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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; 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; 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; ; ; ; ; ; ;

<jats:sec> <jats:title>INTRODUCTION</jats:title> <jats:p>The 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.</jats:p> </jats:sec> <jats:sec> <jats:title>RATIONALE</jats:title> <jats:p>To 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.</jats:p> </jats:sec> <jats:sec> <jats:title>RESULTS</jats:title> <jats:p> We identified 369 nominally genome-wide significant loci ( <jats:italic>P</jats:italic> < 5 × 10 <jats:sup>−8</jats:sup> ) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 360 loci for which replication data were available, 241 loci influencing surface area and 66 influencing thickness remained significant after replication, with 237 loci passing multiple testing correction ( <jats:italic>P</jats:italic> < 8.3 × 10 <jats:sup>−10</jats:sup> ; 187 influencing surface area and 50 influencing thickness). </jats:p> <jats:p> 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 ( <jats:italic>r</jats:italic> <jats:sub>G</jats:sub> = −0.32, SE = 0.05, <jats:italic>P</jats:italic> = 6.5 × 10 <jats:sup>−12</jats:sup> ), 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. </jats:p> <jats:p>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 46 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.</jats:p> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>CONCLUSION</jats:title> <jats:p>This 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.</jats:p> <jats:fig fig-type="image" orientation="portrait" position="float" specific-use="distribute"> <jats:caption> <jats:title>Identifying genetic influences on human cortical structure.</jats:title> <jats:p> ( <jats:bold>A</jats:bold> ) Measurement of cortical surface area and thickness from MRI. ( <jats:bold>B</jats:bold> ) Genomic locations of common genetic variants that influence global and regional cortical structure. ( <jats:bold>C</jats:bold> ) Our results support the radial unit hypothesis that the expansion of cortical surface area is driven by proliferating neural progenitor cells. ( <jats:bold>D</jats:bold> ) Cortical surface area shows genetic correlation with psychiatric and cognitive traits. Error bars indicate SE. </jats:p> </jats:caption> <jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" orientation="portrait" position="float" xlink:href="science.aay6690-fa.tif" /> <jats:attrib>IMAGE CREDITS: (A) K. COURTNEY; (C) M. R. GLASS</jats:attrib> </jats:fig> </jats:sec>