The genetic architecture of the human cerebral cortex

Katrina L Grasby; Nicola J Armstrong; Rachel M Brouwer; Anouk den Braber; Iryna O Fedko; Judith M Ford; Dirk J Heslenfeld; Jouke-Jan Hottenga; Iris E Jansen; Yuri Milaneschi; Gareth E Davies; Dorret I Boomsma; Eco J C de Geus; Jaap Oosterlaan; Brenda W J H Penninx; Tinca J C Polderman; Danielle Posthuma; Dennis van 't Ent; Sarah E Medland; Alzheimer’s Disease Neuroimaging Initiative

doi:10.1126/science.aay6690

The genetic architecture of the human cerebral cortex

Katrina L Grasby, Nicola J Armstrong, Rachel M Brouwer, Anouk den Braber, Iryna O Fedko, Judith M Ford, Dirk J Heslenfeld, Jouke-Jan Hottenga, Iris E Jansen, Yuri Milaneschi, Gareth E Davies, Dorret I Boomsma, Eco J C de Geus, Jaap Oosterlaan, Brenda W J H Penninx, Tinca J C Polderman, Danielle Posthuma, Dennis van 't Ent, Sarah E Medland, Alzheimer’s Disease Neuroimaging Initiative

Research output: Contribution to Journal › Article › Academic › peer-review

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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.

Original language	English
Article number	eaay6690
Pages (from-to)	1-14
Number of pages	17
Journal	Science
Volume	367
Issue number	6484
DOIs	https://doi.org/10.1126/science.aay6690
Publication status	Published - 20 Mar 2020

Bibliographical note

Cohort Studies

Netherlands Twin Register (NTR)

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10.1126/science.aay6690

eaay6690_The genetic architecture of the human cerebral cortexFinal published version, 2.25 MBLicence: Article 25fa Dutch Copyright Act

Cite this

Grasby, K. L., Armstrong, N. J., Brouwer, R. M., den Braber, A., Fedko, I. O., Ford, J. M., Heslenfeld, D. J., Hottenga, J-J., Jansen, I. E., Milaneschi, Y., Davies, G. E., Boomsma, D. I., de Geus, E. J. C., Oosterlaan, J., Penninx, B. W. J. H., Polderman, T. J. C., Posthuma, D., van 't Ent, D., Medland, S. E., & Alzheimer’s Disease Neuroimaging Initiative (2020). The genetic architecture of the human cerebral cortex. Science, 367(6484), 1-14. [eaay6690]. https://doi.org/10.1126/science.aay6690

Grasby, Katrina L ; Armstrong, Nicola J ; Brouwer, Rachel M ; den Braber, Anouk ; Fedko, Iryna O ; Ford, Judith M ; Heslenfeld, Dirk J ; Hottenga, Jouke-Jan ; Jansen, Iris E ; Milaneschi, Yuri ; Davies, Gareth E ; Boomsma, Dorret I ; de Geus, Eco J C ; Oosterlaan, Jaap ; Penninx, Brenda W J H ; Polderman, Tinca J C ; Posthuma, Danielle ; van 't Ent, Dennis ; Medland, Sarah E ; Alzheimer’s Disease Neuroimaging Initiative. / The genetic architecture of the human cerebral cortex. In: Science. 2020 ; Vol. 367, No. 6484. pp. 1-14.

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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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{Ida E} and Emma Sprooten and Tansey, {Katherine E} and Alexander Teumer and Anbupalam Thalamuthu and Diana Tordesillas-Guti{\'e}rrez and Turner, {Jessica A} and Anne Uhlmann and Vallerga, {Costanza Ludovica} and {van der Meer}, Dennis 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-Jos{\'e} and Veldink, {Jan H} and Ellen Verhoef and Esther Walton and Mingyuan Wang and Yunpeng Wang and Wardlaw, {Joanna M} and Wei Wen and Westlye, {Lars T} and Whelan, {Christopher D} and Witt, {Stephanie H} and Katharina Wittfeld and Christiane Wolf and Thomas Wolfers and Wu, {Jing Qin} and Yasuda, {Clarissa L} and Dario Zaremba and Zuo Zhang and Zwiers, {Marcel P} and Eric Artiges and Assareh, {Amelia A} and Rosa Ayesa-Arriola and Aysenil Belger and Brandt, {Christine L} and Brown, {Gregory G} and Sven Cichon and Curran, {Joanne E} and Davies, {Gareth E} and Franziska Degenhardt and Dennis, {Michelle F} and Bruno Dietsche and Srdjan Djurovic and Doherty, {Colin P} and Ryan Espiritu and Daniel Garijo and Yolanda Gil and Gowland, {Penny A} and Green, {Robert C} and H{\"a}usler, {Alexander N} and Walter Heindel and Beng-Choon Ho and Hoffmann, {Wolfgang U} and Florian Holsboer and Georg Homuth and Norbert Hosten and Jack, {Clifford R} and MiHyun Jang and Andreas Jansen and Kimbrel, {Nathan A} and Knut Kolsk{\aa}r and Sanne Koops and Axel Krug and Lim, {Kelvin O} and Luykx, {Jurjen J} and Mathalon, {Daniel H} and Mather, {Karen A} and Mattay, {Venkata S} and Sarah Matthews and {Mayoral Van Son}, Jaqueline and McEwen, {Sarah C} and Ingrid Melle and Morris, {Derek W} and Mueller, {Bryon A} and Matthias Nauck and Nordvik, {Jan E} and N{\"o}then, {Markus M} and O'Leary, {Daniel S} and Nils Opel and Martinot, {Marie-Laure Paill{\`e}re} and Pike, {G Bruce} and Adrian Preda and Quinlan, {Erin B} and Rasser, {Paul E} and Varun Ratnakar and Simone Reppermund and Steen, {Vidar M} and Tooney, {Paul A} and Torres, {F{\'a}bio R} and Veltman, {Dick J} and Voyvodic, {James T} and Robert Whelan and Tonya White and Hidenaga Yamamori and Adams, {Hieab H H} and Bis, {Joshua C} and Stephanie Debette and Charles Decarli and Myriam Fornage and Vilmundur Gudnason and Edith Hofer and Ikram, {M Arfan} and Lenore Launer and Longstreth, {W T} and Lopez, {Oscar L} and Bernard Mazoyer and Mosley, {Thomas H} and Roshchupkin, {Gennady V} and Satizabal, {Claudia L} and Reinhold Schmidt and Sudha Seshadri and Qiong Yang and Alvim, {Marina K M} and David Ames and Anderson, {Tim J} and Andreassen, {Ole A} and Alejandro Arias-Vasquez and Bastin, {Mark E} and Baune, {Bernhard T} and Beckham, {Jean C} and John Blangero and Boomsma, {Dorret I} and Henry Brodaty and Brunner, {Han G} and Buckner, {Randy L} and Buitelaar, {Jan K} and Bustillo, {Juan R} and Wiepke Cahn and Cairns, {Murray J} and Vince Calhoun and Carr, {Vaughan J} and Xavier Caseras and Svenja Caspers and Cavalleri, {Gianpiero L} and Fernando Cendes and Aiden Corvin and Benedicto Crespo-Facorro and Dalrymple-Alford, {John C} and Udo Dannlowski and {de Geus}, {Eco J C} and Deary, {Ian J} and Norman Delanty and Chantal Depondt and Sylvane Desrivi{\`e}res and Gary Donohoe and Thomas Espeseth and Guill{\'e}n Fern{\'a}ndez and Fisher, {Simon E} and Herta Flor and Forstner, {Andreas J} and Clyde Francks and Barbara Franke and Glahn, {David C} and Gollub, {Randy L} and Grabe, {Hans J} and Oliver Gruber and H{\aa}berg, {Asta K} and Hariri, {Ahmad R} and Hartman, {Catharina A} and Ryota Hashimoto and Andreas Heinz 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 J{\"o}nsson, {Erik G} and Kahn, {Ren{\'e} S} and Kennedy, {Martin A} and Kircher, {Tilo T J} and Peter Kochunov and Kwok, {John B J} and {Le Hellard}, Stephanie and Loughland, {Carmel M} and Martin, {Nicholas G} and Jean-Luc Martinot and Colm McDonald and McMahon, {Katie L} and Andreas Meyer-Lindenberg and Michie, {Patricia T} and Morey, {Rajendra A} and Bryan Mowry and Lars Nyberg and Jaap Oosterlaan and Ophoff, {Roel A} and Christos Pantelis and Tomas Paus and Zdenka Pausova and Penninx, {Brenda W J H} and Polderman, {Tinca J C} and Danielle Posthuma and Marcella Rietschel and Roffman, {Joshua L} and Rowland, {Laura M} and Sachdev, {Perminder S} and S{\"a}mann, {Philipp G} and Ulrich Schall and Gunter Schumann and Scott, {Rodney J} and Kang Sim 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 Trollor, {Julian N} and {Van der Wee}, {Nic J A} and {van 't Ent}, Dennis and Henry V{\"o}lzke and Henrik Walter and Bernd Weber and Weinberger, {Daniel R} and Wright, {Margaret J} and Juan Zhou and Stein, {Jason L} and Thompson, {Paul M} and Medland, {Sarah E} and {Alzheimer{\textquoteright}s Disease Neuroimaging Initiative}",

note = "Copyright {\textcopyright} 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.",

year = "2020",

month = mar,

day = "20",

doi = "10.1126/science.aay6690",

language = "English",

volume = "367",

pages = "1--14",

journal = "Science",

issn = "1095-9203",

publisher = "American Association for the Advancement of Science",

number = "6484",

}

Grasby, KL, Armstrong, NJ, Brouwer, RM , den Braber, A, Fedko, IO, Ford, JM, Heslenfeld, DJ, Hottenga, J-J , Jansen, IE , Milaneschi, Y, Davies, GE, Boomsma, DI , de Geus, EJC , Oosterlaan, J, Penninx, BWJH, Polderman, TJC , Posthuma, D , van 't Ent, D, Medland, SE & Alzheimer’s Disease Neuroimaging Initiative 2020, 'The genetic architecture of the human cerebral cortex', Science, vol. 367, no. 6484, eaay6690, pp. 1-14. https://doi.org/10.1126/science.aay6690

The genetic architecture of the human cerebral cortex. / Grasby, Katrina L; Armstrong, Nicola J; Brouwer, Rachel M ; den Braber, Anouk; Fedko, Iryna O; Ford, Judith M; Heslenfeld, Dirk J; Hottenga, Jouke-Jan ; Jansen, Iris E ; Milaneschi, Yuri; Davies, Gareth E; Boomsma, Dorret I ; de Geus, Eco J C ; Oosterlaan, Jaap; Penninx, Brenda W J H; Polderman, Tinca J C ; Posthuma, Danielle ; van 't Ent, Dennis; Medland, Sarah E; Alzheimer’s Disease Neuroimaging Initiative.

In: Science, Vol. 367, No. 6484, eaay6690, 20.03.2020, p. 1-14.

Research output: Contribution to Journal › Article › Academic › peer-review

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AU - Trollor, Julian N

AU - Van der Wee, Nic J A

AU - van 't Ent, Dennis

AU - Völzke, Henry

AU - Walter, Henrik

AU - Weber, Bernd

AU - Weinberger, Daniel R

AU - Wright, Margaret J

AU - Zhou, Juan

AU - Stein, Jason L

AU - Thompson, Paul M

AU - Medland, Sarah E

AU - Alzheimer’s Disease Neuroimaging Initiative

PY - 2020/3/20

Y1 - 2020/3/20

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85082081461&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85082081461&partnerID=8YFLogxK

U2 - 10.1126/science.aay6690

DO - 10.1126/science.aay6690

M3 - Article

C2 - 32193296

VL - 367

SP - 1

EP - 14

JO - Science

JF - Science

SN - 1095-9203

IS - 6484

M1 - eaay6690

ER -

The genetic architecture of the human cerebral cortex

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