hardy, J.

AU - Hashimoto, R.

AU - Hulshoff Pol, H.E.

AU - Jönsson, E.G.

AU - Kloszewska, I.

AU - Lovestone, S.

AU - Mattay, V.S.

AU - Mecocci, P.

AU - McDonald, C.

AU - McIntosh, A.M.

AU - Ophoff, R.A.

AU - Paus, T.

AU - Pausova, Z.

AU - Ryten, M.

AU - Sachdev, P.S.

AU - Saykin, A.J.

AU - Simmons, A.

AU - Singleton, A.

AU - Soininen, H.

AU - Wardlaw, J.M.

AU - Weale, M.E.

AU - Weinberger, D.R.

AU - Adams, H.H.H.

AU - Launer, L.J.

AU - Seiler, S.

AU - Schmidt, R.

AU - Chauhan, G.

AU - Satizabal, C.L.

AU - Becker, J.T.

AU - Yanek, L.

AU - van der Lee, S.J.

AU - Ebling, M.

AU - Fischl, B.

AU - Longstreth, Jr. W.T.

AU - Greve, D.

AU - Schmidt, H.

AU - Nyquist, P.

AU - Vinke, L.N.

AU - van Duijn, C.M.

AU - Xue, L.

AU - Mazoyer, B.

AU - Bis, J.C.

AU - Gudnason, V.

AU - Seshadri, S.

AU - Arfan Ikram, M.

AU - Martin, N.G.

AU - Wright, M.J.

AU - Schumann, G.

AU - Franke, B.

AU - Thompson, P.M.

AU - Medland, S.E.

PY - 2015

Y1 - 2015

N2 - The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. 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 and intracranial volume. 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 = 1.08×10 -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. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. 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 and intracranial volume. 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 = 1.08×10 -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

VL - 520

SP - 224

EP - 229

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7546

ER -

Hibar DP, Stein JL, Renteria ME, Arias-Vasquez A, Desrivières S, Jahanshad N et al. Common genetic variants influence human subcortical brain structures. Nature. 2015;520(7546):224-229. https://doi.org/10.1038/nature14101