Common genetic variants on 6q24 associated with exceptional episodic memory performance in the elderly

Abstract

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 ε4 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 β-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.

Figure. Linkage Analysis and Follow-up Single-Nucleotide Polymorphism (SNP) Association Analyses

A, Multipoint linkage analyses on chromosome 6q24 in 18 Long Life Family Study (LLFS) families. Logarithm of odds (LOD) scores are plotted against the genetic distance in centimorgans. The maximum LOD score of 3.62 is located at 145 cM (139 011 233 base pairs [bp]). Follow-up SNP association analyses evaluated the 112- to 164-megabase region encompassing the linkage peak. B, Plot of the 6324 SNPs associated with exceptional memory in the LLFS families. C, APOE-stratified meta-analysis of 26 candidate SNPs in all 4 replication cohorts (National Institute on Aging Late-Onset Alzheimer Disease, Alzheimer Disease Neuroimaging Initiative, Alzheimer Disease Genetic Consortium, and Washington Heights Aging Project). SNP marker rs6902875, which had the strongest association with episodic memory performance, is located downstream from a potential candidate gene, MOXD1 (123 bp).