Genetic architecture of subcortical brain structures in 38,851 individuals

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 al...

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Vydané v:	Nature genetics Ročník 51; číslo 11; s. 1624 - 1636
Hlavní autori:	Jahanshad, Neda, Smith, Albert V., Bis, Joshua C., Hofer, Edith, van der Lee, Sven J., Yanek, Lisa R., Li, Shuo, Hu, Yanhui, Koh, Jia Yu, Athanasiu, Lavinia, Hoehn, David, Armstrong, Nicola J., Kloszewska, Iwona, Grimm, Oliver, Abramovic, Lucija, Roiz-Santiañez, Roberto, Kraemer, Bernd, Håberg, Asta K., Stein, Dan J., Bralten, Janita, Harris, Tamara B., Filippi, Irina, Guadalupe, Tulio, Wittfeld, Katharina, Mosley, Thomas H., Becker, James T., Cuellar-Partida, Gabriel, Arfanakis, Konstantinos, Ames, David, Boomsma, Dorret I., Mattheisen, Manuel, Schmaal, Lianne, Tordesillas-Gutierrez, Diana, Ipser, Jonathan C., Vinke, Louis N., Hoogman, Martine, Crivello, Fabrice, Carmichael, Owen, Aribisala, Benjamin S., Strike, Lachlan T., Risacher, Shannon L., Pütz, Benno, Mecocci, Patrizia, Penninx, Brenda W. J. H., Oosterlaan, Jaap, Rotter, Jerome I., de Zubicaray, Greig I., Shen, Li, Roffman, Joshua L., McIntosh, Andrew M., Himali, Jayandra J., van Erp, Theo G. M., Delanty, Norman, Shumskaya, Elena, Psaty, Bruce M., Bastin, Mark E., Reppermund, Simone, van Donkelaar, Marjolein M. J., Thalamuthu, Anbupalam, Fletcher, Evan, Gruber, Oliver, Launer, Lenore J., Nyberg, Lars, Steen, Vidar M., Groenewold, Nynke A., Niessen, Wiro J., Longstreth, William T., Ikram, M. Kamran, Sussmann, Jessika E., Andreassen, Ole A., Turner, Jessica A., Pausova, Zdenka, Schumann, Gunter, Djurovic, Srdjan, Deary, Ian J., Müller-Myhsok, Bertram, Cheung, Joshua W., Martinot, Jean-Luc, Zwiers, Marcel P., Kanai, Ryota, Sisodiya, Sanjay M., White, Tonya, Völzke, Henry, Nöthen, Markus M., Ophoff, Roel A., Sachdev, Perminder S., van Haren, Neeltje E. M., Fisher, Simon E., Beiser, Alexa S., Mather, Karen A., Romanczuk-Seiferth, Nina, Hartman, Catharina A., Hoekstra, Pieter J., Nyquist, Paul A., Franke, Barbara, Grabe, Hans J., Johnson, Andrew D., Chen, Christopher, Fornage, Myriam, Villringer, Arno
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	New York Nature Publishing Group US 01.11.2019 Nature Publishing Group
Predmet:	45/43 631/208/205/2138 631/378 692/308/174 Adult Aged Agriculture Alzheimer's disease Amygdala Analysis Animal Genetics and Genomics Animals Annotations Apoptosis Axonal transport Bioinformatics Biomedical and Life Sciences Biomedicine Brain Brain - anatomy & histology Brain - metabolism Brain architecture Brain stem Cancer Research Caudate nucleus Cohort Studies Consortia DNA methylation Drosophila melanogaster - genetics Drosophila melanogaster - growth & development Drosophila melanogaster - metabolism Fruit flies Gene expression Gene Function Gene loci Genes Genetic aspects Genetic diversity Genetic Variation Genome-wide association studies Genome-Wide Association Study Genomes Genomics Globus pallidus Human Genetics Humans Insects Life Sciences Magnetic Resonance Imaging Memory Middle Aged Neurodevelopment Neurodevelopmental Disorders - genetics Neurodevelopmental Disorders - pathology Neuroimaging Neurological diseases NMR Nuclear magnetic resonance Nucleus accumbens Organ Size Pathology Phenotypes Putamen Quality control Santé publique et épidémiologie Stroke Structure Studies Thalamus United States Europe United Kingdom > UK VINTAGE HEALTHY
ISSN:	1061-4036, 1546-1718, 1546-1718
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Popis
Shrnutí:	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. Genome-wide analysis identifies variants associated with the volume of seven different subcortical brain regions defined by magnetic resonance imaging. Implicated genes are involved in neurodevelopmental and synaptic signaling pathways.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 PMCID: PMC7055269 C.L.S. drafted the manuscript with contributions from H.H.H.A., D.P.H., C.C.W., T.V.L., A.A.-V., S.Ehrlich., A.K.H., M.W.V., D.J., T.G.M.v.E., C.D.W., M.J.W., S.E.F., K.A.M., P.J.H., B.F., H.J.G., A.D.J., O.L.L., S.Debette, S.E.M., J.M.S., P.M.T., S.S. and M.A.I. M.S., N.J., L.R.Y., T.V.L., G.C., L.A., M.E.R., A.d.B., I.K., M.A., S.A., S.E., R.R.-S., A.K.H., H.J.J., A.Stevens., J.B., M.W.V., A.V.W., K.W., N.A., S.H., A.L.G., P.H.L., S.G., S.L.H., D.K., L.Schmaal, S.M.L., I.A., E.W., D.T.-G., J.C.I., L.N.V., R.B., F.C., D.J., O.C., U.K.H., B.S.A., C.-Y.C., A.A.A., M.P.B., A.F.M., S.K.M., P.A., A.J.Schork., D.C.M.L., T.Y.W., L.Shen, P.G.S., E.J.C.d.G., M.T., K.R.v.E., N.J.A.v.d.W., A.M.M., J.S.R., N.R., W.H., M.C.V.H., J.B.J.K., L.M.O.L., A.Hofman, G.H., M.E.B., S.R., J.-J.H., A.Simmons, N.H., P.R.S., T.W.M., P.Maillard, O.Gruber, N.A.G., J.E.S., H.Lemaître, B.M.-M., D.v.R., I.J.D., R.M.B., I.M., R.K., H.v.B., M.J.W., D.v.‘t.E., M.M.N., S.E.F., A.S.B., K.A.M., N.R.-S., D.J.H., H.J.G., C.M.v.D., J.M.W., C.DeCarli, P.L.D.J. and V.G. contributed to the preparation of data. C.L.S., H.H.H.A., D.P.H., M.J.K., J.L.S., M.S., M.Sargurupremraj, N.J., G.V.R., A.V.S., J.C.B., X.J., M.Luciano., E.H., A.Teumer, S.J.v.d.L., J.Y., L.R.Y., S.L., K.J.Y., G.C., M.E.R., N.J.A., H.J.J., A.V.W., S.H., N.M.S., S.G., D.T.G., J.S., C.-Y.C., L.M.O.L., Q.Y., A.Thalamuthu, I.O.F., D.v.‘t.E., C.Depondt and P.L.D.J. performed the statistical analyses. C.L.S., H.H.H.A., C.C.W., M.J.K., T.V.L., S.L., Y.H., K.J.Y., J.D.E., Q.Y. and A.D.J. carried out the downstream analyses. All authors reviewed the manuscript for intellectual content. Author contributions
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/s41588-019-0511-y