Genomic analysis of intracranial and subcortical brain volumes yields polygenic scores accounting for variation across ancestries
Authors: García-Marín Luis M , Campos Adrian I , Diaz-Torres Santiago , Rabinowitz Jill A , Ceja Zuriel , Mitchell Brittany L , Grasby Katrina L , Thorp Jackson G , Agartz Ingrid , Alhusaini Saud , Ames David , Amouyel Philippe , Andreassen Ole A , Arfanakis Konstantinos , Arias Vasquez Alejandro , Armstrong Nicola J , Athanasiu Lavinia , Bastin Mark E , Beiser Alexa S , Bennett David A , Bis Joshua C , Boks Marco PM , Boomsma Dorret I , Brodaty Henry , Brouwer Rachel M , Buitelaar Jan K , Burkhardt Ralph , Cahn Wiepke , Calhoun Vince D. , Carmichael Owen T , Chakravarty Mallar , Chen Qiang , Ching Christopher R. K. , Cichon Sven , Crespo-Facorro Benedicto , Crivello Fabrice , Dale Anders M , Davey Smith George , de Geus Eco JC , De Jager Philip L. , de Zubicaray Greig I , Debette Stéphanie , DeCarli Charles , Depondt Chantal , Desrivières Sylvane , Djurovic Srdjan , Ehrlich Stefan , Erk Susanne , Espeseth Thomas , Fernández Guillén , Filippi Irina , Fisher Simon E , Fleischman Debra A , Fletcher Evan , Fornage Myriam , Forstner Andreas J , Francks Clyde , Franke Barbara , Ge Tian , Goldman Aaron L , Grabe Hans J , Green Robert C , Grimm Oliver , Groenewold Nynke A , Gruber Oliver , Gudnason Vilmundur , Håberg Asta K , Haukvik Unn K , Heinz Andreas , Hibar Derrek P , Hilal Saima , Himali Jayandra J , Ho Beng-Choon , Hoehn David F , Hoekstra Pieter J , Hofer Edith , Hoffmann Wolfgang , Holmes Avram J , Homuth Georg , Hosten Norbert , Ikram M. Kamran , Ipser Jonathan C , Jack Clifford R , Jahanshad Neda , Jönsson Erik G , Kahn Rene S , Kanai Ryota , Klein Marieke , Knol Maria J , Launer Lenore J , Lawrie Stephen M , Le Hellard Stephanie , Lee Phil H , Lemaître Hervé , Li Shuo , Liewald David CM , Lin Honghuang , Longstreth W T , Lopez Oscar L , Luciano Michelle , Maillard Pauline , Marquand Andre F , Martin Nicholas G , Martinot Jean-Luc , Mather Karen A , Mattay Venkata S , McMahon Katie L , Mecocci Patrizia , Melle Ingrid , Meyer-Lindenberg Andreas , Mirza-Schreiber Nazanin , Milaneschi Yuri , Mosley Thomas H , Mühleisen Thomas W , Müller-Myhsok Bertram , Muñoz Maniega Susana , Nauck Matthias , Nho Kwangsik , Niessen Wiro J , Nöthen Markus M , Nyquist Paul A , Oosterlaan Jaap , Pandolfo Massimo , Paus Tomas , Pausova Zdenka , Penninx Brenda WJH , Pike G. Bruce , Psaty Bruce M , Pütz Benno , Reppermund Simone , Rietschel Marcella D , Risacher Shannon L , Romanczuk-Seiferth Nina , Romero-Garcia Rafael , Roshchupkin Gennady V , Rotter Jerome I , Sachdev Perminder S , Sämann Philipp G , Saremi Arvin , Sargurupremraj Muralidharan , Saykin Andrew J , Schmaal Lianne , Schmidt Helena , Schmidt Reinhold , Schofield Peter R , Scholz Markus , Schumann Gunter , Schwarz Emanuel , Shen Li , Shin Jean , Sisodiya Sanjay M , Smith Albert V , Smoller Jordan W , Soininen Hilkka S , Steen Vidar M , Stein Dan J , Stein Jason L , Thomopoulos Sophia I , Toga Arthur W. , Tordesillas-Gutiérrez Diana , Trollor Julian N , Valdes-Hernandez Maria C , van ’t Ent Dennis , van Bokhoven Hans , van der Meer Dennis , van der Wee Nic JA , Vázquez-Bourgon Javier , Veltman Dick J , Vernooij Meike W , Villringer Arno , Vinke Louis N , Völzke Henry , Walter Henrik , Wardlaw Joanna M , Weinberger Daniel R , Weiner Michael W , Wen Wei , Westlye Lars T , Westman Eric , White Tonya , Witte A. Veronica , Wolf Christiane , Yang Jingyun , Zwiers Marcel P , Ikram M Arfan , Seshadri Sudha , Thompson Paul M , Satizabal Claudia L , Medland Sarah E , Rentería Miguel E 
Published: August 2024

Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. We performed GWAS meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and, for the first time, the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signalling and brain ageing-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse ancestries. We observed causal genetic effects of brain volumes with Parkinson’s disease and ADHD. Findings implicate specific gene expression patterns in brain development and genetic variants in comorbid neuropsychiatric disorders, which could point to a brain substrate and region of action for risk genes implicated in brain diseases.