Common variants at 12q14 and 12q24 are associated with hippocampal volume

被引：189

作者：

Bis, Joshua C. ^{[2
]}

DeCarli, Charles ^{[3
,4
]}

Smith, Albert Vernon ^{[5
,6
]}

van der Lijn, Fedde ^{[7
,8
]}

Crivello, Fabrice ^{[9
,10
,11
]}

Fornage, Myriam ^{[12
,13
]}

Debette, Stephanie ^{[1
,14
,15
]}

Shulman, Joshua M. ^{[16
,17
]}

Schmidt, Helena ^{[18
]}

Srikanth, Velandai ^{[19
,20
]}

Schuur, Maaike ^{[21
,22
]}

Yu, Lei ^{[23
]}

Choi, Seung-Hoan ^{[24
]}

Sigurdsson, Sigurdur ^{[5
]}

Verhaaren, Benjamin F. J. ^{[8
,25
]}

DeStefano, Anita L. ^{[1
,24
,26
]}

Lambert, Jean-Charles ^{[27
,28
,29
]}

Jack, Clifford R., Jr. ^{[30
]}

Struchalin, Maksim ^{[21
]}

Stankovich, Jim ^{[20
]}

Ibrahim-Verbaas, Carla A. ^{[21
,22
]}

Fleischman, Debra ^{[23
,31
,32
]}

Zijdenbos, Alex ^{[33
]}

den Heijer, Tom ^{[22
,25
,34
]}

Mazoyer, Bernard ^{[9
,10
,11
]}

Coker, Laura H. ^{[35
]}

Enzinger, Christian ^{[36
]}

Danoy, Patrick ^{[37
]}

Amin, Najaf ^{[21
]}

Arfanakis, Konstantinos ^{[23
,38
]}

van Buchem, Mark A. ^{[39
]}

de Bruijn, Renee F. A. G. ^{[22
,25
]}

Beiser, Alexa ^{[1
,24
,26
]}

Dufouil, Carole ^{[14
]}

Huang, Juebin ^{[40
]}

Cavalieri, Margherita ^{[36
]}

Thomson, Russell ^{[20
]}

Niessen, Wiro J. ^{[7
,8
,41
]}

Chibnik, Lori B. ^{[16
,17
]}

Gislason, Gauti K. ^{[5
]}

Hofman, Albert ^{[25
,42
]}

Pikula, Aleksandra ^{[1
]}

Amouyel, Philippe ^{[27
,28
,29
,43
]}

Freeman, Kevin B. ^{[44
]}

Phan, Thanh G. ^{[19
]}

Oostra, Ben A. ^{[21
,45
]}

Stein, Jason L. ^{[46
]}

Medland, Sarah E. ^{[47
,48
]}

Vasquez, Alejandro Arias ^{[49
,50
]}

Hibar, Derrek P. ^{[46
]}

机构：

[1] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA

[2] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA

[3] Univ Calif Davis, Dept Neurol, Sacramento, CA 95817 USA

[4] Univ Calif Davis, Ctr Neurosci, Sacramento, CA 95817 USA

[5] Iceland Heart Assoc, Kopavogur, Iceland

[6] Univ Iceland, Fac Med, Reykjavik, Iceland

[7] Univ Med Ctr, Erasmus Med Ctr, Dept Med Informat, Rotterdam, Netherlands

[8] Univ Med Ctr, Erasmus Med Ctr, Dept Radiol, Rotterdam, Netherlands

[9] Univ Bordeaux, Neurofunct Imaging Grp, UMR 5296, Bordeaux, France

[10] Univ Bordeaux, Neurofunct Imaging Grp, CNRS, UMR 5296, Bordeaux, France

[11] CEA, Neurofunct Imaging Grp, UMR 5296, Bordeaux, France

[12] Univ Texas Hlth Sci Ctr Houston, Brown Fdn Inst Mol Med, Houston, TX USA

[13] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Houston, TX USA

[14] INSERM, U708, Paris, France

[15] Univ Versailles St Quentin En Yvelines, Dept Epidemiol, Paris, France

[16] Brigham & Womens Hosp, Program Translat NeuroPsychiat Genom, Inst Neurosci, Dept Neurol, Boston, MA 02115 USA

[17] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA

[18] Med Univ Graz, Inst Mol Biol & Biochem, Graz, Austria

[19] Monash Univ, Dept Med, Stroke & Ageing Res Ctr, So Clin Sch, Melbourne, Vic 3004, Australia

[20] Univ Tasmania, Menzies Res Inst Tasmania, Hobart, Tas, Australia

[21] Univ Med Ctr, Erasmus Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands

[22] Univ Med Ctr, Erasmus Med Ctr, Dept Neurol, Rotterdam, Netherlands

[23] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA

[24] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[25] Univ Med Ctr, Erasmus Med Ctr, Dept Epidemiol, Rotterdam, Netherlands

[26] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA

[27] INSERM, U744, F-59045 Lille, France

[28] Inst Pasteur, F-59019 Lille, France

[29] Univ Lille Nord France, Lille, France

[30] Mayo Clin, Dept Radiol, Rochester, MN USA

[31] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA

[32] Rush Univ, Med Ctr, Dept Behav Sci, Chicago, IL 60612 USA

[33] Biospective Inc, Montreal, PQ, Canada

[34] St Franciscus Gasthuis, Dept Neurol, Rotterdam, Netherlands

[35] Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC USA

[36] Med Univ Graz, Dept Neurol, Graz, Austria

[37] Univ Queensland, Princess Alexandra Hosp, Diamantina Inst, Brisbane, Qld, Australia

[38] Illinois Inst Technol, Dept Biomed Engn, Chicago, IL USA

[39] Leiden Univ, Med Ctr, Dept Radiol, Leiden, Netherlands

[40] Univ Mississippi, Med Ctr, Dept Neurol, Jackson, MS 39216 USA

[41] Delft Univ Technol, Fac Sci Appl, Delft, Netherlands

[42] Netherlands Consortium Hlth Ageing, Leiden, Netherlands

[43] Ctr Hosp Reg Univ Lille, Lille, France

[44] Univ Mississippi, Med Ctr, Dept Psychiat & Human Behav, Jackson, MS 39216 USA

[45] Univ Med Ctr, Erasmus Med Ctr, Dept Clin Genet, Rotterdam, Netherlands

[46] Univ Calif Los Angeles, David Geffen Sch Med, Lab Neuro Imaging, Los Angeles, CA 90095 USA

[47] Queensland Inst Med Res, Genet Epidemiol Lab, Brisbane, Qld 4006, Australia

[48] Broad Inst Harvard & MIT, Cambridge, MA USA

[49] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands

[50] Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, Donders Inst Brain Cognit & Behav, NL-6525 ED Nijmegen, Netherlands

来源：

NATURE GENETICS | 2012年 / 44卷 / 05期

基金：

奥地利科学基金会; 澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; GLUCAGON-LIKE PEPTIDE-1; IDENTIFIES VARIANTS; ALZHEIMERS-DISEASE; TOTAL HOMOCYSTEINE; CELL-DEATH; ATROPHY; PROTEIN; CLU; EXPRESSION;

D O I：

10.1038/ng.2237

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

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 x 10(-7). In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 x 10(-11)) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 x 10(-11)). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 x 10(-7)) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 x 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.

引用

页码：545 / +

页数：8

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