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@ARTICLE{Grasby:154039,
author = {Grasby, Katrina L. and Jahanshad, Neda and Neuroimaging,
Mary Stevens and Painter, Jodie N. and Colodro-Conde, Lucía
and Bralten, Janita and Hibar, Derrek P. and Neuroimaging,
Mary Stevens and Lind, Penelope A. and Pizzagalli, Fabrizio
and Neuroimaging, Mary Stevens and Ching, Christopher R. K.
and Neuroimaging, Mary Stevens and McMahon, Mary Agnes B.
and Neuroimaging, Mary Stevens and Shatokhina, Natalia and
Neuroimaging, Mary Stevens and Zsembik, Leo C. P. and
Thomopoulos, Sophia I. and Neuroimaging, Mary Stevens and
Zhu, Alyssa H. and Neuroimaging, Mary Stevens and Strike,
Lachlan T. and Agartz, Ingrid and Alhusaini, Saud and
Almeida, Marcio A. A. and Diabetes, South Texas and Alnæs,
Dag and Amlien, Inge K. and Andersson, Micael and Ard, Tyler
and Neuroimaging, Mary Stevens and Armstrong, Nicola J. and
Ashley-Koch, Allison and Atkins, Joshua R. and Bernard,
Manon and Brouwer, Rachel M. and Buimer, Elizabeth E. L. and
Bülow, Robin and Bürger, Christian and Cannon, Dara M. and
Chakravarty, Mallar and Biological and Chen, Qiang and
Cheung, Joshua W. and Neuroimaging, Mary Stevens and
Couvy-Duchesne, Baptiste and Dale, Anders M. and Dalvie,
Shareefa and de Araujo, Tânia K. and de Zubicaray, Greig I.
and de Zwarte, Sonja M. C. and den Braber, Anouk and Doan,
Nhat Trung and Dohm, Katharina and Ehrlich, Stefan and
Medicine, Social and Engelbrecht, Hannah-Ruth and Erk,
Susanne and Psychiatry, Brain Research Department of and
Berlin, Psychotherapy Campus Charité Mitte Charité-
Universitätsmedizin Berlin corporate member of Freie
Universität Berlin Humboldt-Universität zu and Fan, Chun
Chieh and Fedko, Iryna O. and Foley, Sonya F. and Ford,
Judith M. and Fukunaga, Masaki and Garrett, Melanie E. and
Ge, Tian and Giddaluru, Sudheer and Goldman, Aaron L. and
Green, Melissa J. and Groenewold, Nynke A. and Grotegerd,
Dominik and Gurholt, Tiril P. and Gutman, Boris A. and
Neuroimaging, Mary Stevens and Hansell, Narelle K. and
Harris, Mathew A. and Harrison, Marc B. and Neuroimaging,
Mary Stevens and Haswell, Courtney C. and Hauser, Michael
and Herms, Stefan and Heslenfeld, Dirk J. and Ho, New Fei
and Hoehn, David and Hoffmann, Per and Holleran, Laurena and
Hoogman, Martine and Hottenga, Jouke-Jan and Ikeda, Masashi
and Janowitz, Deborah and Jansen, Iris E. and Jia, Tianye
and Jockwitz, Christiane and Kanai, Ryota and Karama, Sherif
and Kasperaviciute, Dalia and Kaufmann, Tobias and Kelly,
Sinead and Kikuchi, Masataka and Klein, Marieke and Knapp,
Michael and Knodt, Annchen R. and Krämer, Bernd and
Psychiatry, Psychiatry Department of and Lam, Max and
Lancaster, Thomas M. and Lee, Phil H. and Lett, Tristram A.
and Psychiatry, Brain Research Department of and Berlin,
Psychotherapy Campus Charité Mitte Charité-
Universitätsmedizin Berlin corporate member of Freie
Universität Berlin Humboldt-Universität zu and Lewis,
Lindsay B. and Lopes-Cendes, Iscia and Luciano, Michelle and
Macciardi, Fabio and Marquand, Andre F. and Mathias, Samuel
R. and Melzer, Tracy R. and Milaneschi, Yuri and
Universiteit, Amsterdam Neuroscience Amsterdam UMC/Vrije and
Mirza-Schreiber, Nazanin and Moreira, Jose C. V. and
Mühleisen, Thomas W. and Müller-Myhsok, Bertram and Najt,
Pablo and Nakahara, Soichiro and Nho, Kwangsik and Olde
Loohuis, Loes M. and Orfanos, Dimitri Papadopoulos and
Pearson, John F. and Pitcher, Toni L. and Pütz, Benno and
Quidé, Yann and Ragothaman, Anjanibhargavi and
Neuroimaging, Mary Stevens and Rashid, Faisal M. and
Neuroimaging, Mary Stevens and Reay, William R. and Redlich,
Ronny and Reinbold, Céline S. and Repple, Jonathan and
Richard, Geneviève and Riedel, Brandalyn C. and
Neuroimaging, Mary Stevens and Risacher, Shannon L. and
Rocha, Cristiane S. and Mota, Nina Roth and Salminen, Lauren
and Neuroimaging, Mary Stevens and Saremi, Arvin and
Neuroimaging, Mary Stevens and Saykin, Andrew J. and Schlag,
Fenja and Schmaal, Lianne and Schofield, Peter R. and
Secolin, Rodrigo and Shapland, Chin Yang and Shen, Li and
Shin, Jean and Shumskaya, Elena and Sønderby, Ida E. and
Sprooten, Emma and Tansey, Katherine E. and Teumer,
Alexander and Thalamuthu, Anbupalam and
Tordesillas-Gutiérrez, Diana and Turner, Jessica A. and
Uhlmann, Anne and Vallerga, Costanza Ludovica and van der
Meer, Dennis and Hospital, Addiction Oslo University and
Medicine, Neuroscience Faculty of Health and van Donkelaar,
Marjolein M. J. and van Eijk, Liza and van Erp, Theo G. M.
and van Haren, Neeltje E. M. and van Rooij, Daan and van
Tol, Marie-José and Veldink, Jan H. and Verhoef, Ellen and
Walton, Esther and Wang, Mingyuan and Wang, Yunpeng and
Wardlaw, Joanna M. and Wen, Wei and Westlye, Lars T. and
Whelan, Christopher D. and Neuroimaging, Mary Stevens and
Witt, Stephanie H. and Wittfeld, Katharina and Wolf,
Christiane and Wolfers, Thomas and Wu, Jing Qin and Yasuda,
Clarissa L. and Zaremba, Dario and Zhang, Zuo and Zwiers,
Marcel P. and Artiges, Eric and Assareh, Amelia A. and
Ayesa-Arriola, Rosa and Belger, Aysenil and Brandt,
Christine L. and Brown, Gregory G. and Cichon, Sven and
Curran, Joanne E. and Diabetes, South Texas and Davies,
Gareth E. and Degenhardt, Franziska and Dennis, Michelle F.
and Dietsche, Bruno and Djurovic, Srdjan and Doherty, Colin
P. and Espiritu, Ryan and Garijo, Daniel and Gil, Yolanda
and Gowland, Penny A. and Green, Robert C. and Häusler,
Alexander N. and Heindel, Walter and Ho, Beng-Choon and
Hoffmann, Wolfgang and Holsboer, Florian and Homuth, Georg
and Hosten, Norbert and Jack, Clifford R. and Jang, MiHyun
and Jansen, Andreas and Kimbrel, Nathan A. and Kolskår,
Knut and Koops, Sanne and Krug, Axel and Lim, Kelvin O. and
Luykx, Jurjen J. and Mathalon, Daniel H. and Mather, Karen
A. and Mattay, Venkata S. and Matthews, Sarah and Mayoral
Van Son, Jaqueline and McEwen, Sarah C. and Melle, Ingrid
and Morris, Derek W. and Mueller, Bryon A. and Nauck,
Matthias and Nordvik, Jan E. and Nöthen, Markus M. and
O’Leary, Daniel S. and Opel, Nils and Martinot,
Marie-Laure Paillère and Pike, G. Bruce and Preda, Adrian
and Quinlan, Erin B. and Rasser, Paul E. and Ratnakar, Varun
and Reppermund, Simone and Steen, Vidar M. and Tooney, Paul
A. and Torres, Fábio R. and Veltman, Dick J. and Voyvodic,
James T. and Whelan, Robert and White, Tonya and Yamamori,
Hidenaga and Adams, Hieab H. H. and Bis, Joshua C. and
Debette, Stephanie and Decarli, Charles and Fornage, Myriam
and Gudnason, Vilmundur and Hofer, Edith and Ikram, M. Arfan
and Launer, Lenore and Longstreth, W. T. and Lopez, Oscar L.
and Mazoyer, Bernard and Mosley, Thomas H. and Roshchupkin,
Gennady V. and Satizabal, Claudia L. and Schmidt, Reinhold
and Seshadri, Sudha and Yang, Qiong and Alvim, Marina K. M.
and Ames, David and Anderson, Tim J. and Andreassen, Ole A
and Arias-Vasquez, Alejandro and Bastin, Mark E. and Baune,
Bernhard T. and Beckham, Jean C. and Blangero, John and
Diabetes, South Texas and Boomsma, Dorret I. and Brodaty,
Henry and Brunner, Han G. and Oncology, School for and
Buckner, Randy L. and Buitelaar, Jan K. and Bustillo, Juan
R. and Cahn, Wiepke and Cairns, Murray J. and Calhoun, Vince
and Carr, Vaughan J. and Caseras, Xavier and Caspers, Svenja
and Cavalleri, Gianpiero L. and Cendes, Fernando and Corvin,
Aiden and Crespo-Facorro, Benedicto and Dalrymple-Alford,
John C. and Dannlowski, Udo and de Geus, Eco J. C. and
Deary, Ian J. and Delanty, Norman and Depondt, Chantal and
Desrivières, Sylvane and Donohoe, Gary and Espeseth, Thomas
and Fernández, Guillén and Fisher, Simon E. and Flor,
Herta and Forstner, Andreas J. and Francks, Clyde and
Franke, Barbara and Glahn, David C. and Gollub, Randy L. and
Grabe, Hans J. and Gruber, Oliver and Håberg, Asta K. and
Hariri, Ahmad R. and Hartman, Catharina A. and Hashimoto,
Ryota and Heinz, Andreas and Henskens, Frans A. and
Hillegers, Manon H. J. and Hoekstra, Pieter J. and Holmes,
Avram J. and Hong, L. Elliot and Hopkins, William D. and
Hulshoff Pol, Hilleke E. and Jernigan, Terry L. and
Jönsson, Erik G. and Kahn, René S. and Kennedy, Martin A.
and Kircher, Tilo T. J. and Kochunov, Peter and Kwok, John
B. J. and Brain, Epigenetics and Le Hellard, Stephanie and
Loughland, Carmel M. and Martin, Nicholas G. and Martinot,
Jean-Luc and McDonald, Colm and McMahon, Katie L. and
Meyer-Lindenberg, Andreas and Michie, Patricia T. and Morey,
Rajendra A. and Mowry, Bryan and Nyberg, Lars and
Oosterlaan, Jaap and Ophoff, Roel A. and Pantelis, Christos
and Paus, Tomas and Pausova, Zdenka and Penninx, Brenda W.
J. H. and Polderman, Tinca J. C. and Posthuma, Danielle and
Rietschel, Marcella and Roffman, Joshua L. and Rowland,
Laura M. and Sachdev, Perminder S. and Sämann, Philipp G.
and Schall, Ulrich and Schumann, Gunter and Scott, Rodney J.
and Sim, Kang and Sisodiya, Sanjay M. and Smoller, Jordan W.
and Sommer, Iris E. and St Pourcain, Beate and Stein, Dan J.
and Toga, Arthur W. and Neuroimaging, Mary Stevens and
Trollor, Julian N. and Van der Wee, Nic J. A. and van ’t
Ent, Dennis and Völzke, Henry and Walter, Henrik and
Psychiatry, Brain Research Department of and Berlin,
Psychotherapy Campus Charité Mitte Charité-
Universitätsmedizin Berlin corporate member of Freie
Universität Berlin Humboldt-Universität zu and Weber,
Bernd and Weinberger, Daniel R. and Wright, Margaret J. and
Zhou, Juan and Stein, Jason L. and Thompson, Paul M. and
Neuroimaging, Mary Stevens and Medland, Sarah E.},
othercontributors = {Psychology, Precision Medicine Institute of Psychiatry and
Psychology, Precision Medicine Institute of Psychiatry},
title = {{T}he genetic architecture of the human cerebral cortex},
journal = {Science / Science now},
volume = {367},
number = {6484},
issn = {1095-9203},
address = {Washington, DC},
publisher = {Assoc.73085},
reportid = {DZNE-2021-00021},
pages = {eaay6690 -},
year = {2020},
abstract = {INTRODUCTIONThe cerebral cortex underlies our complex
cognitive capabilities. Variations in human cortical surface
area and thickness are associated with neurological,
psychological, and behavioral traits and can be measured in
vivo by magnetic resonance imaging (MRI). Studies in model
organisms have identified genes that influence cortical
structure, but little is known about common genetic variants
that affect human cortical structure.RATIONALETo identify
genetic variants associated with human cortical structure at
both global and regional levels, we conducted a genome-wide
association meta-analysis of brain MRI data from 51,665
individuals across 60 cohorts. We analyzed the surface area
and average thickness of the whole cortex and 34 cortical
regions with known functional specializations.RESULTSWe
identified 306 nominally genome-wide significant loci (P < 5
× 10−8) associated with cortical structure in a discovery
sample of 33,992 participants of European ancestry. Of the
299 loci for which replication data were available, 241 loci
influencing surface area and 14 influencing thickness
remained significant after replication, with 199 loci
passing multiple testing correction (P < 8.3 × 10−10; 187
influencing surface area and 12 influencing
thickness).Common genetic variants explained $34\%$ (SE =
$3\%)$ of the variation in total surface area and $26\%$ (SE
= $2\%)$ in average thickness; surface area and thickness
showed a negative genetic correlation (rG = −0.32, SE =
0.05, P = 6.5 × 10−12), which suggests that genetic
influences have opposing effects on surface area and
thickness. Bioinformatic analyses showed that total surface
area is influenced by genetic variants that alter gene
regulatory activity in neural progenitor cells during fetal
development. By contrast, average thickness is influenced by
active regulatory elements in adult brain samples, which may
reflect processes that occur after mid-fetal development,
such as myelination, branching, or pruning. When considered
together, these results support the radial unit hypothesis
that different developmental mechanisms promote surface area
expansion and increases in thickness.To identify specific
genetic influences on individual cortical regions, we
controlled for global measures (total surface area or
average thickness) in the regional analyses. After multiple
testing correction, we identified 175 loci that influence
regional surface area and 10 that influence regional
thickness. Loci that affect regional surface area cluster
near genes involved in the Wnt signaling pathway, which is
known to influence areal identity.We observed significant
positive genetic correlations and evidence of bidirectional
causation of total surface area with both general cognitive
functioning and educational attainment. We found additional
positive genetic correlations between total surface area and
Parkinson’s disease but did not find evidence of
causation. Negative genetic correlations were evident
between total surface area and insomnia, attention deficit
hyperactivity disorder, depressive symptoms, major
depressive disorder, and neuroticism.CONCLUSIONThis
large-scale collaborative work enhances our understanding of
the genetic architecture of the human cerebral cortex and
its regional patterning. The highly polygenic architecture
of the cortex suggests that distinct genes are involved in
the development of specific cortical areas. Moreover, we
find evidence that brain structure is a key phenotype along
the causal pathway that leads from genetic variation to
differences in general cognitive function.},
cin = {AG Hoffmann},
ddc = {320},
cid = {I:(DE-2719)1510600},
pnm = {344 - Clinical and Health Care Research (POF3-344)},
pid = {G:(DE-HGF)POF3-344},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:32193296},
doi = {10.1126/science.aay6690},
url = {https://pub.dzne.de/record/154039},
}
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