1. Genetic variants for head size share genes and pathways with cancer
- Author
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Shihua Li, Melissa J. Green, Nagata M, Miyamoto S, Le Grand Q, Pourcain Bs, Grabe Hj, Catherine Helmer, William R. Reay, Nele Friedrich, Mazoyer B, Seshadri S, Per Hoffmann, Simon Haworth, Veronica Witte A, Yang Q, Max Lam, Teunissen Mw, Fang-Chi Hsu, Debette S, Murray J. Cairns, Amod Ar, Setoh K, Windham Bg, Shareefa Dalvie, Georg Homuth, Charlie S. DeCarli, Gennady V. Roshchupkin, Céline S. Reinbold, Mühleisen Tw, Nakahara S, Van der Auwera S, Xueqiu Jian, Cecil Ca, Jean-François Dartigues, Alexa S. Beiser, Stein Jl, Houlden H, Christiane Jockwitz, Moebus S, Claudia L. Satizabal, Tavia E. Evans, Matsuda F, Cora E. Lewis, Wittfeld K, Calhoun Vd, van der Lugt A, Teumer A, Pausova Z, W. T. Longstreth, Aniket Mishra, Tomáš Paus, Vernooij Mw, Medland Se, Palmer Nd, Ahmad R. Hariri, Adrian Preda, Clifford R. Jack, van Erp Tg, Amaia Carrion-Castillo, Werring Dj, Gwénaëlle Catheline, Asta Håberg, Robin Bülow, Sven Cichon, Yann Quidé, Muetzel R, Tabara Y, Sidney S, Cheung C, Brunner Hg, Annchen R. Knodt, Mosley Th, van Dam-Nolen Dh, Hostettler Ic, Jean Shin, Shapland Cy, Reut Avinun, Crivello F, Mäkitie O, Fornage M, Yoshida K, Villringer A, Lim K, Schreiner Pj, Bowden Dw, Thompson Pm, Daniel Bos, Uhlmann A, Enlund-Cerullo M, Schmidt R, Hieab H.H. Adams, Neda Jahanshad, Frauke Beyer, Gloria H.Y. Li, Fabio Macciardi, Lamballais S, Kämpe A, Judith M. Ford, Poot Ra, J. C. Bis, Yoichiro Kamatani, Ami Tsuchida, Markus Scholz, Ikram Ma, Andersson S, Lenore J. Launer, Stein Dj, Koudstaal Pj, Barry I. Freedman, Barbara Franke, Ikram Mk, Sim K, Marie-Gabrielle Duperron, Bryan Rn, Svenja Caspers, Pawlak Ma, Tonya White, Maria J. Knol, Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, and Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium
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Genetics ,0303 health sciences ,education.field_of_study ,biology ,Population ,Wnt signaling pathway ,Macrocephaly ,Cancer ,medicine.disease ,Biological pathway ,03 medical and health sciences ,0302 clinical medicine ,medicine ,biology.protein ,PTEN ,Human height ,medicine.symptom ,education ,Gene ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
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 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.
- Published
- 2020
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