Genetic variants for head size share genes and pathways with cancer
Authors: Maria J. Knol, Raymond A. Poot, Tavia E. Evans, Claudia L. Satizabal, Aniket Mishra, Muralidharan Sargurupremraj, Sandra van der Auwera, Marie-Gabrielle Duperron, Xueqiu Jian, Isabel C. Hostettler, Dianne H.K. van Dam-Nolen, Sander Lamballais, Mikolaj A. Pawlak, Cora E. Lewis, Amaia Carrion-Castillo, Theo G.M. van Erp, Céline S. Reinbold, Jean Shin, Markus Scholz, Asta K. Håberg, Anders Kämpe, Gloria H.Y. Li, Reut Avinun, Joshua R. Atkins, Fang-Chi Hsu, Alyssa R. Amod, Max Lam, Ami Tsuchida, Mariël W.A. Teunissen, Nil Aygün, Yash Patel, Dan Liang, Alexa S. Beiser, Frauke Beyer, Joshua C. Bis, Daniel Bos, R. Nick Bryan, Robin Bülow, Svenja Caspers, Gwenaëlle Catheline, Charlotte A.M. Cecil, Shareefa Dalvie, Jean-François Dartigues, Charles DeCarli, Maria Enlund-Cerullo, Judith M. Ford, Barbara Franke, Barry I. Freedman, Nele Friedrich, Melissa J. Green, Simon Haworth, Catherine Helmer, Per Hoffmann, Georg Homuth, M. Kamran Ikram, Clifford R. Jack, Neda Jahanshad, Christiane Jockwitz, Yoichiro Kamatani, Annchen R. Knodt, Shuo Li, Keane Lim, W.T. Longstreth, Fabio Macciardi, Philippe Amouyel, Konstantinos Arfanakis, Benjamin S. Aribisala, Mark E. Bastin, Ganesh Chauhan, Christopher Chen, Ching-Yu Cheng, Philip L. de Jager, Ian J. Deary, Debra A. Fleischman, Rebecca F. Gottesman, Vilmundur Gudnason, Saima Hilal, Edith Hofer, Deborah Janowitz, J. Wouter Jukema, David C.M. Liewald, Lorna M. Lopez, Oscar Lopez, Michelle Luciano, Oliver Martinez, Wiro J. Niessen, Paul Nyquist, Jerome I. Rotter, Tatjana Rundek, Ralph L. Sacco, Helena Schmidt, Henning Tiemeier, Stella Trompet, Jeroen van der Grond, Henry Völzke, Joanna M. Wardlaw, Lisa Yanek, Jingyun Yang, Ingrid Agartz, Saud Alhusaini, Laura Almasy, David Ames, Katrin Amunts, Ole A. Andreassen, Nicola Armstrong, Manon Bernard, John Blangero, Laura M.E. Blanken, Marco P. Boks, Dorret I. Boomsma, Adam M. Brickman, Henry Brodaty, Randy L. Buckner, Jan K. Buitelaar, Dara M. Cannon, Vaughan J. Carr, Stanley V. Catts, M. Mallar Chakravarty, Qiang Chen, Christopher R.K. Ching, Aiden Corvin, Benedicto Crespo-Facorro, Joanne E. Curran, Gareth E. Davies, Eco J.C. de Geus, Greig I. de Zubicaray, Anouk den Braber, Sylvane Desrivières, Allissa Dillman, Srdjan Djurovic, Wayne C. Drevets, Ravi Duggirala, Stefan Ehrlich, Susanne Erk, Thomas Espeseth, Iryna O. Fedko, Guillén Fernández, Simon E. Fisher, Tatiana M. Foroud, Tian Ge, Sudheer Giddaluru, David C. Glahn, Aaron L. Goldman, Robert C. Green, Corina U. Greven, Oliver Grimm, Narelle K. Hansell, Catharina A. Hartman, Ryota Hashimoto, Andreas Heinz, Frans Henskens, Derrek P. Hibar, Beng-Choon Ho, Pieter J. Hoekstra, Avram J. Holmes, Martine Hoogman, Jouke-Jan Hottenga, Hilleke E. Hulshoff Pol, Assen Jablensky, Mark Jenkinson, Tianye Jia, Karl-Heinz Jöckel, Erik G. Jönsson, Sungeun Kim, Marieke Klein, Peter Kochunov, John B. Kwok, Stephen M. Lawrie, Stephanie Le Hellard, Hervé Lemaître, Carmel Loughland, Andre F. Marquand, Nicholas G. Martin, Jean-Luc Martinot, Mar Matarin, Daniel H. Mathalon, Karen A. Mather, Venkata S. Mattay, Colm McDonald, Francis J. McMahon, Katie L. McMahon, Rebekah E, None McWhirter, Patrizia Mecocci, Ingrid Melle, Andreas Meyer-Lindenberg, Patricia T. Michie, Yuri Milaneschi, Derek W. Morris, Bryan Mowry, Kwangsik Nho, Thomas E. Nichols, Markus N. Nöthen, Rene L. Olvera, Jaap Oosterlaan, Roel A. Ophoff, Massimo Pandolfo, Christos Pantelis, Irene Pappa, Brenda Penninx, G. Bruce Pike, Paul E. Rasser, Miguel E. Rentería, Simone Reppermund, Marcella Rietschel, Shannon L. Risacher, Nina Romanczuk-Seiferth, Emma Jane Rose, Perminder S. Sachdev, Philipp G. Sämann, Andrew J. Saykin, Ulrich Schall, Peter R. Schofield, Sara Schramm, Gunter Schumann, Rodney Scott, Li Shen, Sanjay M. Sisodiya, Hilkka Soininen, Emma Sprooten, Velandai Srikanth, Vidar M. Steen, Lachlan T. Strike, Anbupalam Thalamuthu, Arthur W. Toga, Paul Tooney, Diana Tordesillas-Gutiérrez, Jessica A. Turner, Maria del C. Valdés Hernández, Dennis van der Meer, Nic J.A. Van der Wee, Neeltje E.M. Van Haren, Dennis van 't Ent, Dick J. Veltman, Henrik Walter, Daniel R. Weinberger, Michael W. Weiner, Wei Wen, Lars T. Westlye, Eric Westman, Anderson M. Winkler, Girma Woldehawariat, Margaret J. Wright, Jingqin Wu, Outi Mäkitie, Bernard Mazoyer, Sarah E. Medland, Susumu Miyamoto, Susanne Moebus, Thomas H. Mosley, Ryan Muetzel, Thomas W. Mühleisen, Manabu Nagata, Soichiro Nakahara, Nicholette D. Palmer, Zdenka Pausova, Adrian Preda, Yann Quidé, William R. Reay, Gennady V. Roshchupkin, Reinhold Schmidt, Pamela J. Schreiner, Kazuya Setoh, Chin Yang Shapland, Stephen Sidney, Beate St Pourcain, Jason L. Stein, Yasuharu Tabara, Alexander Teumer, Anne Uhlmann, Aad van der Lugt, Meike W. Vernooij, David J. Werring, B. Gwen Windham, A. Veronica Witte, Katharina Wittfeld, Qiong Yang, Kazumichi Yoshida, Han G. Brunner, Quentin Le Grand, Kang Sim, Dan J. Stein, Donald W. Bowden, Murray J. Cairns, Ahmad R. Hariri, Ching-Lung Cheung, Sture Andersson, Arno Villringer, Tomas Paus, Sven Cichon, Vince D. Calhoun, Fabrice Crivello, Lenore J. Launer, Tonya White, Peter J. Koudstaal, Henry Houlden, Myriam Fornage, Fumihiko Matsuda, Hans J. Grabe, M. Arfan Ikram, Stéphanie Debette, Paul M. Thompson, Sudha Seshadri, Hieab H.H. Adams
Journal: Cell Reports Medicine (2024)

The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer.