Maria J. Knol, Raymond A. Poot, Tavia E. Evans, Claudia L. Satizabal, Aniket Mishra, 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, 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, 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,
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2020-07-16;
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DOI: 10.1101/2020.07.15.191114
AbstractThe size of the human head is determined by growth in the first years of life, while the rest of the body typically grows until early adulthood1. Such complex developmental processes are regulated by various genes and growth pathways2. Rare genetic syndromes have revealed genes that affect head size3, but the genetic drivers of variation in head size within the general population remain largely unknown. To elucidate biological pathways underlying the growth of the human head, we performed the largest genome-wide association study on human head size to date (N = 79,107). We identified 67 genetic loci, 50 of which are novel, and found that these loci are preferentially associated with head size and mostly independent from height. In subsequent neuroimaging analyses, the majority of genetic variants demonstrated widespread effects on the brain, whereas the effects of 17 variants could be localized to one or two specific brain regions. Through hypothesis-free approaches, we find a strong overlap of head size variants with both cancer pathways and cancer genes. Gene set analyses showed enrichment for different types of cancer and the p53, Wnt and ErbB signalling pathway. Genes overlapping or close to lead variants – such as TP53, PTEN and APC – were enriched for genes involved in macrocephaly syndromes (up to 37-fold) and high-fidelity cancer genes (up to 9-fold), whereas this enrichment was not seen for human height variants. This indicates that genes regulating early brain and cranial growth are associated with a propensity to neoplasia later in life, irrespective of height. Our results warrant further investigations of the link between head size and cancer, as well as its clinical implications in the general population.
