Search

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.

Genomics; Perivascular space Genòmica; Espai perivascular Genómica; Espacio perivascular Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort (N = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets. Austrian Stroke Prevention Study (ASPS)/Austrian Stroke Prevention Family Study (ASPS-Fam) (E.H., P.G.G., H.S. and R.S.): We thank the staff and the participants for their valuable contributions. We thank B. Reinhart for her long-term administrative commitment, E. Hofer for the technical assistance in creating the DNA bank, J. Semmler and A. Harb for DNA sequencing and DNA analyses by TaqMan assays, and I. Poelzl for supervising the quality management processes after ISO9001 in the biobanking and DNA analyses. The Medical University of Graz and the Steiermärkische Krankenanstaltengesellschaft support the databank of the ASPS/ASPS-Fam. The research reported in this article was funded by the Austrian Science Fund (FWF) (grant nos. PI904, P20545-P05 and P13180) and supported by the Austrian National Bank Anniversary Fund (grant no. P15435) and the Austrian Ministry of Science under the aegis of the EU Joint Programme–Neurodegenerative Disease Research (JPND): www.jpnd.eu. Epidemiology of Dementia in Singapore (EDIS) (S.H., C.Chen, C.-Y.C., T.Y.W. and W.Z.): The EDIS study is supported by the National Medical Research Council (NMRC), Singapore (NMRC/CG/NUHS/2010 (grant no. R-184-006-184-511), NMRC/CSA/038/2013) and a Ministry of Education Tier 1 grant (no. A-0006106-00-00). Framingham Heart Study (FHS) (J.R.R., A.B., J.J.H., S.L., P.P., C.L.S., Q.Y. and S.Seshadri): This work was supported by the National Heart, Lung and Blood Institute’s FHS Contract (no. N01-HC-25195, no. HHSN268201500001I and no. 75N92019D00031). This study was also supported by grants from the National Institute of Aging (R01 grant nos. AG031287, AG054076, AG049607, AG059421, AG059725; U01 grant nos. AG049505, AG052409) and the National Institute of Neurological Disorders and Stroke (R01 grant no. NS017950). Funding for SHARe Affymetrix genotyping was provided by NHLBI Contract no. N02-HL64278. The computational work reported in this paper was performed on the Shared Computing Cluster which is administered by Boston University’s Research Computing Services. We also thank all the FHS study participants. Internet-based Students’ Health Research Enterprise (i-Share) study (C.B., J.Z., M.M., Q.LG., S. Schilling, Y.-C.Z., A.Tsuchida, M.-G.D., B.M., S.D. and C.T.): The i-Share study is conducted by the Universities of Bordeaux and Versailles Saint-Quentin-en-Yvelines (France). The i-Share study has received funding by the French National Agency (Agence Nationale de la Recherche, ANR), via the Investment for the Future program (grant nos. ANR-10-COHO-05 and ANR-18-RHUS-0002) and from the University of Bordeaux Initiative of Exellence (IdEX). This project has also received funding from the European Research Council under the European Union’s Horizon 2020 research and innovation program under grant agreement no. 640643 and from the Fondation pour la Recherche Médicale (grant no. DIC202161236446). Q.L.G. was supported by the Digital Public Health Graduate Program (DPH), a PhD program supported by the French Investment for the Future Program (grant no. 17-EURE-0019). Investigating Silent Strokes in Hypertensives: a Magnetic Resonance Imaging Study (ISSYS) (P.D., C.C. and I.F.-C.): This research was funded by the Instituto de Salud Carlos III (grant nos. PI10/0705, PI14/01535, PI17/02222), cofinanced by the European Regional Development Fund. Lothian Birth Cohort 1936 (LBC1936) (M.L., M.E.B., I.J.D., Z.M., S.M.M., M.C.V.H. and J.M.W.): We thank the LBC1936 cohort members and research staff involved in data collection, processing and preparation. The LBC1936 is supported by Age UK (Disconnected Mind program grant). The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross-council Lifelong Health and Wellbeing Initiative (grant no. MR/K026992/1). The brain imaging was performed in the Brain Research Imaging Centre (www.bric.ed.ac.uk), a center in the SINAPSE Collaboration (www.sinapse.ac.uk) supported by the Scottish Funding Council and Chief Scientist Office. Funding from the UK Biotechnology and Biological Sciences Research Council (BBSRC), the UK Medical Research Council (MRC), the Row Fogo Charitable Trust (M.C.V.H.) and the UK Dementia Research Institute, which receives its funding from the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK (J.M.W.), is gratefully acknowledged. Genotyping was supported by a grant from the BBSRC (no. BB/F019394/1). The Nagahama Study (T.K., S.M., M.O., K.S., Y.T., K.Y., A.Tsuchida, P.B., B.M., M.J., M.-G.D. and F.M.): We are grateful to the Nagahama City Office and nonprofit organization Zeroji Club for their help in conducting the study. This project is supported by operational funds of Kyoto University and the Top Global University Project of the Ministry of Education, Culture, Sports, Science and Technology (MEXT) in Japan. We also received a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science, research grants from the Japan Agency for Medical Research and Development for the Practical Research Project for Rare/Intractable Diseases, and the Comprehensive Research on Aging and Health Science for Dementia R&D. We thank C. Galmiche for rating PVS in the validation dataset for the artificial intelligence-based method. The Northern Manhattan Study (NOMAS) (N.D.D., T.J. and R.L.S.): We gratefully acknowledge and thank the NOMAS participants. Funding was awarded through grants from the National Institute of Neurological Disorders and Stroke (R01 grant no. NS 29993) and the Evelyn F. McKnight Brain Institute. Rotterdam Study (M.J.K., F.D., M.W.V., M.A.I. and H.H.H.A.): The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The generation and management of GWAS genotype data for the Rotterdam Study (RS I, RS II, RS III) were executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands. The GWAS datasets are supported by the Netherlands Organisation for Scientific Research (NWO) Investments (no. 175.010.2005.011, 911-03-012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (grant no. 014-93-015; RIDE2), the Netherlands Genomics Initiative/NWO, the Netherlands Consortium for Healthy Aging, project no. 050-060-810. We thank P. Arp, M. Jhamai, M. Verkerk, L. Herrera, M. Peters and C. Medina-Gomez for their help in creating the GWAS database; and K. Estrada, Y. Aulchenko and C. Medina-Gomez for the creation and analysis of imputed data. H.H.H.A. is supported by ZonMW grant no. 916.19.151. Study of Health in Pomerania (SHIP) (S.F., R.B., A.T., K.W., H.J.G. and U.V.): SHIP is part of the Community Medicine Research net (CMR) (http://www.medizin.uni-greifswald.de/icm) of the University Medicine Greifswald, which is funded by the Federal Ministry of Education and Research (grant nos. 01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network ‘Greifswald Approach to Individualized Medicine (GANI_MED)’ funded by the Federal Ministry of Education and Research (grant no. 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthineers, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the Caché Campus program of the InterSystems GmbH. This study was further supported by the EU-JPND Funding for BRIDGET (grant no. FKZ:01ED1615). H.J.G. has received travel grants and speakers’ honoraria from Fresenius Medical Care, Servier, Neuraxpharm and Janssen Cilag, as well as research funding from Fresenius Medical Care. Sydney Memory and Ageing Study (MAS) & Older Australian Twins Study (OATS) (R.M.T., N.J.A., H.B., J.J., M.P., A.T., J.N.T., P.S.S., W.W., K.A.M. and M.J.W.): Sydney MAS: The Sydney MAS has been funded by three National Health & Medical Research Council (NHMRC) Program Grants (grant nos. ID350833, ID568969 and APP1093083). Collection of WGS data was supported by the NHMRC National Institute for Dementia Research Grants no. APP1115575 and no. APP1115462. MRI scans were processed with the support of NHMRC Project Grants (grant nos. 510175 and 1025243) and an Australian Research Council (ARC) Discovery Project Grant (no. DP0774213) and the John Holden Family Foundation. We also thank the MRI Facility at NeuRA. We thank the participants and their informants for their time and generosity in contributing to this research. We also acknowledge the MAS research team: https://cheba.unsw.edu.au/research-projects/sydney-memory-and-ageing-study. OATS: The OATS study has been funded by an NHMRC and ARC Strategic Award Grant of the Ageing Well, Ageing Productively Program (grant no. 401162); NHMRC Project (seed) Grants (grant nos. 1024224 and 1025243); NHMRC Project Grants (grant nos. 1045325 and 1085606); and NHMRC Program Grants (grant nos. 568969 and 1093083). Collection of WGS data was supported by the NHMRC National Institute for Dementia Research Grants no. APP1115575 and no. APP1115462. This research was facilitated through access to Twins Research Australia, a national resource supported by a Centre of Research Excellence Grant (no. 1079102) from the National Health and Medical Research Council. We thank the participants for their time and generosity in contributing to this research. We acknowledge the contribution of the OATS research team (https://cheba.unsw.edu.au/project/older-australian-twins-study) to this study. Three-City Dijon Study (3C-Dijon) (S.D., M.-G.D., S. Schilling, C.T., B.M. and A.M.): This project is supported by a grant overseen by the French National Research Agency (ANR) as part of the ‘Investment for the Future Program’ no. ANR-18-RHUS-0002. It is also supported by a JPND project through the following funding organizations under the aegis of JPND: www.jpnd.eu: Australia, National Health and Medical Research Council; Austria, Federal Ministry of Science, Research and Economy; Canada, Canadian Institutes of Health Research; France, French National Research Agency; Germany, Federal Ministry of Education and Research; the Netherlands, the Netherlands Organisation for Health Research and Development; United Kingdom, Medical Research Council. This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement nos. 643417, 640643, 667375 and 754517. The project also received funding from the French National Research Agency (ANR) through the VASCOGENE and SHIVA projects, and from the Initiative of Excellence of the University of Bordeaux (C-SMART project). Computations were performed on the Bordeaux Bioinformatics Center (CBiB) computer resources, University of Bordeaux. Funding support for additional computer resources at the CREDIM (Centre de Recherche et Développement en Informatique Médicale, University of Bordeaux) has been provided to S.D. by the Fondation Claude Pompidou. The Three-City (3C) Study: The 3C Study is conducted under a partnership agreement among the Institut National de la Santé et de la Recherche Médicale (INSERM), the University of Bordeaux and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study is also supported by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, Mutuelle Générale de l’Education Nationale (MGEN), Institut de la Longévité, Conseils Régionaux of Aquitaine and Bourgogne, Fondation de France and Ministry of Research–INSERM program ‘Cohortes et collections de données biologiques.’ C.T. and S.D. have received investigator-initiated research funding from the French National Research Agency (ANR) and from the Fondation Leducq. M.-G.D. received a grant from the ‘Fondation Bettencourt Schueller’. We thank P. Amouyel, U1167 Institut Pasteur de Lille - University of Lille - Inserm, for supporting funding of genome-wide genotyping of the 3C Study. This work was supported by the National Foundation for Alzheimer’s disease and related disorders, the Institut Pasteur de Lille, the labex DISTALZ and the Centre National de Génotypage. We thank A. Boland (CNG) for her technical help in preparing the DNA samples for analyses. UK Biobank (UKB) (M.J.K., F.D., M.W.V., M.A.I., H.H.H.A., A.M. and T.E.): This research has been conducted using the UK Resource under application no. 23509. McGill Genome Center (M.B., P.M., G.B. and M.Lathrop): Work done at the Canadian Center for Computational Genomics was supported by Genome Canada. Data analyses were enabled by computing and storage resources provided by Compute Canada and Calcul Québec. G.B. is supported by the Fonds de Recherche Santé Québec and the Canada Research Chair program. We thank all the participating cohorts for contributing to this study. We thank H. Jacqmin-Gadda, Bordeaux Population Health research center, University of Bordeaux/Inserm U1219 for statistical advice. We thank J. Thomas-Crusells, Bordeaux Population Health Research Center, University of Bordeaux/Inserm U1219, for editorial assistance. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.