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Meta-Analysis
. 2020 Mar 20;367(6484):eaay6690.
doi: 10.1126/science.aay6690.

The genetic architecture of the human cerebral cortex

Katrina L Grasby #, Neda Jahanshad #, Jodie N Painter #, Lucía Colodro-Conde #, Janita Bralten #, Derrek P Hibar #, Penelope A Lind #, Fabrizio Pizzagalli #, Christopher R K Ching, Mary Agnes B McMahon, Natalia Shatokhina, Leo C P Zsembik, Sophia I Thomopoulos, Alyssa H Zhu, Lachlan T Strike, Ingrid Agartz, Saud Alhusaini, Marcio A A Almeida, Dag Alnæs, Inge K Amlien, Micael Andersson, Tyler Ard, Nicola J Armstrong, Allison Ashley-Koch, Joshua R Atkins, Manon Bernard, Rachel M Brouwer, Elizabeth E L Buimer, Robin Bülow, Christian Bürger, Dara M Cannon, Mallar Chakravarty, Qiang Chen, Joshua W Cheung, Baptiste Couvy-Duchesne, Anders M Dale, Shareefa Dalvie, Tânia K de Araujo, Greig I de Zubicaray, Sonja M C de Zwarte, Anouk den Braber, Nhat Trung Doan, Katharina Dohm, Stefan Ehrlich, Hannah-Ruth Engelbrecht, Susanne Erk, Chun Chieh Fan, Iryna O Fedko, Sonya F Foley, Judith M Ford, Masaki Fukunaga, Melanie E Garrett, Tian Ge, Sudheer Giddaluru, Aaron L Goldman, Melissa J Green, Nynke A Groenewold, Dominik Grotegerd, Tiril P Gurholt, Boris A Gutman, Narelle K Hansell, Mathew A Harris, Marc B Harrison, Courtney C Haswell, Michael Hauser, Stefan Herms, Dirk J Heslenfeld, New Fei Ho, David Hoehn, Per Hoffmann, Laurena Holleran, Martine Hoogman, Jouke-Jan Hottenga, Masashi Ikeda, Deborah Janowitz, Iris E Jansen, Tianye Jia, Christiane Jockwitz, Ryota Kanai, Sherif Karama, Dalia Kasperaviciute, Tobias Kaufmann, Sinead Kelly, Masataka Kikuchi, Marieke Klein, Michael Knapp, Annchen R Knodt, Bernd Krämer, Max Lam, Thomas M Lancaster, Phil H Lee, Tristram A Lett, Lindsay B Lewis, Iscia Lopes-Cendes, Michelle Luciano, Fabio Macciardi, Andre F Marquand, Samuel R Mathias, Tracy R Melzer, Yuri Milaneschi, Nazanin Mirza-Schreiber, Jose C V Moreira, Thomas W Mühleisen, Bertram Müller-Myhsok, Pablo Najt, Soichiro Nakahara, Kwangsik Nho, Loes M Olde Loohuis, Dimitri Papadopoulos Orfanos, John F Pearson, Toni L Pitcher, Benno Pütz, Yann Quidé, Anjanibhargavi Ragothaman, Faisal M Rashid, William R Reay, Ronny Redlich, Céline S Reinbold, Jonathan Repple, Geneviève Richard, Brandalyn C Riedel, Shannon L Risacher, Cristiane S Rocha, Nina Roth Mota, Lauren Salminen, Arvin Saremi, Andrew J Saykin, Fenja Schlag, Lianne Schmaal, Peter R Schofield, Rodrigo Secolin, Chin Yang Shapland, Li Shen, Jean Shin, Elena Shumskaya, Ida E Sønderby, Emma Sprooten, Katherine E Tansey, Alexander Teumer, Anbupalam Thalamuthu, Diana Tordesillas-Gutiérrez, Jessica A Turner, Anne Uhlmann, Costanza Ludovica Vallerga, Dennis van der Meer, Marjolein M J van Donkelaar, Liza van Eijk, Theo G M van Erp, Neeltje E M van Haren, Daan van Rooij, Marie-José van Tol, Jan H Veldink, Ellen Verhoef, Esther Walton, Mingyuan Wang, Yunpeng Wang, Joanna M Wardlaw, Wei Wen, Lars T Westlye, Christopher D Whelan, Stephanie H Witt, Katharina Wittfeld, Christiane Wolf, Thomas Wolfers, Jing Qin Wu, Clarissa L Yasuda, Dario Zaremba, Zuo Zhang, Marcel P Zwiers, Eric Artiges, Amelia A Assareh, Rosa Ayesa-Arriola, Aysenil Belger, Christine L Brandt, Gregory G Brown, Sven Cichon, Joanne E Curran, Gareth E Davies, Franziska Degenhardt, Michelle F Dennis, Bruno Dietsche, Srdjan Djurovic, Colin P Doherty, Ryan Espiritu, Daniel Garijo, Yolanda Gil, Penny A Gowland, Robert C Green, Alexander N Häusler, Walter Heindel, Beng-Choon Ho, Wolfgang U Hoffmann, Florian Holsboer, Georg Homuth, Norbert Hosten, Clifford R Jack Jr, MiHyun Jang, Andreas Jansen, Nathan A Kimbrel, Knut Kolskår, Sanne Koops, Axel Krug, Kelvin O Lim, Jurjen J Luykx, Daniel H Mathalon, Karen A Mather, Venkata S Mattay, Sarah Matthews, Jaqueline Mayoral Van Son, Sarah C McEwen, Ingrid Melle, Derek W Morris, Bryon A Mueller, Matthias Nauck, Jan E Nordvik, Markus M Nöthen, Daniel S O'Leary, Nils Opel, Marie-Laure Paillère Martinot, G Bruce Pike, Adrian Preda, Erin B Quinlan, Paul E Rasser, Varun Ratnakar, Simone Reppermund, Vidar M Steen, Paul A Tooney, Fábio R Torres, Dick J Veltman, James T Voyvodic, Robert Whelan, Tonya White, Hidenaga Yamamori, Hieab H H Adams, Joshua C Bis, Stephanie Debette, Charles Decarli, Myriam Fornage, Vilmundur Gudnason, Edith Hofer, M Arfan Ikram, Lenore Launer, W T Longstreth, Oscar L Lopez, Bernard Mazoyer, Thomas H Mosley, Gennady V Roshchupkin, Claudia L Satizabal, Reinhold Schmidt, Sudha Seshadri, Qiong Yang; Alzheimer’s Disease Neuroimaging Initiative; CHARGE Consortium; EPIGEN Consortium; IMAGEN Consortium; SYS Consortium; Parkinson’s Progression Markers Initiative; Marina K M Alvim, David Ames, Tim J Anderson, Ole A Andreassen, Alejandro Arias-Vasquez, Mark E Bastin, Bernhard T Baune, Jean C Beckham, John Blangero, Dorret I Boomsma, Henry Brodaty, Han G Brunner, Randy L Buckner, Jan K Buitelaar, Juan R Bustillo, Wiepke Cahn, Murray J Cairns, Vince Calhoun, Vaughan J Carr, Xavier Caseras, Svenja Caspers, Gianpiero L Cavalleri, Fernando Cendes, Aiden Corvin, Benedicto Crespo-Facorro, John C Dalrymple-Alford, Udo Dannlowski, Eco J C de Geus, Ian J Deary, Norman Delanty, Chantal Depondt, Sylvane Desrivières, Gary Donohoe, Thomas Espeseth, Guillén Fernández, Simon E Fisher, Herta Flor, Andreas J Forstner, Clyde Francks, Barbara Franke, David C Glahn, Randy L Gollub, Hans J Grabe, Oliver Gruber, Asta K Håberg, Ahmad R Hariri, Catharina A Hartman, Ryota Hashimoto, Andreas Heinz, Frans A Henskens, Manon H J Hillegers, Pieter J Hoekstra, Avram J Holmes, L Elliot Hong, William D Hopkins, Hilleke E Hulshoff Pol, Terry L Jernigan, Erik G Jönsson, René S Kahn, Martin A Kennedy, Tilo T J Kircher, Peter Kochunov, John B J Kwok, Stephanie Le Hellard, Carmel M Loughland, Nicholas G Martin, Jean-Luc Martinot, Colm McDonald, Katie L McMahon, Andreas Meyer-Lindenberg, Patricia T Michie, Rajendra A Morey, Bryan Mowry, Lars Nyberg, Jaap Oosterlaan, Roel A Ophoff, Christos Pantelis, Tomas Paus, Zdenka Pausova, Brenda W J H Penninx, Tinca J C Polderman, Danielle Posthuma, Marcella Rietschel, Joshua L Roffman, Laura M Rowland, Perminder S Sachdev, Philipp G Sämann, Ulrich Schall, Gunter Schumann, Rodney J Scott, Kang Sim, Sanjay M Sisodiya, Jordan W Smoller, Iris E Sommer, Beate St Pourcain, Dan J Stein, Arthur W Toga, Julian N Trollor, Nic J A Van der Wee, Dennis van 't Ent, Henry Völzke, Henrik Walter, Bernd Weber, Daniel R Weinberger, Margaret J Wright, Juan Zhou, Jason L Stein #, Paul M Thompson #, Sarah E Medland #; Enhancing NeuroImaging Genetics through Meta-Analysis Consortium (ENIGMA)—Genetics working group
Collaborators
Meta-Analysis

The genetic architecture of the human cerebral cortex

Katrina L Grasby et al. Science. .

Erratum in

Abstract

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.

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Figures

Fig. 1.
Fig. 1.. Regions of the human cortex and associated genetic loci.
(A) The 34 cortical regions defined by the Desikan-Killiany atlas. (B) Ideogram of loci that influence cortical SA and TH.
Fig. 2.
Fig. 2.. Genetics of global measures.
(A) Genetic correlations between global measures and selected traits (red indicates significant correlation, FDR < 0.05). Error bars indicate SE. (B) Partitioned heritability enrichment in active regulatory elements across tissues and cell types. ESC, embryonic stem cells; iPSC, induced pluripotent stem cells; ES–deriv, embryonic stem derived; HSC, hematopoietic stem cells; Mesench, mesenchymal; Myosat, myosatellite; Neurosph, neurosphere; Sm. Muscle, smooth muscle. (C) Partitioned heritability enrichment in temporally specific active regulatory elements. (D) Partitioned heritability enrichment in regulatory elements of cell type–specific genes in the fetal brain. (E) Manhattan plot of loci associated with total SA (top) and average TH (bottom). Green diamonds indicate lead SNPs in the principal meta-analysis, black diamonds indicate changes in P value after replication, dashed horizontal lines denote genome-wide significance, and solid horizontal lines represent the multiple testing correction threshold.
Fig. 3.
Fig. 3.. Genetic and phenotypic correlations between cortical regions.
(A) Surface area. (B) Thickness. Regions are numbered according to the inset key of Fig. 1A. The proportion of variance accounted for by common genetic variants is shown in the first column (h2SNP). Phenotypic correlations from the UK Biobank are in the upper right triangle. Genetic correlations from the principal meta-analysis are in the lower left triangle. Only significant correlations are shown.
Fig. 4.
Fig. 4.. Genetics of regional measures.
(A) Regional plot for rs1080066, including additional lead SNPs within the LD block and surrounding genes, chromatin interactions in neural progenitor cells, chromatin state in RoadMap brain tissues, and BRAINSPAN candidate gene expression in brain tissue. (B) Ideogram of 15q14, detailing the significant independent loci and cortical regions. (C) rs1080066 (G allele) association with SA of regions. (D) rs1080066 association with central sulcus depth and depth of several primate species. RoadMap chromatin states: TssA, active transcription start site (TSS); TssAFlnk, flanking active TSS; TxFlnk, transcription at gene 5′ and 3′; Tx, strong transcription; TxWk, weak transcription; EnhG, genic enhancers; Enh, enhancers; Het, heterochromatin; TssBiv, bivalent/poised TSS; BivFlnk, flanking bivalent TSS/enhancer; EnhBiv, bivalent enhancer; ReprPC, repressed Polycomb; ReprPCWk, weak repressed Polycomb; Quies, quiescent/low. BRAINSPAN cortical tissue types: DFC, dorsolateral prefrontal cortex; VFC, ventrolateral prefrontal cortex; MFC, anterior cingulate cortex; OFC, orbital frontal cortex; M1C, primary motor cortex; M1C-S1C, primary motor-sensory cortex; PCx, parietal neocortex; S1C, primary somatosensory cortex; IPC, posteroventral parietal cortex; A1C, primary auditory cortex;TCx, temporal neocortex; STC, posterior superior temporal cortex; ITC, inferolateral temporal cortex; Ocx, occipital neocortex; V1C, primary visual cortex.
Fig. 5.
Fig. 5.. Genetic correlations with neuropsychiatric and psychological traits.
(A) Genetic correlations with total SA and average TH. Significant positive correlations are shown in red; significant negative correlations are shown in blue. Error bars indicate SE. (B) Regional variation in the strength of genetic correlations between regional SA (without correction for total SA) and traits showing significant genetic correlations with total SA.
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