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Nature. 2015 Apr 9;520(7546):224-9. doi: 10.1038/nature14101. Epub 2015 Jan 21.

Common genetic variants influence human subcortical brain structures.

Hibar DP, Stein JL, Renteria ME, Arias-Vasquez A, Desrivières S, Jahanshad N, Toro R, Wittfeld K, Abramovic L, Andersson M, Aribisala BS, Armstrong NJ, Bernard M, Bohlken MM, Boks MP, Bralten J, Brown AA, Chakravarty MM, Chen Q, Ching CR, Cuellar-Partida G, den Braber A, Giddaluru S, Goldman AL, Grimm O, Guadalupe T, Hass J, Woldehawariat G, Holmes AJ, Hoogman M, Janowitz D, Jia T, Kim S, Klein M, Kraemer B, Lee PH, Olde Loohuis LM, Luciano M, Macare C, Mather KA, Mattheisen M, Milaneschi Y, Nho K, Papmeyer M, Ramasamy A, Risacher SL, Roiz-Santiañez R, Rose EJ, Salami A, Sämann PG, Schmaal L, Schork AJ, Shin J, Strike LT, Teumer A, van Donkelaar MM, van Eijk KR, Walters RK, Westlye LT, Whelan CD, Winkler AM, Zwiers MP, Alhusaini S, Athanasiu L, Ehrlich S, Hakobjan MM, Hartberg CB, Haukvik UK, Heister AJ, Hoehn D, Kasperaviciute D, Liewald DC, Lopez LM, Makkinje RR, Matarin M, Naber MA, McKay DR, Needham M, Nugent AC, Pütz B, Royle NA, Shen L, Sprooten E, Trabzuni D, van der Marel SS, van Hulzen KJ, Walton E, Wolf C, Almasy L, Ames D, Arepalli S, Assareh AA, Bastin ME, Brodaty H, Bulayeva KB, Carless MA, Cichon S, Corvin A, Curran JE, Czisch M, de Zubicaray GI, Dillman A, Duggirala R, Dyer TD, Erk S, Fedko IO, Ferrucci L, Foroud TM, Fox PT, Fukunaga M, Gibbs JR, Göring HH, Green RC, Guelfi S, Hansell NK, Hartman CA, Hegenscheid K, Heinz A, Hernandez DG, Heslenfeld DJ, Hoekstra PJ, Holsboer F, Homuth G, Hottenga JJ, Ikeda M, Jack CR Jr, Jenkinson M, Johnson R, Kanai R, Keil M, Kent JW Jr, Kochunov P, Kwok JB, Lawrie SM, Liu X, Longo DL, McMahon KL, Meisenzahl E, Melle I, Mohnke S, Montgomery GW, Mostert JC, Mühleisen TW, Nalls MA, Nichols TE, Nilsson LG, Nöthen MM, Ohi K, Olvera RL, Perez-Iglesias R, Pike GB, Potkin SG, Reinvang I, Reppermund S, Rietschel M, Romanczuk-Seiferth N, Rosen GD, Rujescu D, Schnell K, Schofield PR, Smith C, Steen VM, Sussmann JE, Thalamuthu A, Toga AW, Traynor BJ, Troncoso J, Turner JA, Valdés Hernández MC, van 't Ent D, van der Brug M, van der Wee NJ, van Tol MJ, Veltman DJ, Wassink TH, Westman E, Zielke RH, Zonderman AB, Ashbrook DG, Hager R, Lu L, McMahon FJ, Morris DW, Williams RW, Brunner HG, Buckner RL, Buitelaar JK, Cahn W, Calhoun VD, Cavalleri GL, Crespo-Facorro B, Dale AM, Davies GE, Delanty N, Depondt C, Djurovic S, Drevets WC, Espeseth T, Gollub RL, Ho BC, Hoffmann W, Hosten N, Kahn RS, Le Hellard S, Meyer-Lindenberg A, Müller-Myhsok B, Nauck M, Nyberg L, Pandolfo M, Penninx BW, Roffman JL, Sisodiya SM, Smoller JW, van Bokhoven H, van Haren NE, Völzke H, Walter H, Weiner MW, Wen W, White T, Agartz I, Andreassen OA, Blangero J, Boomsma DI, Brouwer RM, Cannon DM, Cookson MR, de Geus EJ, Deary IJ, Donohoe G, Fernández G, Fisher SE, Francks C, Glahn DC, Grabe HJ, Gruber O, Hardy J, Hashimoto R, Hulshoff Pol HE, Jönsson EG, Kloszewska I, Lovestone S, Mattay VS, Mecocci P, McDonald C, McIntosh AM, Ophoff RA, Paus T, Pausova Z, Ryten M, Sachdev PS, Saykin AJ, Simmons A, Singleton A, Soininen H, Wardlaw JM, Weale ME, Weinberger DR, Adams HH, Launer LJ, Seiler S, Schmidt R, Chauhan G, Satizabal CL, Becker JT, Yanek L, van der Lee SJ, Ebling M, Fischl B, Longstreth WT Jr, Greve D, Schmidt H, Nyquist P, Vinke LN, van Duijn CM, Xue L, Mazoyer B, Bis JC, Gudnason V, Seshadri S, Ikram MA; Alzheimer’s Disease Neuroimaging Initiative; CHARGE Consortium; EPIGEN; IMAGEN; SYS, Martin NG, Wright MJ, Schumann G, Franke B, Thompson PM, Medland SE.

Collaborators (469)

Weiner M, Aisen P, Petersen R, Jack CR Jr, Jagust W, Trojanowki JQ, Toga AW, Beckett L, Green RC, Saykin AJ, Morris J, Shaw LM, Khachaturian Z, Sorensen G, Carrillo M, Kuller L, Raichle M, Paul S, Davies P, Fillit H, Hefti F, Holtzman D, Mesulman M, Potter W, Snyder P, Schwartz A, Green RC, Montine T, Petersen R, Aisen P, Thomas RG, Donohue M, Walter S, Gessert D, Sather T, Jiminez G, Beckett L, Harvey D, Donohue M, Jack CR Jr, Bernstein M, Fox N, Thompson P, Schuff N, DeCarli C, Borowski B, Gunter J, Senjem M, Vemuri P, Jones D, Kantarci K, Ward C, Jagust W, Koeppe RA, Foster N, Reiman EM, Chen K, Mathis C, Landau S, Morris J, Cairns NJ, Householder E, Taylor-Reinwald L, Trojanowki JQ, Shaw L, Lee VM, Korecka M, Figurski M, Toga AW, Crawford K, Neu S, Saykin AJ, Foroud TM, Potkin S, Shen L, Faber K, Kim S, Nho K, Weiner MW, Thal L, Khachaturian Z, Khachaturian Z, Frank R, Snyder PJ, Weiner MW, Thal L, Buckholtz N, Potter W, Paul S, Albert M, Hsiao J, Kaye J, Quinn J, Lind B, Carter R, Dolen S, Gutman BA, Schneider LS, Pawluczyk S, Beccera M, Teodoro L, Spann BM, Brewer J, Vanderswag H, Fleisher A, Heidebrink JL, Lord JL, Petersen R, Mason SS, Albers CS, Knopman D, Johnson K, Doody RS, Villanueva-Meyer J, Chowdhury M, Rountree S, Dang M, Stern Y, Honig LS, Bell KL, Ances B, Morris JC, Carroll M, Leon S, Householder E, Mintun MA, Schneider S, Oliver A, Marson D, Griffith R, Clark D, Geldmacher D, Brockington J, Roberson E, Grossman H, Mitsis E, deToledo-Morrell L, Shah RC, Duara R, Varon D, Greig MT, Roberts P, Albert M, Onyike C, D'Agostino D 2nd, Kielb S, Galvin JE, Pogorelec DM, Cerbone B, Michel CA, Rusinek H, de Leon MJ, Glodzik L, De Santi S, Doraiswamy P, Petrella JR, Wong TZ, Arnold SE, Karlawish JH, Wolk D, Smith CD, Jicha G, Hardy P, Sinha P, Oates E, Conrad G, Lopez OL, Oakley M, Simpson DM, Porsteinsson AP, Goldstein BS, Martin K, Makino KM, Ismail M, Brand C, Mulnard RA, Thai G, Mc-Adams-Ortiz C, Womack K, Mathews D, Quiceno M, Diaz-Arrastia R, King R, Weiner M, Martin-Cook K, DeVous M, Levey AI, Lah JJ, Cellar JS, Burns JM, Anderson HS, Swerdlow RH, Apostolova L, Tingus K, Woo E, Silverman DH, Lu PH, Bartzokis G, Graff-Radford NR, Parfitt F, Kendall T, Johnson H, Farlow MR, Hake AM, Matthews BR, Herring S, Hunt C, van Dyck CH, Carson RE, MacAvoy MG, Chertkow H, Bergman H, Hosein C, Black S, Stefanovic B, Caldwell C, Hsiung YR, Feldman H, Mudge B, Assaly M, Kertesz A, Rogers J, Trost D, Bernick C, Munic D, Kerwin D, Mesulam MM, Lipowski K, Wu CK, Johnson N, Sadowsky C, Martinez W, Villena T, Turner RS, Johnson K, Reynolds B, Sperling RA, Johnson KA, Marshall G, Frey M, Yesavage J, Taylor JL, Lane B, Rosen A, Tinklenberg J, Sabbagh MN, Belden CM, Jacobson SA, Sirrel SA, Kowall N, Killiany R, Budson AE, Norbash A, Johnson PL, Obisesan TO, Wolday S, Allard J, Lerner A, Ogrocki P, Hudson L, Fletcher E, Carmichael O, Olichney J, DeCarli C, Kittur S, Borrie M, Lee TY, Bartha R, Johnson S, Asthana S, Carlsson CM, Potkin SG, Preda A, Nguyen D, Tariot P, Fleisher A, Reeder S, Bates V, Capote H, Rainka M, Scharre DW, Kataki M, Adeli A, Zimmerman EA, Celmins D, Brown AD, Pearlson GD, Blank K, Anderson K, Santulli RB, Kitzmiller TJ, Schwartz ES, Sink KM, Williamson JD, Garg P, Watkins F, Ott BR, Querfurth H, Tremont G, Salloway S, Malloy P, Correia S, Rosen HJ, Miller BL, Mintzer J, Spicer K, Bachman D, Finger E, Pasternak S, Rachinsky I, Rogers J, Kertesz A, Drost D, Pomara N, Hernando R, Sarrael A, Schultz SK, Ponto LL, Shim H, Smith KE, Relkin N, Chaing G, Raudin L, Smith A, Fargher K, Raj BA, Amin N, Becker D, Beiser A, Debette S, DeStefano A, Hofer E, Hofman A, Niessen WJ, Seiler S, Smith A, Tzourio C, Vaidya D, Vernooij MW, Goldstein DB, Heinzen EL, Shianna K, Radtke R, Ottmann R, Albrecht L, Andrew C, Arroyo M, Artiges E, Aydin S, Bach C, Banaschewski T, Barbot A, Barker G, Boddaert N, Bokde A, Bricaud Z, Bromberg U, Bruehl R, Büchel C, Cachia A, Cattrell A, Conrod P, Constant P, Crombag H, Czech K, Dalley J, Decideur B, Desrivieres S, Fadai T, Flor H, Frouin V, Fuchs B, Gallinat J, Garavan H, Briand FG, Gowland P, Head K, Heinrichs B, Heinz A, Heym N, Hübner T, Ihlenfeld A, Ireland J, Ittermann B, Ivanov N, Jia T, Jones J, Klaassen A, Lalanne C, Lathrop M, Lanzerath D, Lemaitre H, Lüdemann K, Macare C, Mallik C, Mangin JF, Mann K, Mar A, Martinot JL, Massicotte J, Mennigen E, Mesquita de Carvahlo F, Mignon X, Miranda R, Müller K, Nees F, Nymberg C, Paillere ML, Paus T, Pausova Z, Pena-Oliver Y, Poline JB, Poustka L, Rapp M, Reed L, Robert G, Reuter J, Rietschel M, Ripke S, Ripley T, Robbins T, Rodehacke S, Rogers J, Romanowski A, Ruggeri B, Schilling C, Schmäl C, Schmidt D, Schneider S, Schroeder M, Schubert F, Schwartz Y, Smolka M, Sommer W, Spanagel R, Speiser C, Spranger T, Stedman A, Steiner S, Stephens D, Strache N, Ströhle A, Struve M, Subramaniam N, Theobald D, Topper L, Vollstaedt-Klein S, Walaszek B, Walter H, Weiß K, Werts H, Whelan R, Williams S, Yacubian J, Ziesch V, Zilbovicius M, Wong CP, Lubbe S, Martinez-Medina L, Kepa A, Fernandes A, Tahmasebi A, Abrahamowicz M, Gaudet D, Leonard G, Perron M, Richer L, Seguin J, Veillette S.

Abstract

The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

PMID:
25607358
PMCID:
PMC4393366
DOI:
10.1038/nature14101
[Indexed for MEDLINE]
Free PMC Article

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