Nat Genet. 2012 Apr 15;44(5):545-51. doi: 10.1038/ng.2237.
Common variants at 12q14 and 12q24 are associated with hippocampal volume.
Bis JC,
DeCarli C,
Smith AV,
van der Lijn F,
Crivello F,
Fornage M,
Debette S,
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,
Stein JL,
Medland SE,
Vasquez AA,
Hibar DP,
Wright MJ,
Franke B,
Martin NG,
Thompson PM;
Enhancing Neuro Imaging Genetics through Meta-Analysis Consortium,
Nalls MA,
Uitterlinden AG,
Au R,
Elbaz A,
Beare RJ,
van Swieten JC,
Lopez OL,
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;
Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium.
Stein JL, Medland SE, Arias Vasquez A, Hibar DP, Senstad RE, Winkler AM, Toro R, Appel K, Bartecek R, Bergmann Ø, Bernard M, Brown AA, Cannon DM, Chakravarty M, 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 E, Lourdusamy A, Maniega SM, Mattingsdal M, Mohnke S, Nho K, Nugent AC, O'Brien C, Papmeyer M, Pütz B, Ramasamy A, Rasmussen J, Rijpkema M, Risacher SL, Roddey JC, Rose EJ, Ryten M, Shen L, Sprooten E, Strengman E, Teumer A, Trabzuni D, Turner J, van Eijk K, van Erp TG, van Tol MJ, Wittfeld K, Wolf C, Woudstra S, Aleman A, Alhusaini S, Almasy L, Binder EB, Brohawn DG, Cantor RM, Carless MA, Corvin A, Czisch M, Curran JE, Davies G, de Almeida MA, Delanty N, Depondt C, Duggirala R, Dyer TD, Erk S, Fagerness J, Fox PT, Freimer NB, Gill M, Göring HH, 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, 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.
Source
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.
Abstract
Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10(-7). In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10(-11)) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10(-11)). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10(-7)) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10(-7)); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia.
- PMID:
- 22504421
- [PubMed - indexed for MEDLINE]
- PMCID:
- PMC3427729
Free PMC ArticleFigure 1Genome-wide Manhattan plot for hippocampal volume
The plot shows the individual p-values (based on discovery meta-analysis) against their genomic position for hippocampal volume. Within each chromosome, shown on the x-axis, the results are plotted left to right from the p-terminal end. The dashed line indicates the threshold for follow-up, p<4 ×10-7 and the solid line indicates the threshold for genome-wide significance, p<5×10-8. The nearest genes are indicated above points that surpassed our significance threshold for follow-up.
Nat Genet. 2012 April 15;44(5):545-551.
Figure 2Regional plots for hippocampal volume SNPs
Plots are centered on the most significant SNP at a given locus along with the meta-analysis results for SNPs in a region surrounding it (typically ± 100kb). All SNPs are plotted with their discovery meta-analysis p-values against their genomic position, with the most significant SNP in the region indicated as a diamond and other SNPs shaded according to their pairwise correlation (r2) with the signal SNP. The light blue line represents the estimated recombination rates. Gene annotations are shown as dark green lines.
Nat Genet. 2012 April 15;44(5):545-551.
Figure 3Forest plots for hippocampal volume SNP associations
Plots show the study-specific association estimates (β) and 95% confidence intervals for the discovery and replication stage studies, presented as rectangles and bars. Arrowheads indicate confidence intervals that span beyond the x-axis. Study specific results are indicated by: AGES, Aging Gene-Environment Susceptibility—Reykjavik Study; ARIC, Atherosclerosis Risk in Communities Study, ASPS, Austrian Stroke Prevention Study; ERF, Erasmus Ruchphen Family study; FHS, Framingham Heart Study; RUSH, Religious Order Study & Rush Memory and Aging Project; RS I, RS II, RS III, RS R, independent phases of the Rotterdam Study; TASCOG, Tasmanian Study of Cognition and Gait; 3C, Three City Study. Estimates from the replication phase (3C, RS R) are indicated by open rectangles. The scale is mm3. The association estimate and confidence interval for the meta-analysis combining discovery and second stage results is presented as a diamond. Blank spaces indicate occasions in which a particular study was not able to provide results for a given SNP.
Nat Genet. 2012 April 15;44(5):545-551.
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