Genetic variants for head size share genes and pathways with cancer
Authors: Knol Maria J. , Poot Raymond A. , Evans Tavia E. , Satizabal Claudia L. , Mishra Aniket , van der Auwera Sandra , Duperron Marie-Gabrielle , Jian Xueqiu , Hostettler Isabel C. , van Dam-Nolen Dianne H.K. , Lamballais Sander , Pawlak Mikolaj A. , Lewis Cora E. , Carrion-Castillo Amaia , van Erp Theo G.M. , Reinbold Céline S. , Shin Jean , Scholz Markus , Håberg Asta K. , Kämpe Anders , Li Gloria H.Y. , Avinun Reut , Atkins Joshua R. , Hsu Fang-Chi , Amod Alyssa R. , Lam Max , Tsuchida Ami , Teunissen Mariël W.A. , Beiser Alexa S. , Beyer Frauke , Bis Joshua C. , Bos Daniel , Bryan R. Nick , Bülow Robin , Caspers Svenja , Catheline Gwenaëlle , Cecil Charlotte A.M. , Dalvie Shareefa , Dartigues Jean-François , DeCarli Charles , Enlund-Cerullo Maria , Ford Judith M. , Franke Barbara , Freedman Barry I. , Friedrich Nele , Green Melissa J. , Haworth Simon , Helmer Catherine , Hoffmann Per , Homuth Georg , Ikram M. Kamran , Jack Clifford R. , Jahanshad Neda , Jockwitz Christiane , Kamatani Yoichiro , Knodt Annchen R. , Li Shuo , Lim Keane , Longstreth W. T. , Macciardi Fabio ,   The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium,   The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium, Mäkitie Outi , Mazoyer Bernard , Medland Sarah E. , Miyamoto Susumu , Moebus Susanne , Mosley Thomas H. , Muetzel Ryan , Mühleisen Thomas W. , Nagata Manabu , Nakahara Soichiro , Palmer Nicholette D. , Pausova Zdenka , Preda Adrian , Quidé Yann , Reay William R. , Roshchupkin Gennady V. , Schmidt Reinhold , Schreiner Pamela J. , Setoh Kazuya , Shapland Chin Yang , Sidney Stephen , Pourcain Beate St , Stein Jason L. , Tabara Yasuharu , Teumer Alexander , Uhlmann Anne , van der Lugt Aad , Vernooij Meike W. , Werring David J. , Windham B. Gwen , Veronica Witte A. , Wittfeld Katharina , Yang Qiong , Yoshida Kazumichi , Brunner Han G. , Le Grand Quentin , Sim Kang , Stein Dan J. , Bowden Donald W. , Cairns Murray J. , Hariri Ahmad R. , Cheung Ching-Lung , Andersson Sture , Villringer Arno , Paus Tomas , Cichon Sven , Calhoun Vince D. , Crivello Fabrice , Launer Lenore J. , White Tonya , Koudstaal Peter J. , Houlden Henry , Fornage Myriam , Matsuda Fumihiko , Grabe Hans J. , Ikram M. Arfan , Debette Stéphanie , Thompson Paul M. , Seshadri Sudha , Adams Hieab H.H. 
Published: July 2020

The 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 asTP53,PTENandAPC– 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.