Evidence for an association between KIBRA and late-onset Alzheimer's disease.
We recently reported evidence for an association between the individual variation in normal human episodic memory and a common variant of the KIBRA gene, KIBRA rs17070145 (T-allele). Since memory impairment is a cardinal clinical feature of Alzheimer's disease (AD), we investigated the possibility of an association between the KIBRA gene and AD using data from neuronal gene expression, brain imaging studies, and genetic association tests. KIBRA was significantly over-expressed and three of its four known binding partners under-expressed in AD-affected hippocampal, posterior cingulate and temporal cortex regions (P<0.010, corrected) in a study of laser-capture microdissected neurons. Using positron emission tomography in a cohort of cognitively normal, late-middle-aged persons genotyped for KIBRA rs17070145, KIBRA T non-carriers exhibited lower glucose metabolism than did carriers in posterior cingulate and precuneus brain regions (P<0.001, uncorrected). Lastly, non-carriers of the KIBRA rs17070145 T-allele had increased risk of late-onset AD in an association study of 702 neuropathologically verified expired subjects (P=0.034; OR=1.29) and in a combined analysis of 1026 additional living and expired subjects (P=0.039; OR=1.26). Our findings suggest that KIBRA is associated with both individual variation in normal episodic memory and predisposition to AD.
Corneveaux
Jason J
JJ
Translational Genomics Research Institute (TGen), Neurogenomics Division, Phoenix, AZ 85004, USA.
Liang
Winnie S
WS
Reiman
Eric M
EM
Webster
Jennifer A
JA
Myers
Amanda J
AJ
Zismann
Victoria L
VL
Joshipura
Keta D
KD
Pearson
John V
JV
Hu-Lince
Diane
D
Craig
David W
DW
Coon
Keith D
KD
Dunckley
Travis
T
Bandy
Daniel
D
Lee
Wendy
W
Chen
Kewei
K
Beach
Thomas G
TG
Mastroeni
Diego
D
Grover
Andrew
A
Ravid
Rivka
R
Sando
Sigrid B
SB
Aasly
Jan O
JO
Heun
Reinhard
R
Jessen
Frank
F
Kölsch
Heike
H
Rogers
Joseph
J
Hutton
Michael L
ML
Melquist
Stacey
S
Petersen
Ron C
RC
Alexander
Gene E
GE
Caselli
Richard J
RJ
Papassotiropoulos
Andreas
A
Stephan
Dietrich A
DA
Huentelman
Matthew J
MJ
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology*; D001057:Apolipoproteins E / Q000235:genetics; D001921:Brain / Q000000981:diagnostic imaging / Q000201:enzymology / Q000473:pathology*; D001931:Brain Mapping; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009483:Neuropsychological Tests; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010750:Phosphoproteins; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D049268:Positron-Emission Tomography / Q000379:methods; D011506:Proteins / Q000235:genetics*
D001057:Apolipoproteins E; D005904:Glial Fibrillary Acidic Protein; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D011506:Proteins; C513637:WWC1 protein, human
Neurology. 1998 Oct;51(4):993-9
9781519
Science. 2006 Oct 20;314(5798):475-8
17053149
J Neurosci. 2005 Aug 24;25(34):7709-17
16120771
Am J Med Genet B Neuropsychiatr Genet. 2008 Jul 5;147B(5):667-8
18205171
AJNR Am J Neuroradiol. 2005 Feb;26(2):333-40
15709131
Am J Psychiatry. 1997 Feb;154(2):165-72
9016263
Neuron. 2007 Jun 7;54(5):713-20
17553421
Neurology. 2003 Feb 11;60(3):481-6
12578931
J Int Neuropsychol Soc. 2002 Mar;8(3):448-60
11939702
Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8299-302
15932949
Physiol Genomics. 2008 Apr 22;33(2):240-56
18270320
Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):284-9
14688411
Proc Natl Acad Sci U S A. 2000 May 23;97(11):6037-42
10811879
J Cell Mol Med. 2008 Sep-Oct;12(5A):1672-6
18194457
Neurology. 1991 Apr;41(4):479-86
2011243
Neurology. 1999 Jan 1;52(1):91-100
9921854
Acta Neuropathol. 1991;82(4):239-59
1759558
Physiol Genomics. 2007 Feb 12;28(3):311-22
17077275
J Nucl Med. 1995 Jul;36(7):1141-9
7790936
Neurology. 1995 Jan;45(1):55-60
7824135
Neurosci Lett. 2008 May 9;436(2):145-7
18378080
Neurobiol Aging. 2009 Feb;30(2):322-4
17707552
Neurobiol Aging. 2003 Jul-Aug;24(4):563-72
12714113
Bioinformatics. 2005 Jan 15;21(2):263-5
15297300
Neurology. 1984 Jul;34(7):939-44
6610841
Bioinformatics. 2007 Jan 1;23(1):57-63
17062589
Am J Hum Genet. 2007 Sep;81(3):559-75
17701901
Neurobiol Aging. 2006 Oct;27(10):1359-71
16242812
Am J Psychiatry. 2002 May;159(5):738-45
11986126
Hum Mol Genet. 2007 Apr 15;16(8):865-73
17317784
Neurobiol Aging. 2008 Jul;29(7):1123-5
17353070