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Genetic architecture of subcortical brain structures in 38,851 individuals.


ABSTRACT: Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

SUBMITTER: Satizabal CL 

PROVIDER: S-EPMC7055269 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Genetic architecture of subcortical brain structures in 38,851 individuals.

Satizabal Claudia L CL   Adams Hieab H H HHH   Hibar Derrek P DP   White Charles C CC   Knol Maria J MJ   Stein Jason L JL   Scholz Markus M   Sargurupremraj Muralidharan M   Jahanshad Neda N   Roshchupkin Gennady V GV   Smith Albert V AV   Bis Joshua C JC   Jian Xueqiu X   Luciano Michelle M   Hofer Edith E   Teumer Alexander A   van der Lee Sven J SJ   Yang Jingyun J   Yanek Lisa R LR   Lee Tom V TV   Li Shuo S   Hu Yanhui Y   Koh Jia Yu JY   Eicher John D JD   Desrivières Sylvane S   Arias-Vasquez Alejandro A   Chauhan Ganesh G   Athanasiu Lavinia L   Rentería Miguel E ME   Kim Sungeun S   Hoehn David D   Armstrong Nicola J NJ   Chen Qiang Q   Holmes Avram J AJ   den Braber Anouk A   Kloszewska Iwona I   Andersson Micael M   Espeseth Thomas T   Grimm Oliver O   Abramovic Lucija L   Alhusaini Saud S   Milaneschi Yuri Y   Papmeyer Martina M   Axelsson Tomas T   Ehrlich Stefan S   Roiz-Santiañez Roberto R   Kraemer Bernd B   Håberg Asta K AK   Jones Hannah J HJ   Pike G Bruce GB   Stein Dan J DJ   Stevens Allison A   Bralten Janita J   Vernooij Meike W MW   Harris Tamara B TB   Filippi Irina I   Witte A Veronica AV   Guadalupe Tulio T   Wittfeld Katharina K   Mosley Thomas H TH   Becker James T JT   Doan Nhat Trung NT   Hagenaars Saskia P SP   Saba Yasaman Y   Cuellar-Partida Gabriel G   Amin Najaf N   Hilal Saima S   Nho Kwangsik K   Mirza-Schreiber Nazanin N   Arfanakis Konstantinos K   Becker Diane M DM   Ames David D   Goldman Aaron L AL   Lee Phil H PH   Boomsma Dorret I DI   Lovestone Simon S   Giddaluru Sudheer S   Le Hellard Stephanie S   Mattheisen Manuel M   Bohlken Marc M MM   Kasperaviciute Dalia D   Schmaal Lianne L   Lawrie Stephen M SM   Agartz Ingrid I   Walton Esther E   Tordesillas-Gutierrez Diana D   Davies Gareth E GE   Shin Jean J   Ipser Jonathan C JC   Vinke Louis N LN   Hoogman Martine M   Jia Tianye T   Burkhardt Ralph R   Klein Marieke M   Crivello Fabrice F   Janowitz Deborah D   Carmichael Owen O   Haukvik Unn K UK   Aribisala Benjamin S BS   Schmidt Helena H   Strike Lachlan T LT   Cheng Ching-Yu CY   Risacher Shannon L SL   Pütz Benno B   Fleischman Debra A DA   Assareh Amelia A AA   Mattay Venkata S VS   Buckner Randy L RL   Mecocci Patrizia P   Dale Anders M AM   Cichon Sven S   Boks Marco P MP   Matarin Mar M   Penninx Brenda W J H BWJH   Calhoun Vince D VD   Chakravarty M Mallar MM   Marquand Andre F AF   Macare Christine C   Kharabian Masouleh Shahrzad S   Oosterlaan Jaap J   Amouyel Philippe P   Hegenscheid Katrin K   Rotter Jerome I JI   Schork Andrew J AJ   Liewald David C M DCM   de Zubicaray Greig I GI   Wong Tien Yin TY   Shen Li L   Sämann Philipp G PG   Brodaty Henry H   Roffman Joshua L JL   de Geus Eco J C EJC   Tsolaki Magda M   Erk Susanne S   van Eijk Kristel R KR   Cavalleri Gianpiero L GL   van der Wee Nic J A NJA   McIntosh Andrew M AM   Gollub Randy L RL   Bulayeva Kazima B KB   Bernard Manon M   Richards Jennifer S JS   Himali Jayandra J JJ   Loeffler Markus M   Rommelse Nanda N   Hoffmann Wolfgang W   Westlye Lars T LT   Valdés Hernández Maria C MC   Hansell Narelle K NK   van Erp Theo G M TGM   Wolf Christiane C   Kwok John B J JBJ   Vellas Bruno B   Heinz Andreas A   Olde Loohuis Loes M LM   Delanty Norman N   Ho Beng-Choon BC   Ching Christopher R K CRK   Shumskaya Elena E   Singh Baljeet B   Hofman Albert A   van der Meer Dennis D   Homuth Georg G   Psaty Bruce M BM   Bastin Mark E ME   Montgomery Grant W GW   Foroud Tatiana M TM   Reppermund Simone S   Hottenga Jouke-Jan JJ   Simmons Andrew A   Meyer-Lindenberg Andreas A   Cahn Wiepke W   Whelan Christopher D CD   van Donkelaar Marjolein M J MMJ   Yang Qiong Q   Hosten Norbert N   Green Robert C RC   Thalamuthu Anbupalam A   Mohnke Sebastian S   Hulshoff Pol Hilleke E HE   Lin Honghuang H   Jack Clifford R CR   Schofield Peter R PR   Mühleisen Thomas W TW   Maillard Pauline P   Potkin Steven G SG   Wen Wei W   Fletcher Evan E   Toga Arthur W AW   Gruber Oliver O   Huentelman Matthew M   Davey Smith George G   Launer Lenore J LJ   Nyberg Lars L   Jönsson Erik G EG   Crespo-Facorro Benedicto B   Koen Nastassja N   Greve Douglas N DN   Uitterlinden André G AG   Weinberger Daniel R DR   Steen Vidar M VM   Fedko Iryna O IO   Groenewold Nynke A NA   Niessen Wiro J WJ   Toro Roberto R   Tzourio Christophe C   Longstreth William T WT   Ikram M Kamran MK   Smoller Jordan W JW   van Tol Marie-Jose MJ   Sussmann Jessika E JE   Paus Tomas T   Lemaître Hervé H   Schroeter Matthias L ML   Mazoyer Bernard B   Andreassen Ole A OA   Holsboer Florian F   Depondt Chantal C   Veltman Dick J DJ   Turner Jessica A JA   Pausova Zdenka Z   Schumann Gunter G   van Rooij Daan D   Djurovic Srdjan S   Deary Ian J IJ   McMahon Katie L KL   Müller-Myhsok Bertram B   Brouwer Rachel M RM   Soininen Hilkka H   Pandolfo Massimo M   Wassink Thomas H TH   Cheung Joshua W JW   Wolfers Thomas T   Martinot Jean-Luc JL   Zwiers Marcel P MP   Nauck Matthias M   Melle Ingrid I   Martin Nicholas G NG   Kanai Ryota R   Westman Eric E   Kahn René S RS   Sisodiya Sanjay M SM   White Tonya T   Saremi Arvin A   van Bokhoven Hans H   Brunner Han G HG   Völzke Henry H   Wright Margaret J MJ   van 't Ent Dennis D   Nöthen Markus M MM   Ophoff Roel A RA   Buitelaar Jan K JK   Fernández Guillén G   Sachdev Perminder S PS   Rietschel Marcella M   van Haren Neeltje E M NEM   Fisher Simon E SE   Beiser Alexa S AS   Francks Clyde C   Saykin Andrew J AJ   Mather Karen A KA   Romanczuk-Seiferth Nina N   Hartman Catharina A CA   DeStefano Anita L AL   Heslenfeld Dirk J DJ   Weiner Michael W MW   Walter Henrik H   Hoekstra Pieter J PJ   Nyquist Paul A PA   Franke Barbara B   Bennett David A DA   Grabe Hans J HJ   Johnson Andrew D AD   Chen Christopher C   van Duijn Cornelia M CM   Lopez Oscar L OL   Fornage Myriam M   Wardlaw Joanna M JM   Schmidt Reinhold R   DeCarli Charles C   De Jager Philip L PL   Villringer Arno A   Debette Stéphanie S   Gudnason Vilmundur V   Medland Sarah E SE   Shulman Joshua M JM   Thompson Paul M PM   Seshadri Sudha S   Ikram M Arfan MA  

Nature genetics 20191021 11


Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysi  ...[more]

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