title: Bridging Integrator 1 (BIN1) Genotype Effects on Working Memory, Hippocampal Volume, and Functional Connectivity in Young Healthy Individuals.
abstract: Alzheimer's disease (AD) is the most common form of dementia and exhibits a considerable level of heritability. The bridging integrator 1 (BIN1) gene has recently been identified in several large genome-wide association studies (GWAS) as the second most important risk locus for AD following apolipoprotein E (APOE). However, how and when the established genetic risk locus BIN1 rs744373 confers risk to late-onset AD has yet to be determined. Here using an imaging genetic strategy in large-sample Chinese subjects, we show that healthy homozygous carriers of the rs744373 risk allele exhibit worse high-load working memory (WM) performance, larger hippocampal volume and lower functional connectivity between the bilateral hippocampus and the right dorsolateral prefrontal cortex (DLPFC), mirroring clinical evidence of disturbed memory and connectivity in patients. Our findings demonstrate that rs744373 itself or a variation in linkage disequilibrium may provide a neurogenetic mechanism for BIN1 while further validating the possibility of combining genetic and neuroimaging strategies to monitor individuals at risk for AD.
authors: 1] Brainnetome Center, Institute of Automation, Chinese Academy of Sciences, Beijing, China [2] National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China.
authors: Xiaolong
authors: 0000000302627854
authors: X
authors: Zhang
authors: 1] Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China [2] Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
authors: Jin-Tai
authors: JT
authors: Yu
authors: 1] Brainnetome Center, Institute of Automation, Chinese Academy of Sciences, Beijing, China [2] National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China.
authors: Jin
authors: J
authors: Li
authors: Key Laboratory for NeuroInformation of Ministry of Education, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China.
authors: Chao
authors: C
authors: Wang
authors: Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China.
authors: Lan
authors: L
authors: Tan
authors: 1] Brainnetome Center, Institute of Automation, Chinese Academy of Sciences, Beijing, China [2] National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China.
authors: Bing
authors: B
authors: Liu
authors: 1] Brainnetome Center, Institute of Automation, Chinese Academy of Sciences, Beijing, China [2] National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China [3] Key Laboratory for NeuroInformation of Ministry of Education, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China [4] Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
authors: Tianzi
authors: T
authors: Jiang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000704:Analysis of Variance; D001931:Brain Mapping; D016009:Chi-Square Distribution; D005260:Female; D005838:Genotype; D064368:Healthy Volunteers; D006624:Hippocampus / Q000033:anatomy & histology* / Q000098:blood supply; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D009483:Neuropsychological Tests; D009687:Nuclear Proteins / Q000235:genetics*; D010100:Oxygen / Q000097:blood; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012146:Rest; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C101410:BIN1 protein, human; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D010100:Oxygen
references: Neuropsychologia. 2002;40(13):2226-33
references: 12417453
references: J Alzheimers Dis. 2012;31(3):475-92
references: 22669013
references: Am J Psychiatry. 2006 Sep;163(9):1603-10
references: 16946187
references: Arch Neurol. 2007 Oct;64(10):1482-7
references: 17923631
references: Brain. 2001 Apr;124(Pt 4):739-56
references: 11287374
references: Neuroimage. 2007 Oct 1;37(4):1122-31
references: 17683950
references: Age (Dordr). 2013 Oct;35(5):1637-50
references: 22903189
references: AJNR Am J Neuroradiol. 2013 Jun-Jul;34(6):1197-202
references: 23275593
references: Neurology. 1999 Apr 22;52(7):1397-403
references: 10227624
references: J Neurosci. 2005 Aug 24;25(34):7709-17
references: 16120771
references: Neuroimage. 2006 Jun;31(2):496-504
references: 16473024
references: Alzheimers Dement. 2013 Sep;9(5):546-53
references: 23232270
references: Schizophr Bull. 2009 Nov;35(6):1142-62
references: 18556667
references: Aging Clin Exp Res. 2011 Oct-Dec;23(5-6):487-90
references: 22526081
references: Lancet Neurol. 2014 Jun;13(6):614-29
references: 24849862
references: Arch Gen Psychiatry. 2006 Feb;63(2):168-74
references: 16461860
references: Cogn Affect Behav Neurosci. 2013 Mar;13(1):135-51
references: 23055092
references: Mol Psychiatry. 2013 Nov;18(11):1225-34
references: 23399914
references: Neuroimage. 2005 Feb 15;24(4):1205-13
references: 15670698
references: Neuroimage. 2003 Jul;19(3):1233-9
references: 12880848
references: Am J Geriatr Psychiatry. 2014 Jul;22(7):698-707
references: 23672944
references: Neurobiol Aging. 2014 Jul;35(7):1781.e1-8
references: 24582639
references: Int J Geriatr Psychiatry. 2010 Feb;25(2):121-32
references: 19672843
references: Biol Psychiatry. 2009 Jun 1;65(11):951-8
references: 19028382
references: Nat Genet. 2012 Apr 15;44(5):552-61
references: 22504417
references: Neurology. 2008 Feb 12;70(7):512-20
references: 17898323
references: Neuroimage. 2007 Oct 15;38(1):95-113
references: 17761438
references: Biol Psychiatry. 1996 Mar 15;39(6):389-99
references: 8679784
references: N Engl J Med. 2000 Aug 17;343(7):450-6
references: 10944562
references: Neuroscience. 2006 Apr 28;139(1):277-89
references: 16343785
references: Neuropsychology. 2011 Mar;25(2):226-36
references: 21090897
references: Trends Mol Med. 2013 Oct;19(10):594-603
references: 23871436
references: Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4637-42
references: 15070770
references: Trends Cogn Sci. 2006 Nov;10(11):487-93
references: 17015030
references: Arch Gen Psychiatry. 2011 Dec;68(12):1207-17
references: 21810628
references: Sci Transl Med. 2011 Apr 6;3(77):77sr1
references: 21471435
references: Biol Psychiatry. 2008 Nov 15;64(10):871-9
references: 18723162
references: Nat Genet. 2007 Jan;39(1):17-23
references: 17192785
references: Cereb Cortex. 2008 Jul;18(7):1618-29
references: 17999985
references: Nat Genet. 2013 Dec;45(12):1452-8
references: 24162737
references: Neuropsychopharmacology. 2014 Aug;39(9):2153-60
references: 24625753
references: J Neurosci. 2008 Jul 16;28(29):7304-12
references: 18632934
references: Nat Genet. 2012 Apr 15;44(5):545-51
references: 22504421
references: Neuroreport. 2002 Oct 28;13(15):1939-43
references: 12395096
references: Eur Neuropsychopharmacol. 2011 Dec;21(12):880-4
references: 21397462
references: Mol Psychiatry. 2011 Feb;16(2):184-92
references: 20038948
references: JAMA. 2010 May 12;303(18):1832-40
references: 20460622
references: Curr Biol. 2013 Sep 9;23(17):R764-73
references: 24028960
references: Ann Neurol. 2003 Feb;53(2):181-8
references: 12557284
references: Neurosci Lett. 2013 Jun 7;544:47-51
references: 23570733
references: Sci Transl Med. 2014 Mar 19;6(228):228fs13
references: 24648338
references: Arch Gen Psychiatry. 2005 Apr;62(4):379-86
references: 15809405
references: J Alzheimers Dis. 2014;42(4):1221-7
references: 25024306
references: Hippocampus. 2001;11(4):337-46
references: 11530838
references: J Neurosci. 2011 Dec 7;31(49):18180-4
references: 22159129
references: Arch Neurol. 2010 Jun;67(6):677-85
references: 20558387
references: Neuroimage. 2006 Dec;33(4):1207-17
references: 17011215
references: Hum Brain Mapp. 2005 May;25(1):46-59
references: 15846822
references: Annu Rev Clin Psychol. 2013;9:621-48
references: 23297785