Dataset Information

Association of common KIBRA variants with episodic memory and AD risk.

ABSTRACT: KIBRA single nucleotide polymorphism (SNP) rs17070145 was identified in a genome-wide association study (GWAS) of memory performance, with some but not all follow-up studies confirming association of its T allele with enhanced memory. This allele was associated with reduced Alzheimer's disease (AD) risk in 1 study, which also found overexpression of KIBRA in memory-related brain regions of AD. We genotyped rs17070145 and 14 additional SNPs in 2571 late onset Alzheimer's disease (LOAD) patients vs. 2842 controls, including African-Americans. We found significantly reduced risk for rs17070145 T allele in the older African-American subjects (p = 0.007) and a suggestive effect in the older Caucasian series. Meta-analysis of this allele in > 8000 subjects from our and published series showed a suggestive protective effect (p = 0.07). Analysis of episodic memory in control subjects did not identify associations with rs17070145, though other SNPs showed significant associations in 1 series. KIBRA showed evidence of overexpression in the AD temporal cortex (p = 0.06) but not cerebellum. These results suggest a modest role for KIBRA as a cognition and AD risk gene, and also highlight the multifactorial complexity of its genetic associations.

SUBMITTER: Burgess JD

PROVIDER: S-EPMC3065956 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Association of common KIBRA variants with episodic memory and AD risk.

Burgess Jeremy D JD Pedraza Otto O Graff-Radford Neill R NR Hirpa Meron M Zou Fanggeng F Miles Richard R Nguyen Thuy T Li Ma M Lucas John A JA Ivnik Robert J RJ Crook Julia J Pankratz V Shane VS Dickson Dennis W DW Petersen Ronald C RC Younkin Steven G SG Ertekin-Taner Nilüfer N

Neurobiology of aging 20101224 3

KIBRA single nucleotide polymorphism (SNP) rs17070145 was identified in a genome-wide association study (GWAS) of memory performance, with some but not all follow-up studies confirming association of its T allele with enhanced memory. This allele was associated with reduced Alzheimer's disease (AD) risk in 1 study, which also found overexpression of KIBRA in memory-related brain regions of AD. We genotyped rs17070145 and 14 additional SNPs in 2571 late onset Alzheimer's disease (LOAD) patients v ...[more]

PMID: 21185624

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Project description:IMPORTANCE:There are genetic influences on memory ability as we age, but no specific genes have been identified. OBJECTIVE:To use a cognitive endophenotype, exceptional episodic memory (EEM) performance, derived from nondemented offspring from the Long Life Family Study (LLFS) to identify genetic variants that may be responsible for the high cognitive performance of LLFS participants and further replicate these variants using an additional 4006 nondemented individuals from 4 independent elderly cohorts. DESIGN, SETTING, AND PARTICIPANTS:A total of 467 LLFS participants from 18 families with 2 or more offspring that exhibited exceptional memory performance were used for genome-wide linkage analysis. Adjusted multivariate linear analyses in the 40-megabase region encompassing the linkage peak were conducted using 4 independent replication data sets that included 4006 nondemented elderly individuals. Results of the individual replication cohorts were combined by meta-analysis. MAIN OUTCOME MEASURE:Episodic memory scores computed as the mean of the 2 standardized measures of Logical Memory IA and IIA. RESULTS:Heritability estimates indicated a significant genetic component for EEM (h2 = 0.21; SE = 0.09). Genome-wide linkage analysis revealed that EEM was linked to the 6q24 region (maximum logarithm of odds score, 3.64). Association analysis in LLFS families identified single-nucleotide polymorphisms (SNPs) nominally associated with EEM in the 40-megabase window encompassing the linkage peak. Replication in one cohort identified a set of 26 SNPs associated with episodic memory (P ? .05). Meta-analysis of the 26 SNPs using the 4 independent replication cohorts found SNPs rs9321334 and rs6902875 to be nominally significantly associated with episodic memory (P = .009 and P = .013, respectively). With meta-analysis restricted to individuals lacking an APOE ?4 allele, SNP rs6902875 became statistically significant (meta-analysis, P = 6.7 × 10-5). Haplotype analysis incorporating the 2 SNPs flanking rs6902875 (rs9321334 and rs4897574) revealed that the A-A-C haplotype was significantly associated with episodic memory performance (P = 2.4 × 10-5). This genomic region harbors monooxygenase dopamine ?-hydroxylase-like 1 gene (MOXD1), implicated in the biosynthesis of norepinephrine, which is prominently involved in cognitive functions. CONCLUSIONS AND RELEVANCE:The results provide strong evidence for potential candidate genes related to EEM on 6q24. Identifying the genes will help in understanding the biological basis of memory performance and allow interventions for enhancement of cognitive function.

Dataset Information

Association of common KIBRA variants with episodic memory and AD risk.

Publications

Association of common KIBRA variants with episodic memory and AD risk.

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