Identification of common variants associated with human hippocampal and intracranial volumes.

Jason L Stein et al
Nat Genet. 2012-04-15; 44(5): 552-561
DOI: 10.1038/ng.2250

PubMed
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Stein JL, Medland SE, Vasquez AA, Hibar DP, Senstad RE, Winkler AM, Toro R, Appel
K, Bartecek R, Bergmann Ø, Bernard M, Brown AA, Cannon DM, Chakravarty MM,
Christoforou A, Domin M, Grimm O, Hollinshead M, Holmes AJ, Homuth G, Hottenga
JJ, Langan C, Lopez LM, Hansell NK, Hwang KS, Kim S, Laje G, Lee PH, Liu X, Loth
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JC, Rose EJ, Ryten M, Shen L, Sprooten E, Strengman E, Teumer A, Trabzuni D,
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Hagler DJ, Hoehn D, Holsboer F, Hoogman M, Hosten N, Jahanshad N, Johnson MP,
Kasperaviciute D, Kent JW Jr, Kochunov P, Lancaster JL, Lawrie SM, Liewald DC,
Mandl R, Matarin M, Mattheisen M, Meisenzahl E, Melle I, Moses EK, Mühleisen TW,
Nauck M, Nöthen MM, Olvera RL, Pandolfo M, Pike GB, Puls R, Reinvang I, Rentería
ME, Rietschel M, Roffman JL, Royle NA, Rujescu D, Savitz J, Schnack HG, Schnell
K, Seiferth N, Smith C, Steen VM, Valdés Hernández MC, Van den Heuvel M, van der
Wee NJ, Van Haren NE, Veltman JA, Völzke H, Walker R, Westlye LT, Whelan CD,
Agartz I, Boomsma DI, Cavalleri GL, Dale AM, Djurovic S, Drevets WC, Hagoort P,
Hall J, Heinz A, Jack CR Jr, Foroud TM, Le Hellard S, Macciardi F, Montgomery GW,
Poline JB, Porteous DJ, Sisodiya SM, Starr JM, Sussmann J, Toga AW, Veltman DJ,
Walter H, Weiner MW; Alzheimer’s Disease Neuroimaging Initiative; EPIGEN
Consortium; IMAGEN Consortium; Saguenay Youth Study Group, Bis JC, Ikram MA,
Smith AV, Gudnason V, Tzourio C, Vernooij MW, Launer LJ, DeCarli C, Seshadri S;
Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium,
Andreassen OA, Apostolova LG, Bastin ME, Blangero J, Brunner HG, Buckner RL,
Cichon S, Coppola G, de Zubicaray GI, Deary IJ, Donohoe G, de Geus EJ, Espeseth
T, Fernández G, Glahn DC, Grabe HJ, Hardy J, Hulshoff Pol HE, Jenkinson M, Kahn
RS, McDonald C, McIntosh AM, McMahon FJ, McMahon KL, Meyer-Lindenberg A, Morris
DW, Müller-Myhsok B, Nichols TE, Ophoff RA, Paus T, Pausova Z, Penninx BW, Potkin
SG, Sämann PG, Saykin AJ, Schumann G, Smoller JW, Wardlaw JM, Weale ME, Martin
NG, Franke B, Wright MJ, Thompson PM; Enhancing Neuro Imaging Genetics through
Meta-Analysis Consortium.

Collaborators: Weiner M, Aisen P, Petersen R, Jack CR Jr, Jagust W, Trojanowki
JQ, Toga AW, Beckett L, Green RC, Saykin AJ, Morris J, Liu E, Green RC, Montine
T, Petersen R, Aisen P, Gamst A, Thomas RG, Donohue M, Walter S, Gessert D,
Sather T, Beckett L, Harvey D, Gamst A, Donohue M, Kornak J, Jack CR Jr, Dale A,
Bernstein M, Felmlee J, Fox N, Thompson P, Schuff N, Alexander G, Jagust W, Bandy
D, Koeppe RA, Foster N, Reiman EM, Chen K, Mathis C, Morris J, Cairns NJ,
Taylor-Reinwald L, Trojanowki JQ, Shaw L, Lee VM, Korecka M, Toga AW, Crawford K,
Neu S, Saykin AJ, Foroud TM, Potkin S, Shen L, Kachaturian Z, Frank R, Snyder PJ,
Molchan S, Kaye J, Quinn J, Lind B, Dolen S, Schneider LS, Pawluczyk S, Spann BM,
Brewer J, Vanderswag H, Heidebrink JL, Lord JL, Petersen R, Johnson K, Doody RS,
Villanueva-Meyer J, Chowdhury M, Stern Y, Honig LS, Bell KL, Morris JC, Ances B,
Carroll M, Leon S, Mintun MA, Schneider S, Marson D, Griffith R, Clark D,
Grossman H, Mitsis E, Romirowsky A, deToledo-Morrell L, Shah RC, Duara R, Varon
D, Roberts P, Albert M, Onyike C, Kielb S, Rusinek H, de Leon MJ, Glodzik L, De
Santi S, Doraiswamy P, Petrella JR, Coleman R, Arnold SE, Karlawish JH, Wolk D,
Smith CD, Jicha G, Hardy P, Lopez OL, Oakley M, Simpson DM, Porsteinsson AP,
Goldstein BS, Martin K, Makino KM, Ismail M, 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, Lu PH, Bartzokis G, Silverman DH, Graff-Radford NR, Parfitt F,
Johnson H, Farlow MR, Hake AM, Matthews BR, Herring S, van Dyck CH, Carson RE,
MacAvoy MG, Chertkow H, Bergman H, Hosei C, Black S, Stefanovic B, Caldwell C,
Hsiung GY, 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 M,
Belden C, Jacobson S, Kowall N, Killiany R, Budson AE, Norbash A, Johnson PL,
Obisesan TO, Wolday S, Bwayo SK, Lerner A, Hudson L, Ogrocki P, 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,
Zimmerman EA, Celmins D, Brown AD, Pearlson GD, Blank K, Anderson K, Saykin AJ,
Santulli RB, 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, Longmire CF, Spicer K, Finger E, Rachinsky I, Rogers J, Kertesz A,
Drost D, Cavalleri G, Alhusaini S, Delanty N, Whelan C, Sisodiya S,
Kasperaviciute D, Matarin M, Depondt C, Goldstein DB, Heinzen EL, Shianna K,
Radtke R, Ottmann R, Sergievsky GH, Schumann G, Conrod P, Reed L, Barker G,
Williams S, Loth E, Struve M, Lourdusamy A, Cattrell A, Nymberg C, Topper L,
Smith L, Havatzias S, Stueber K, Mallik C, Stacey D, Wong CP, Werts H, Williams
S, Andrew C, Desrivieres S, Heinz A, Gallinat J, Häke I, Ivanov N, Klär A, Reuter
J, Palafox C, Hohmann C, Schilling C, Lüdemann K, Romanowski A, Ströhle A, Wolff
E, Rapp M, Ittermann B, Brühl R, Ihlenfeld A, Walaszek B, Schubert F, Garavan H,
Connolly C, Jones J, Lalor E, McCabe E, Ní Shiothcháin A, Whelan R, Spanagel R,
Leonardi-Essmann F, Sommer W, Flor H, Vollstaedt-Klein S, Nees F, Banaschewski T,
Poustka L, Steiner S, Mann K, Buehler M, Rietschel M, Stolzenburg E, Schmal C,
Schirmbeck F, Paus T, Gowland P, Heym N, Lawrence C, Newman C, Pausova Z, Smolka
M, Huebner T, Ripke S, Mennigen E, Muller K, Ziesch V, Büchel C, Bromberg U,
Fadai T, Lueken L, Yacubian J, Finsterbusch J, Martinot JL, Artiges E, Bordas N,
de Bournonville S, Bricaud Z, Gollier Briand F, Lemaitre H, Massicotte J, Miranda
R, Paillère Martinot ML, Penttilä J, Poline JB, Barbot A, Schwartz Y, Lalanne C,
Frouin V, Thyreau B, Dalley J, Mar A, Robbins T, Subramaniam N, Theobald D,
Richmond N, de Rover M, Molander A, Jordan E, Robinson E, Hipolata L, Moreno M,
Arroyo M, Stephens D, Ripley T, Crombag H, Pena Y, Lathrop M, Zelenika D, Heath
S, Lanzerath D, Heinrichs B, Spranger T, Fuchs B, Speiser C, Resch F, Haffner J,
Parzer P, Brunner R, Klaassen A, Klaassen I, Constant P, Mignon X, Thomsen T,
Zysset S, Vestboe A, Ireland J, Rogers J, Paus T, Pausova Z, Bernard M,
Chakravarty M, Pike GB, Bis JC, DeCarli C, Smith AV, van der Lijn F, Crivello F,
Fornage M, Shulman JM, Schmidt H, Srikanth V, Schuur M, Yu L, Choi SH, Sigurdsson
S, Verhaaren BF, DeStefano AL, Lambert JC, Jack CR Jr, Struchalin M, Stankovich
J, Ibrahim-Verbaas CA, Fleischman D, Zijdenbos A, den Heijer T, Mazoyer B, Coker
LH, Enzinger C, Danoy P, Amin N, Arfanakis K, van Buchem MA, de Bruijn RF, Beiser
A, Dufouil C, Huang J, Cavalieri M, Thomson R, Niessen WJ, Chibnik LB, Gislason
GK, Hofman A, Pikula A, Amouyel P, Freeman KB, Phan TG, Oostra BA, Nalls MA,
Uitterlinden AG, Au R, Elbaz A, Beare RJ, van Swieten JC, Lopez O, Harris TB,
Chouraki V, Breteler MM, De Jager PL, Becker JT, Vernooij MW, Knopman D, Fazekas
F, Wolf PA, van der Lugt A, Gudnason V, Longstreth WT Jr, Brown MA, Bennett DA,
van Duijn CM, Mosley TH, Schmidt R, Tzourio C, Launer LJ, Ikram MA, Seshadri S.

Identifying genetic variants influencing human brain structures may reveal new
biological mechanisms underlying cognition and neuropsychiatric illness. The
volume of the hippocampus is a biomarker of incipient Alzheimer’s disease and is
reduced in schizophrenia, major depression and mesial temporal lobe epilepsy.
Whereas many brain imaging phenotypes are highly heritable, identifying and
replicating genetic influences has been difficult, as small effects and the high
costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here
we report genome-wide association meta-analyses and replication for mean
bilateral hippocampal, total brain and intracranial volumes from a large
multinational consortium. The intergenic variant rs7294919 was associated with
hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10(-16)) and the expression
levels of the positional candidate gene TESC in brain tissue. Additionally,
rs10784502, located within HMGA2, was associated with intracranial volume
(12q14.3; N = 15,782; P = 1.12 × 10(-12)). We also identified a suggestive
association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500;
P = 5.81 × 10(-7)).

DOI: 10.1038/ng.2250
PMCID: PMC3635491
PMID: 22504417 [Indexed for MEDLINE]

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