The genetic architecture of the human cerebral cortex
Authors: Grasby Katrina L. , Jahanshad Neda , Painter Jodie N. , Colodro-Conde Lucía , Bralten Janita , Hibar Derrek P. , Lind Penelope A. , Pizzagalli Fabrizio , Ching Christopher R. K. , McMahon Mary Agnes B. , Shatokhina Natalia , Zsembik Leo C. P. , Thomopoulos Sophia I. , Zhu Alyssa H. , Strike Lachlan T. , Agartz Ingrid , Alhusaini Saud , Almeida Marcio A. A. , Alnæs Dag , Amlien Inge K. , Andersson Micael , Ard Tyler , Armstrong Nicola J. , Ashley-Koch Allison , Atkins Joshua R. , Bernard Manon , Brouwer Rachel M. , Buimer Elizabeth E. L. , Bülow Robin , Bürger Christian , Cannon Dara M. , Chakravarty Mallar , Chen Qiang , Cheung Joshua W. , Couvy-Duchesne Baptiste , Dale Anders M. , Dalvie Shareefa , de Araujo Tânia K. , de Zubicaray Greig I. , de Zwarte Sonja M. C. , den Braber Anouk , Doan Nhat Trung , Dohm Katharina , Ehrlich Stefan , Engelbrecht Hannah-Ruth , Erk Susanne , Fan Chun Chieh , Fedko Iryna O. , Foley Sonya F. , Ford Judith M. , Fukunaga Masaki , Garrett Melanie E. , Ge Tian , Giddaluru Sudheer , Goldman Aaron L. , Green Melissa J. , Groenewold Nynke A. , Grotegerd Dominik , Gurholt Tiril P. , Gutman Boris A. , Hansell Narelle K. , Harris Mathew A. , Harrison Marc B. , Haswell Courtney C. , Hauser Michael , Herms Stefan , Heslenfeld Dirk J. , Ho New Fei , Hoehn David , Hoffmann Per , Holleran Laurena , Hoogman Martine , Hottenga Jouke-Jan , Ikeda Masashi , Janowitz Deborah , Jansen Iris E. , Jia Tianye , Jockwitz Christiane , Kanai Ryota , Karama Sherif , Kasperaviciute Dalia , Kaufmann Tobias , Kelly Sinead , Kikuchi Masataka , Klein Marieke , Knapp Michael , Knodt Annchen R. , Krämer Bernd , Lam Max , Lancaster Thomas M. , Lee Phil H. , Lett Tristram A. , Lewis Lindsay B. , Lopes-Cendes Iscia , Luciano Michelle , Macciardi Fabio , Marquand Andre F. , Mathias Samuel R. , Melzer Tracy R. , Milaneschi Yuri , Mirza-Schreiber Nazanin , Moreira Jose C. V. , Mühleisen Thomas W. , Müller-Myhsok Bertram , Najt Pablo , Nakahara Soichiro , Nho Kwangsik , Olde Loohuis Loes M. , Orfanos Dimitri Papadopoulos , Pearson John F. , Pitcher Toni L. , Pütz Benno , Quidé Yann , Ragothaman Anjanibhargavi , Rashid Faisal M. , Reay William R. , Redlich Ronny , Reinbold Céline S. , Repple Jonathan , Richard Geneviève , Riedel Brandalyn C. , Risacher Shannon L. , Rocha Cristiane S. , Mota Nina Roth , Salminen Lauren , Saremi Arvin , Saykin Andrew J. , Schlag Fenja , Schmaal Lianne , Schofield Peter R. , Secolin Rodrigo , Shapland Chin Yang , Shen Li , Shin Jean , Shumskaya Elena , Sønderby Ida E. , Sprooten Emma , Tansey Katherine E. , Teumer Alexander , Thalamuthu Anbupalam , Tordesillas-Gutiérrez Diana , Turner Jessica A. , Uhlmann Anne , Vallerga Costanza Ludovica , van der Meer Dennis , van Donkelaar Marjolein M. J. , van Eijk Liza , van Erp Theo G. M. , van Haren Neeltje E. M. , van Rooij Daan , van Tol Marie-José , Veldink Jan H. , Verhoef Ellen , Walton Esther , Wang Mingyuan , Wang Yunpeng , Wardlaw Joanna M. , Wen Wei , Westlye Lars T. , Whelan Christopher D. , Witt Stephanie H. , Wittfeld Katharina , Wolf Christiane , Wolfers Thomas , Wu Jing Qin , Yasuda Clarissa L. , Zaremba Dario , Zhang Zuo , Zwiers Marcel P. , Artiges Eric , Assareh Amelia A. , Ayesa-Arriola Rosa , Belger Aysenil , Brandt Christine L. , Brown Gregory G. , Cichon Sven , Curran Joanne E. , Davies Gareth E. , Degenhardt Franziska , Dennis Michelle F. , Dietsche Bruno , Djurovic Srdjan , Doherty Colin P. , Espiritu Ryan , Garijo Daniel , Gil Yolanda , Gowland Penny A. , Green Robert C. , Häusler Alexander N. , Heindel Walter , Ho Beng-Choon , Hoffmann Wolfgang U. , Holsboer Florian , Homuth Georg , Hosten Norbert , Jack Clifford R. , Jang MiHyun , Jansen Andreas , Kimbrel Nathan A. , Kolskår Knut , Koops Sanne , Krug Axel , Lim Kelvin O. , Luykx Jurjen J. , Mathalon Daniel H. , Mather Karen A. , Mattay Venkata S. , Matthews Sarah , Mayoral Van Son Jaqueline , McEwen Sarah C. , Melle Ingrid , Morris Derek W. , Mueller Bryon A. , Nauck Matthias , Nordvik Jan E. , Nöthen Markus M. , O’Leary Daniel S. , Opel Nils , Martinot Marie-Laure Paillère , Pike G. Bruce , Preda Adrian , Quinlan Erin B. , Rasser Paul E. , Ratnakar Varun , Reppermund Simone , Steen Vidar M. , Tooney Paul A. , Torres Fábio R. , Veltman Dick J. , Voyvodic James T. , Whelan Robert , White Tonya , Yamamori Hidenaga , Adams Hieab H. H. , Bis Joshua C. , Debette Stephanie , Decarli Charles , Fornage Myriam , Gudnason Vilmundur , Hofer Edith , Ikram M. Arfan , Launer Lenore , Longstreth W. T. , Lopez Oscar L. , Mazoyer Bernard , Mosley Thomas H. , Roshchupkin Gennady V. , Satizabal Claudia L. , Schmidt Reinhold , Seshadri Sudha , Yang Qiong ,   Alzheimer’s Disease Neuroimaging Initiative¶,   CHARGE Consortium¶,   EPIGEN Consortium¶,   IMAGEN Consortium¶,   SYS Consortium¶,   Parkinson’s Progression Markers Initiative¶, Alvim Marina K. M. , Ames David , Anderson Tim J. , Andreassen Ole A. , Arias-Vasquez Alejandro , Bastin Mark E. , Baune Bernhard T. , Beckham Jean C. , Blangero John , Boomsma Dorret I. , Brodaty Henry , Brunner Han G. , Buckner Randy L. , Buitelaar Jan K. , Bustillo Juan R. , Cahn Wiepke , Cairns Murray J. , Calhoun Vince , Carr Vaughan J. , Caseras Xavier , Caspers Svenja , Cavalleri Gianpiero L. , Cendes Fernando , Corvin Aiden , Crespo-Facorro Benedicto , Dalrymple-Alford John C. , Dannlowski Udo , de Geus Eco J. C. , Deary Ian J. , Delanty Norman , Depondt Chantal , Desrivières Sylvane , Donohoe Gary , Espeseth Thomas , Fernández Guillén , Fisher Simon E. , Flor Herta , Forstner Andreas J. , Francks Clyde , Franke Barbara , Glahn David C. , Gollub Randy L. , Grabe Hans J. , Gruber Oliver , Håberg Asta K. , Hariri Ahmad R. , Hartman Catharina A. , Hashimoto Ryota , Heinz Andreas , Henskens Frans A. , Hillegers Manon H. J. , Hoekstra Pieter J. , Holmes Avram J. , Hong L. Elliot , Hopkins William D. , Hulshoff Pol Hilleke E. , Jernigan Terry L. , Jönsson Erik G. , Kahn René S. , Kennedy Martin A. , Kircher Tilo T. J. , Kochunov Peter , Kwok John B. J. , Le Hellard Stephanie , Loughland Carmel M. , Martin Nicholas G. , Martinot Jean-Luc , McDonald Colm , McMahon Katie L. , Meyer-Lindenberg Andreas , Michie Patricia T. , Morey Rajendra A. , Mowry Bryan , Nyberg Lars , Oosterlaan Jaap , Ophoff Roel A. , Pantelis Christos , Paus Tomas , Pausova Zdenka , Penninx Brenda W. J. H. , Polderman Tinca J. C. , Posthuma Danielle , Rietschel Marcella , Roffman Joshua L. , Rowland Laura M. , Sachdev Perminder S. , Sämann Philipp G. , Schall Ulrich , Schumann Gunter , Scott Rodney J. , Sim Kang , Sisodiya Sanjay M. , Smoller Jordan W. , Sommer Iris E. , St Pourcain Beate , Stein Dan J. , Toga Arthur W. , Trollor Julian N. , Van der Wee Nic J. A. , van ’t Ent Dennis , Völzke Henry , Walter Henrik , Weber Bernd , Weinberger Daniel R. , Wright Margaret J. , Zhou Juan , Stein Jason L. , Thompson Paul M. , Medland Sarah E. ,   Enhancing NeuroImaging Genetics through Meta-Analysis Consortium (ENIGMA)—Genetics working group
Published: March 2020

INTRODUCTION
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.

RATIONALE
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.

RESULTS

We identified 369 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 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 (
P
< 8.3 × 10
−10
; 187 influencing surface area and 50 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 (
r
G
= −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 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.
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.

CONCLUSION
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.

Identifying genetic influences on human cortical structure.

(
A
) Measurement of cortical surface area and thickness from MRI. (
B
) Genomic locations of common genetic variants that influence global and regional cortical structure. (
C
) Our results support the radial unit hypothesis that the expansion of cortical surface area is driven by proliferating neural progenitor cells. (
D
) Cortical surface area shows genetic correlation with psychiatric and cognitive traits. Error bars indicate SE.

IMAGE CREDITS: (A) K. COURTNEY; (C) M. R. GLASS