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Dynamics of Brain Structure and its Genetic Architecture over the Lifespan

By Rachel M Brouwer, Marieke Klein, Katrina L. Grasby, Hugo G. Schnack, Neda Jahanshad, Jalmar Teeuw, Sophia I Thomopoulos, Emma Sprooten, Carol E. Franz, Nitin Gogtay, William S. Kremen, Matthew S. Panizzon, Loes M. Olde Loohuis, Christopher D. Whelan, Moji Aghajani, Clara Alloza, Dag Alnæs, Eric Artiges, Rosa Ayesa-Arriola, Gareth J. Barker, Elisabet Blok, Erlend Bøen, Isabella A Breukelaar, Joanna K Bright, Elizabeth E. L. Buimer, Robin Bülow, Dara M. Cannon, Simone Ciufolini, Nicolas A Crossley, Christienne G. Damatac, Paola Dazzan, Casper L de Mol, Sonja M. C. de Zwarte, Sylvane Desrivières, Covadonga M. Díaz-Caneja, Nhat Trung Doan, Katharina Dohm, Juliane H. Fröhner, Janik Goltermann, Antoine Grigis, Dominik Grotegerd, Laura K M Han, Catharina A Hartman, Sarah J. Heany, Walter Heindel, Dirk J. Heslenfeld, Sarah Hohmann, Bernd Ittermann, Philip R Jansen, Joost Janssen, Tianye Jia, Jiyang Jiang, Christiane Jockwitz, Temmuz Karali, Daniel Keeser, Martijn G. J. C. Koevoets, Rhoshel K Lenroot, Berend Malchow, René C. W. Mandl, Vicente Medel, Susanne Meinert, Catherine A Morgan, Thomas W. Mühleisen, Leila Nabulsi, Nils Opel, Víctor Ortiz-García de la Foz, Bronwyn J Overs, Marie-Laure Paillère Martinot, Erin B. Quinlan, Ronny Redlich, Tiago Reis Marques, Jonathan Repple, Gloria Roberts, Gennady V. Roshchupkin, Nikita Setiaman, Elena Shumskaya, Frederike Stein, Gustavo Sudre, Shun Takahashi, Anbupalam Thalamuthu, Diana Tordesillas-Gutiérrez, Aad van der Lugt, Neeltje E. M. van Haren, Wei Wen, Henk-Jan Westeneng, Katharina Wittfeld, Andre Zugman, Nicola J. Armstrong, Janita Bralten, Shareefa Dalvie, Marta Di Forti, Linda Ding, Gary Donohoe, Andreas J. Forstner, Javier Gonzalez-Peñas, Joao P. O. F. T. Guimaraes, Georg Homuth, Jouke-Jan Hottenga, Maria J. Knol, John B. J. Kwok, Stephanie Le Hellard, Karen A. Mather, Yuri Milaneschi, Derek W. Morris, Markus M. Nöthen, Sergi Papiol, Marcella Rietschel, Marcos L. Santoro, Vidar M. Steen, Jason L. Stein, Fabian Streit, Rick M Tankard, Alexander Teumer, Dennis van ’t Ent, Dennis van der Meer, Kristel R. van Eijk, Evangelos Vassos, Javier Vázquez-Bourgon, Stephanie H. Witt, Alzheimer’s Disease Neuroimaging Initiative, Hieab H. H. Adams, Ingrid Agartz, David Ames, Katrin Amunts, Ole A. Andreassen, Celso Arango, Tobias Banaschewski, Bernhard T. Baune, Sintia I Belangero, Arun L. W. Bokde, Dorret I. Boomsma, Rodrigo A. Bressan, Henry Brodaty, Jan K. Buitelaar, Wiepke Cahn, Svenja Caspers, Sven Cichon, Benedicto Crespo Facorro, Udo Dannlowski, Torbjørn Elvsåshagen, Thomas Espeseth, Peter G Falkai, Simon E Fisher, Herta Flor, Janice M. Fullerton, Hugh Garavan, Penny A. Gowland, Hans J. Grabe, Tim Hahn, Andreas Heinz, Manon Hillegers, Jacqueline Hoare, Pieter J Hoekstra, Mohammad A Ikram, Andrea P Jackowski, Andreas Jansen, Erik G. Jönsson, Rene S Kahn, Tilo Kircher, Mayuresh S. Korgaonkar, Axel Krug, Herve Lemaitre, Ulrik F. Malt, Jean-Luc Martinot, Colm McDonald, Philip B Mitchell, Ryan L Muetzel, Robin M Murray, Frauke Nees, Igor Nenadic, Jaap Oosterlaan, Roel A. Ophoff, Pedro M Pan, Brenda W. J. H. Penninx, Luise Poustka, Perminder S Sachdev, Giovanni A. Salum, Peter R. Schofield, Gunter Schumann, Philip Shaw, Kang Sim, Michael N. Smolka, Dan J. Stein, Julian Trollor, Leonard H. van den Berg, Jan H. Veldink, Henrik Walter, Lars T. Westlye, Robert Whelan, Tonya White, Margaret J Wright, Sarah E. Medland, Barbara Franke, Paul M. Thompson, Hilleke E Hulshoff Pol

Posted 27 Apr 2020
bioRxiv DOI: 10.1101/2020.04.24.031138

Human brain structure changes throughout our lives. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental, and neurodegenerative diseases. While heritable, specific loci in the genome that influence these rates are largely unknown. Here, we sought to find common genetic variants that affect rates of brain growth or atrophy, in the first genome-wide association analysis of longitudinal changes in brain morphology across the lifespan. Longitudinal magnetic resonance imaging data from 10,163 individuals aged 4 to 99 years, on average 3.5 years apart, were used to compute rates of morphological change for 15 brain structures. We discovered 5 genome-wide significant loci and 15 genes associated with brain structural changes. Most individual variants exerted age-dependent effects. All identified genes are expressed in fetal and adult brain tissue, and some exhibit developmentally regulated expression across the lifespan. We demonstrate genetic overlap with depression, schizophrenia, cognitive functioning, height, body mass index and smoking. Several of the discovered loci are implicated in early brain development and point to involvement of metabolic processes. Gene-set findings also implicate immune processes in the rates of brain changes. Taken together, in the world's largest longitudinal imaging genetics dataset we identified genetic variants that alter age-dependent brain growth and atrophy throughout our lives. ### Competing Interest Statement BF has received speaking fees from MEDICE Arzneimittel Pütter GmbH & Co. BWJHP has received research funding from Jansen Research and Boehringer Ingelheim. CA has been a consultant to or has received honoraria or grants from Acadia, Angelini, Gedeon Richter, Janssen Cilag, Lundbeck, Minerva, Otsuka, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda. CDW is an employee of Biogen Inc. DJS has received research grants and/or consultancy honoraria from Lundbeck and Sun. GJB receives honoraria for teaching from GE Healthcare. HB is on the Advisory Board Nutricia Australia. HEH has received travel fees for membership of the Steering Committee of the Lundbeck Foundation Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research and for two presentations from Philips. These concerned activities unrelated to the submitted work. HJG has received travel grants and speaker's honoraria from Fresenius Medical Care, Neuraxpharm, Servier and Janssen Cilag as well as research funding from Fresenius Medical Care. LP has served as an advisor or consultant to Shire, Takeda and Roche. She has received speaking fees from Shire and Infectopharm. The present work is unrelated to these relationships. MHJ received grant support from the Brain and behavior Foundation (NARSAD) Independent Investigator grant number 20244. MMN has received fees for memberships in Scientific Advisory Boards from the Lundbeck Foundation and the Robert-Bosch-Stiftung, and for membership in the Medical-Scientific Editorial Office of the Deutsches Ärzteblatt. MMN was reimbursed travel expenses for a conference participation by Shire Deutschland GmbH. MMN receives salary payments from Life & Brain GmbH and holds shares in Life & Brain GmbH. All these concerned activities outside the submitted work. NJ and PMT are MPI's of a research grant from Biogen, Inc (Boston, USA) for work unrelated to the contents of this manuscript. OAA has received Speaker's honorarium from Lundbeck, Consultant for HealthLytix. PSS reports on-off payment for an advisory board meeting of Biogen. TB served in an advisory or consultancy role for Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Shire, and Infectopharm. He received conference support or speaker's fee by Lilly, Medice, and Shire. He received royalties from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press; the present work is unrelated to these relationships. TEl has received speaker's fee from Lundbeck AS. TRM has received honoraria for speaking and chairing engagements from Lundbeck, Janssen and Astellas.

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