Genetic variants for head size share genes and pathways with cancer
Maria J. Knol, Raymond A. Poot, Tavia E. Evans, Claudia L. Satizábal, Aniket Mishra, Muralidharan Sargurupremraj, Sandra Van der Auwera, Marie‐Gabrielle Duperron, Xueqiu Jian, Isabel C. Hostettler, Dianne H.K. van Dam-Nolen, Sander Lamballais, Mikołaj A. Pawlak, Cora E. Lewis, Amaia Carrión-Castillo, Theo G.M. van Erp, Céline S. Reinbold, Jean Shin, Markus Scholz, Asta K. Håberg, Anders Kämpe, Gloria Hoi‐Yee Li, Reut Avinun, Joshua Atkins, Fang‐Chi Hsu, Alyssa R. Amod, Max Lam, Ami Tsuchida, Mariël W.A. Teunissen, Nil Aygün, Yash Patel, Dan Liang, Alexa Beiser, Frauke Beyer, Joshua C. Bis, Daniël Bos, R. Nick Bryan, Robin Bülow, Svenja Caspers, Gwénaëlle 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, Fabìo 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 Fleischman, Rebecca F. Gottesman, Vilmundur Guðnason, Saima Hilal, Edith Hofer, Deborah Janowitz, J. Wouter Jukema, David C. Liewald, Lorna M. Lopez, Oscar L. López, 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 R. Yanek, Jingyun Yang, Ingrid Agartz, Saud Alhusaini
Abstract
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.