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Age-dependent genetic variants associated with longitudinal changes in brain structure across 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 Kremen, Matthew S. Panizzon, Loes M Olde Loohuis, Christopher D. Whelan, Moji Aghajani, Clara Alloza, Dag Alnaes, Eric Artiges, Rosa Ayesa-Arriola, Gareth J. Barker, Mark E Bastin, Elisabet Blok, Erlend Bøen, Isabella A Breukelaar, Joanna K Bright, Elizabeth EL Buimer, Robin Bülow, Dara M Cannon, Simone Ciufolini, Nicolas A Crossley, Christienne G Damatac, Paola Dazzan, Casper L de Mol, Sonja MC de Zwarte, Sylvane Desrivières, Covadonga M Díaz-Caneja, Nhat Trung Doan, Katharina Dohm, Juliane H. Fröhner, Janik Goltermann, Antoine Grigis, Dominik Grotegerd, Laura KM Han, Mathew Harris, 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 GJC Koevoets, Rhoshel K Lenroot, Berend Malchow, René CW 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 EM van Haren, Joanna M. Wardlaw, Wei Wen, Henk-Jan Westeneng, Katharina Wittfeld, Alyssa H Zhu, Andre Zugman, Nicola J. Armstrong, Gaia Bonfiglio, Janita Bralten, Shareefa Dalvie, Joanna M Wardlaw, Marta Di Forti, Linda Ding, Gary Donohoe, Andreas J. Forstner, Javier Gonzalez-Peňas, Joao Guimaraes, Georg Homuth, Jouke-Jan Hottenga, Maria J Knol, John Kwok, Stephanie Le Hellard, Karen A. Mather, Yuri Milaneschi, Derek W Morris, Markus M Nothen, 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, the IMAGEN consortium, Hieab HH 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 Buitelaar, Wiepke Cahn, Svenja Caspers, Sven Cichon, Benedicto Crespo Facorro, Simon R Cox, Udo Dannlowski, Torbjørn Elvsåshagen, Thomas Espeseth, Peter G Falkai, Simon E. Fisher, Herta Flor, Janice M. Fullerton, Hugh Garavan, Penny A Gowland, Hans-Jorgen Grabe, Tim Hahn, Andreas Heinz, Manon Hillegers, Jacqueline Hoare, Pieter J Hoekstra, Mohammad A Ikram, Andrea P. Jackowski, Andreas Jansen, Erik G Jönsson, René S. Kahn, Tilo Kircher, Mayuresh S. Korgaonkar, Axel Krug, Herve Lemaitre, Ulrik F. Malt, Jean-Luc Martinot, Colm McDonald, Philip Mitchell, Ryan L Muetzel, Robin M Murray, Frauke Nees, Igor Nenadic, Jaap Oosterlaan, Roel A Ophoff, Pedro M. Pan, Brenda WJH Penninx, Luise Poustka, Perminder S. Sachdev, Giovanni A Salum, Peter Schofield, Gunter Schumann, Philip Shaw, Kang Sim, Michael N Smolka, Dan J. Stein, Julian N 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. Here, we identified common genetic variants that affect rates of brain growth or atrophy, in the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal MRI data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genes GPR139, DACH1 and APOE are associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene-set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and ageing.

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