Novel genetic loci underlying human intracranial volume identified through genome-wide association

Adams, Hieab H. H., Hibar, Derrek P., Chouraki, Vincent, Stein, Jason L., Nyquist, Paul A., Renteria, Miguel E., Trompet, Stella, Arias-Vasquez, Alejandro, Seshadri, Sudha, Desrivieres, Sylvane, Beecham, Ashley H., Jahanshad, Neda, Wittfeld, Katharina, Van der Lee, Sven J., Abramovic, Lucija, Alhusaini, Saud, Amin, Najaf, Andersson, Micael, Arfanakis, Konstantinos, Aribisala, Benjamin S., Armstrong, Nicola J., Athanasiu, Lavinia, Axelsson, Tomas, Beiser, Alexa, Bernard, Manon, Bis, Joshua C., Blanken, Laura M. E., Blanton, SusanH., Bohlken, Marc M., Boks, Marco P., Bralten, Janita, Brickman, Adam M., Carmichael, Owen, Chakravarty, M. Mallar, Chauhan, Ganesh, Chen, Qiang, Ching, Christopher R. K., Cuellar-Partida, Gabriel, Braber, Anouk Den, Doan, Nhat Trung, Ehrlich, Stefan, Filippi, Irina, Ge, Tian, Giddaluru, Sudheer, Goldman, Aaron L., Gottesman, Rebecca F., Greven, Corina U., Grimm, Oliver, Griswold, Michael E., Guadalupe, Tulio, Hass, Johanna, Haukvik, Unn K., Hilal, Saima, Hofer, Edith, Hoehn, David, Holmes, Avram J., Hoogman, Martine, Janowitz, Deborah, Jia, Tianye, Kasperaviciute, Dalia, Kim, Sungeun, Klein, Marieke, Kraemer, Bernd, Lee, Phil H., Liao, Jiemin, Liewald, David C. M., Lopez, Lorna M., Luciano, Michelle, Macare, Christine, Marquand, Andre, Matarin, Mar, Mather, Karen A., Mattheisen, Manuel, Mazoyer, Bernard, McKay, David R., McWhirter, Rebekah, Milaneschi, Yuri, Mirza-Schreiber, Nazanin, Muetzel, Ryan L., Maniega, Susana Munoz, Nho, Kwangsik, Nugent, Allison C., Loohuis, Loes M. Olde, Oosterlaan, Jaap, Papmeyer, Martina, Pappa, Irene, Pirpamer, Lukas, Pudas, Sara, Putz, Benno, Rajan, Kumar B., Ramasamy, Adaikalavan, Richards, Jennifer S., Risacher, Shannon L., Roiz-Santianez, Roberto, Rommelse, Nanda, Rose, Emma J., Royle, Natalie A., Rundek, Tatjana, Samann, Phillip G., Satizabal, Claudia L., Schmaal, Lianne, Schork, Andrew J., Shen, Li, Shin, Jean, Shumskaya, Elena, Smith, Albert V., Sprooten, Emma, Strike, Lachlan T., Teumer, Alexander, Thomson, Russell, Tordesillas-Gutierrez, Diana, Toro, Roberto, Trabzuni, Daniah, Vaidya, Dhananjay, Van der Grond, Jeroen, Van der Meer, Dennis, Van Donkelaar, Maejolein M. J., Van Eijk, Kristel R., Van Erp, Thero G. M., Van Rooij, Daan, Walton, Esther, Westlye, Lars T., Whelan, Christopher D., Windham, Beverly G., Winkler, Anderson M., Woldehawariat, Girma, Wolf, Christiane, Wolfers, Thomas, Xu, Bing, Yanek, Lisa R., Yang, Jingyun, Zijdenbos, Aijdenbos, Zwiers, Marcel P., Agartz, Ingrid, Aggarwal, Neelum T., Almasy, Laura, Ames, David, Amouyel, Philippe, Andreassen, Ole A., Arepalli, Sampath, Assareh, Amelia A., Barral, Sandra, Bastin, Mark E., Becker, Diane M., Becker, James T., Bennett, David A., Blangero, John, van Bokhoven, Hans, Boomsma, Dorret I., Brodaty, Henry, Brouwer, Rachel M., Brunner, Han G., Buckner, Randy L., Buitelaar, Jan K., Bulayeva, Kazima B., Cahn, Wiepke, Calhoun, Vince D., Cannon, Dara M., Cavalleri, Gianpiero L., Chen, Christopher, Cheng, Ching-Yu, Cichon, Sven, Cookson, Mark R., Corvin, Aiden, Crespo-Facorro, Benedicto, Curran, Joanne E., Czisch, Michael, Dale, Anders M., Davies, Gareth E., De Geus, Eco J. C., De Jager, Philip L., de Zubicaray, Greig I., Delanty, Norman, Depondt, Chantal, Destefano, Anita L., Dillman, Allissa, Djurovic, Srdjan, Donohoe, Gary, Drevets, Wayne C., Duggirala, Ravi, Dyer, Thomas D., Erk, Susanne, Espeseth, Thomas, Evans, Denis A., Fedko, Iryna O., Fernandez, Guillen, Ferrucci, Luigi, Fisher, Simon E., Fleischman, Debra A., Ford, Ian, Foroud, Tatiana M., Fox, Peter T., Francks, Clyde, Fukunaga, Masaki, Gibbs, J. Raphael, Glahn, David C., Gollub, Randy L., Goring, Harald H. H., Grabe, Hans J., Green, Robert C., Gruber, Oliver, Gudnason, Vilmundur, Guelfi, Sebastian, Hansell, Narelle K., Hardy, John, Hartman, Catharina A., Hashimoto, Ryota, Hegenscheid, Katrin, Heinz, Adreas, Le Hellard, Stephanie, Hernandez, Dena G., Heslenfeld, Dirk J., Ho, Beng-Choon, Hoekstra, Pieter J., Hoffmann, Wolfgang, Hofman, Albert, Holsboer, Florian, Homuth, Georg, Hosten, Norbert, Hottenga, Jouke-Jan, Pol, Hilleke E. Hulshoff, Ikeda, Masashi, Ikram, M. Kamran, Jack, Clifford R., Jenkinson, Mark, Johnson, Robert, Jonsson, Erik G., Jukema, J. Wouter, Kahn, Rene S., Kanai, Ryota, Kloszewska, Iwona, Knopman, David S., Kochunov, Peter, Kwok, John B., Lawrie, Stephen M., Lemaitre, Herve, Liu, Xinmin, Longo, Dan L., Longstreth Jr., W. T., Lopez, Oscar L., Lovestone, Simon, Martinez, Oliver, Martinot, Jean-Luc, Mattay, Venkata S., McDonald, Colm, McIntosh, Andrew M., McMahon, Katie L., McMahon, Francis J., Mecocci, Patrizia, Melle, Ingrid, Meyer-Lindenberg, Andreas, Mohnke, Sebastian, Montgomery, Grant W., Morris, Derek W., Mosley, Thomas H., Muhleisen, Thomas W., Muller-Myhsok, Bertram, Nalls, Michael A., Nauck, Matthias, Nichols, Thomas E., Niessen, Wiro J., Nothen, Markus M., Nyberg, Lars, Ohi, Kazutaka, Olvera, Rene L., Ophoff, Roel A., Pandolfo, Massimo, Paus, Tomas, Pausova, Zdenka, Penninx, Brenda W. J. H., Pike, G. Bruce, Potkin, Steven G., Psaty, Bruce M., Reppermund, Simone, Rietschel, Marcella, Roffman, Joshua L., Romanczuk-Seiferth, Nina, Rotter, Jerome I., Ryten, Mina, Sacco, Ralph L., Sachdev, Perminder S., Saykin, Andrew J., Schmidt, Reinhold, Schofield, Peter R., Sigurdsson, Sigurdur, Simmons, Andy, Singleton, Andrew, Sisodiya, Sanjay M., Smith, Colin, Smoller, Jordan W., Soininen, Hilkka, Srikanth, Velandai, Steen, Vidar M., Stott, David J., Sussmann, Jessika E., Thalamuthu, Anbupalam, Tiemeier, Henning, Toga, Arthur W., Traynor, Bryan J., Troncoso, Juan, Turner, Jessica A., Tzourio, Christophe, Uitterlinden, Andrew G., Hernandez, Maria C. Valdes, Van der Brug, Marcel, Van der Lugt, Aad, Van der Wee, Nic J. A., Van Duijn, Cornelia M., Van Haren, Neeltje E.M., Van't Ent, Dennis, Van Tol, Marie-Jose, Vardarajan, Badri N., Veltman, Dick J., Vernooij, Meike W., Volzke, Henry, Walter, Henrik, Wardlaw, Joanna M., Wassink, Thomas H., Weale, Michael E., Weinberger, Daniel R., Weiner, Michael W., Wen, Wei, Westman, Eric, White, Tonya, Wong, Tien Y., Wright, Clinton B., Zielke, H. Ronald, Zonderman, Alan B., Deary, Ian J., Decarli, Charles, Schmidt, Helena, Martin, Nicholas G., De Craen, Anton J.M., Wright, Margaret J., Launer, Lenore J., Schumann, Gunter, Fornage, Myriam, Franke, Barbara, Debette, Stephanie, Medland, Sarah E., Ikram, M. Arfan and Thompson, Paul M. (2016) Novel genetic loci underlying human intracranial volume identified through genome-wide association. Nature Neuroscience, 19 12: 1569-1582. doi:10.1038/nn.4398


Author Adams, Hieab H. H.
Hibar, Derrek P.
Chouraki, Vincent
Stein, Jason L.
Nyquist, Paul A.
Renteria, Miguel E.
Trompet, Stella
Arias-Vasquez, Alejandro
Seshadri, Sudha
Desrivieres, Sylvane
Beecham, Ashley H.
Jahanshad, Neda
Wittfeld, Katharina
Van der Lee, Sven J.
Abramovic, Lucija
Alhusaini, Saud
Amin, Najaf
Andersson, Micael
Arfanakis, Konstantinos
Aribisala, Benjamin S.
Armstrong, Nicola J.
Athanasiu, Lavinia
Axelsson, Tomas
Beiser, Alexa
Bernard, Manon
Bis, Joshua C.
Blanken, Laura M. E.
Blanton, SusanH.
Bohlken, Marc M.
Boks, Marco P.
Bralten, Janita
Brickman, Adam M.
Carmichael, Owen
Chakravarty, M. Mallar
Chauhan, Ganesh
Chen, Qiang
Ching, Christopher R. K.
Cuellar-Partida, Gabriel
Braber, Anouk Den
Doan, Nhat Trung
Ehrlich, Stefan
Filippi, Irina
Ge, Tian
Giddaluru, Sudheer
Goldman, Aaron L.
Gottesman, Rebecca F.
Greven, Corina U.
Grimm, Oliver
Griswold, Michael E.
Guadalupe, Tulio
Hass, Johanna
Haukvik, Unn K.
Hilal, Saima
Hofer, Edith
Hoehn, David
Holmes, Avram J.
Hoogman, Martine
Janowitz, Deborah
Jia, Tianye
Kasperaviciute, Dalia
Kim, Sungeun
Klein, Marieke
Kraemer, Bernd
Lee, Phil H.
Liao, Jiemin
Liewald, David C. M.
Lopez, Lorna M.
Luciano, Michelle
Macare, Christine
Marquand, Andre
Matarin, Mar
Mather, Karen A.
Mattheisen, Manuel
Mazoyer, Bernard
McKay, David R.
McWhirter, Rebekah
Milaneschi, Yuri
Mirza-Schreiber, Nazanin
Muetzel, Ryan L.
Maniega, Susana Munoz
Nho, Kwangsik
Nugent, Allison C.
Loohuis, Loes M. Olde
Oosterlaan, Jaap
Papmeyer, Martina
Pappa, Irene
Pirpamer, Lukas
Pudas, Sara
Putz, Benno
Rajan, Kumar B.
Ramasamy, Adaikalavan
Richards, Jennifer S.
Risacher, Shannon L.
Roiz-Santianez, Roberto
Rommelse, Nanda
Rose, Emma J.
Royle, Natalie A.
Rundek, Tatjana
Samann, Phillip G.
Satizabal, Claudia L.
Schmaal, Lianne
Schork, Andrew J.
Shen, Li
Shin, Jean
Shumskaya, Elena
Smith, Albert V.
Sprooten, Emma
Strike, Lachlan T.
Teumer, Alexander
Thomson, Russell
Tordesillas-Gutierrez, Diana
Toro, Roberto
Trabzuni, Daniah
Vaidya, Dhananjay
Van der Grond, Jeroen
Van der Meer, Dennis
Van Donkelaar, Maejolein M. J.
Van Eijk, Kristel R.
Van Erp, Thero G. M.
Van Rooij, Daan
Walton, Esther
Westlye, Lars T.
Whelan, Christopher D.
Windham, Beverly G.
Winkler, Anderson M.
Woldehawariat, Girma
Wolf, Christiane
Wolfers, Thomas
Xu, Bing
Yanek, Lisa R.
Yang, Jingyun
Zijdenbos, Aijdenbos
Zwiers, Marcel P.
Agartz, Ingrid
Aggarwal, Neelum T.
Almasy, Laura
Ames, David
Amouyel, Philippe
Andreassen, Ole A.
Arepalli, Sampath
Assareh, Amelia A.
Barral, Sandra
Bastin, Mark E.
Becker, Diane M.
Becker, James T.
Bennett, David A.
Blangero, John
van Bokhoven, Hans
Boomsma, Dorret I.
Brodaty, Henry
Brouwer, Rachel M.
Brunner, Han G.
Buckner, Randy L.
Buitelaar, Jan K.
Bulayeva, Kazima B.
Cahn, Wiepke
Calhoun, Vince D.
Cannon, Dara M.
Cavalleri, Gianpiero L.
Chen, Christopher
Cheng, Ching-Yu
Cichon, Sven
Cookson, Mark R.
Corvin, Aiden
Crespo-Facorro, Benedicto
Curran, Joanne E.
Czisch, Michael
Dale, Anders M.
Davies, Gareth E.
De Geus, Eco J. C.
De Jager, Philip L.
de Zubicaray, Greig I.
Delanty, Norman
Depondt, Chantal
Destefano, Anita L.
Dillman, Allissa
Djurovic, Srdjan
Donohoe, Gary
Drevets, Wayne C.
Duggirala, Ravi
Dyer, Thomas D.
Erk, Susanne
Espeseth, Thomas
Evans, Denis A.
Fedko, Iryna O.
Fernandez, Guillen
Ferrucci, Luigi
Fisher, Simon E.
Fleischman, Debra A.
Ford, Ian
Foroud, Tatiana M.
Fox, Peter T.
Francks, Clyde
Fukunaga, Masaki
Gibbs, J. Raphael
Glahn, David C.
Gollub, Randy L.
Goring, Harald H. H.
Grabe, Hans J.
Green, Robert C.
Gruber, Oliver
Gudnason, Vilmundur
Guelfi, Sebastian
Hansell, Narelle K.
Hardy, John
Hartman, Catharina A.
Hashimoto, Ryota
Hegenscheid, Katrin
Heinz, Adreas
Le Hellard, Stephanie
Hernandez, Dena G.
Heslenfeld, Dirk J.
Ho, Beng-Choon
Hoekstra, Pieter J.
Hoffmann, Wolfgang
Hofman, Albert
Holsboer, Florian
Homuth, Georg
Hosten, Norbert
Hottenga, Jouke-Jan
Pol, Hilleke E. Hulshoff
Ikeda, Masashi
Ikram, M. Kamran
Jack, Clifford R.
Jenkinson, Mark
Johnson, Robert
Jonsson, Erik G.
Jukema, J. Wouter
Kahn, Rene S.
Kanai, Ryota
Kloszewska, Iwona
Knopman, David S.
Kochunov, Peter
Kwok, John B.
Lawrie, Stephen M.
Lemaitre, Herve
Liu, Xinmin
Longo, Dan L.
Longstreth Jr., W. T.
Lopez, Oscar L.
Lovestone, Simon
Martinez, Oliver
Martinot, Jean-Luc
Mattay, Venkata S.
McDonald, Colm
McIntosh, Andrew M.
McMahon, Katie L.
McMahon, Francis J.
Mecocci, Patrizia
Melle, Ingrid
Meyer-Lindenberg, Andreas
Mohnke, Sebastian
Montgomery, Grant W.
Morris, Derek W.
Mosley, Thomas H.
Muhleisen, Thomas W.
Muller-Myhsok, Bertram
Nalls, Michael A.
Nauck, Matthias
Nichols, Thomas E.
Niessen, Wiro J.
Nothen, Markus M.
Nyberg, Lars
Ohi, Kazutaka
Olvera, Rene L.
Ophoff, Roel A.
Pandolfo, Massimo
Paus, Tomas
Pausova, Zdenka
Penninx, Brenda W. J. H.
Pike, G. Bruce
Potkin, Steven G.
Psaty, Bruce M.
Reppermund, Simone
Rietschel, Marcella
Roffman, Joshua L.
Romanczuk-Seiferth, Nina
Rotter, Jerome I.
Ryten, Mina
Sacco, Ralph L.
Sachdev, Perminder S.
Saykin, Andrew J.
Schmidt, Reinhold
Schofield, Peter R.
Sigurdsson, Sigurdur
Simmons, Andy
Singleton, Andrew
Sisodiya, Sanjay M.
Smith, Colin
Smoller, Jordan W.
Soininen, Hilkka
Srikanth, Velandai
Steen, Vidar M.
Stott, David J.
Sussmann, Jessika E.
Thalamuthu, Anbupalam
Tiemeier, Henning
Toga, Arthur W.
Traynor, Bryan J.
Troncoso, Juan
Turner, Jessica A.
Tzourio, Christophe
Uitterlinden, Andrew G.
Hernandez, Maria C. Valdes
Van der Brug, Marcel
Van der Lugt, Aad
Van der Wee, Nic J. A.
Van Duijn, Cornelia M.
Van Haren, Neeltje E.M.
Van't Ent, Dennis
Van Tol, Marie-Jose
Vardarajan, Badri N.
Veltman, Dick J.
Vernooij, Meike W.
Volzke, Henry
Walter, Henrik
Wardlaw, Joanna M.
Wassink, Thomas H.
Weale, Michael E.
Weinberger, Daniel R.
Weiner, Michael W.
Wen, Wei
Westman, Eric
White, Tonya
Wong, Tien Y.
Wright, Clinton B.
Zielke, H. Ronald
Zonderman, Alan B.
Deary, Ian J.
Decarli, Charles
Schmidt, Helena
Martin, Nicholas G.
De Craen, Anton J.M.
Wright, Margaret J.
Launer, Lenore J.
Schumann, Gunter
Fornage, Myriam
Franke, Barbara
Debette, Stephanie
Medland, Sarah E.
Ikram, M. Arfan
Thompson, Paul M.
Title Novel genetic loci underlying human intracranial volume identified through genome-wide association
Journal name Nature Neuroscience   Check publisher's open access policy
ISSN 1546-1726
1097-6256
Publication date 2016-10-03
Year available 2016
Sub-type Article (original research)
DOI 10.1038/nn.4398
Open Access Status Not yet assessed
Volume 19
Issue 12
Start page 1569
End page 1582
Total pages 14
Place of publication New York, NY United States
Publisher Nature Publishing Group
Language eng
Subject 2800 Neuroscience
Abstract Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.
Formatted abstract
Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.
Keyword Neurosciences
Neurosciences & Neurology
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID HHSN268201100012C
RC2 MH089951
P41 EB015922
R01 HL103612
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U01 AG049505
Institutional Status UQ

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Sub-type: Article (original research)
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