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Genetic Variants in A Neurobiology of Aging 35 (2014) 2881.e7e2881.e10 Contents lists available at ScienceDirect Neurobiology of Aging journal homepage: www.elsevier.com/locate/neuaging Brief communication Genetic variants in a ‘cAMP element binding protein’ (CREB)-dependent histone acetylation pathway influence memory performance in cognitively healthy elderly individuals Sandra Barral a,b, Christiane Reitz a,b, Scott A. Small a,b, Richard Mayeux a,b,* a Department of Neurology, Columbia University Medical Center, New York, NY, USA b Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, NY, USA article info abstract Article history: The molecular pathways underlying age-related memory changes remain unclear. There is a substantial Received 5 March 2014 genetic contribution to memory performance through life span. A recent study has implicated RbAp48, Received in revised form 17 June 2014 which mediates its effect on age-related memory decline by interacting with cyclic adenosine mono- Accepted 24 June 2014 phosphate responsive element binding protein (CREB)1 binding protein and influencing this histone Available online 28 June 2014 acetylation pathway. To validate these findings, we tested whether genetic variants in RbAp48, CREB1, and CREBBP are associated with memory performance in 3 independent data sets consisting of 2674 Keywords: cognitively healthy elderly individuals. Genetic variant rs2526690 in the CREBBP gene was significantly Histone metabolism ¼ Â À4 Meta-analysis associated with episodic memory performance (pmeta 3.7 10 ) in a multivariate model adjusted for Episodic memory performance age, sex, and apolipoprotein E status. Identifying genetic variants that modulate mechanisms of cognitive aging will allow identifying valid targets for therapeutic intervention. Ó 2014 Elsevier Inc. All rights reserved. 1. Introduction therapeutic intervention to ameliorate cognitive impairment in the elderly individuals. Although there is substantial evidence that decline in cognitive Recently, gene expression analysis of human postmortem tissue performance occurs with normal aging, the neurobiological basis of harvested from the hippocampal formation identified a substantial these age-related cognitive changes remains unclear. Cross- age-related decline in the expression of the histone-binding protein sectional and longitudinal studies showed that across cognitive RbAp48 gene (Pavlopoulos et al., 2013). Inhibition of RbAp48 in domains, memory performance undergoes significant decline with young genetically engineered mice caused memory deficits similar increasing age (Small et al., 1999). Heritability estimates from twin to those associated with aging, whereas increasing RbAp48 and family studies indicate that genetic variants strongly influence expression in old mice reversed age-related memory impairment. cognitive ability differences throughout the life span, including in Rbap48 gene is known to facilitate the action of the cyclic old age (Harris and Deary, 2011). To date, however, most associa- adenosine monophosphate responsive element binding protein tions in or surrounding common variants are largely unreplicated, (CREB)1 gene’s-binding protein CREBBP, which is acetylates histones with the exception of the apolipoprotein E (APOE) gene (Wisdom and affects age-related memory loss. In the present study, we et al., 2011) and have little biological support. investigated whether genetic variants in these histone acetylation In our increasingly aging society, the population aged 60 years pathway genes (RbAp48, CREBBP, and CREB1)influence memory and older is set to rise 3-fold to 2 billion by 2050 (Publications, performance in cognitive healthy elderly individuals. 2001), consequently the burden of age-related cognitive impair- ment will increase. Characterizing genetic factors accounting for the age-related memory deficits will identify valid targets for 2. Methods 2.1. Study cohorts * Corresponding author at: Department of Neurology, G. H. Sergievsky Center & 2.1.1. The National Institute of Aging Late-Onset Alzheimer’s Disease Taub Institute, Columbia University Medical Center, 630 West 168th Street, New ’ York, NY 10032, USA. Tel.: þ1 212 305 2391; fax: þ1 212 305 2518. The National Institute of Aging Late-Onset Alzheimer s Disease E-mail address: [email protected] (R. Mayeux). Family Study was described elsewhere (Wijsman et al., 2011). From 0197-4580/$ e see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.neurobiolaging.2014.06.024 2881.e8 S. Barral et al. / Neurobiology of Aging 35 (2014) 2881.e7e2881.e10 the total cohort, 494 nondemented and unrelated healthy in- 2007). In each of the cohorts, interaction analysis between SNP dividuals were included in the present study. Episodic memory markers significant in single-marker association tests and the APOE scores at the last cognitive assessment were computed as the locus (coded as 0 or 1 based on the absence or the presence of e4 average of the 2 standardized measures of Logical Memory IA and allele) was performed using linear regression analyses which IIA (Wechsler, 1987). Genome-wide genotyping was performed modeled the main effect of both loci, an interaction term of the using Illumina Human610Quadv1_B BeadChips (Illumina, San SNP Â APOE, and covariates (sex, age, and education). Diego, CA, USA) (Naj et al., 2011). 2.3.2. Statistical significance ’ 2.1.2. The Alzheimer s Disease Genetic Consortium Multiple testing adjustment of the obtained p-values was car- A total of 1744 cognitively normal elderly individuals from Alz- ried out using The Genetic Type I error calculator tool (Li et al., ’ heimer s Disease Genetic Consortium (ADGC) cohort consisting of 5 2012) to compute gene-specific thresholds of significance based different independent NIA-funded Alzheimer’s disease centers (Naj on the number of SNPs used to tag (tag-SNPs) each of the analyzed et al., 2011) were used to test the association of histone acetylation genes: 37 tag-SNPs in CREB1 (p 0.001), 98 tag-SNPs in CREBBP pathway genes and episodic memory performance. Episodic À (p 5 Â 10 4), and 40 tag-SNPs in RBBP4 (p 0.001). memory scores at the last cognitive assessment were computed as the average of the 2 standardized measures of Logical Memory IA 2.3.3. Meta-analysis and IIA (Wechsler, 1987). Genome-wide genotyping was performed SNP association with episodic memory performance was ob- using various genotyping arrays (Saykin et al., 2010). To test the tained from the 3 independent cohorts and combined by meta- ’ possible association of the histone pathway genes and Alzheimer s analysis using METAL (Willer et al., 2010). Results obtained from disease, we additionally used a sample of 11,840 demented subjects SNP-APOE interaction models within each cohort were also meta- from 15 different independent ADGC subcohorts. analyzed. Because of the known APOE-e4 association with 2.1.3. The Washington Heights Aging Project impaired cognitive performance (Mayeux et al., 2001) and the fi The Washington Heights Aging Project is a population-based suggestive interaction between the most signi cant SNP and APOE ¼ fi study of elderly individuals residing in New York (Mayeux et al., locus (pmeta 0.07), we strati ed our analysis by APOE classifying ’ 2001). The memory domain included the total and delayed recall the cohort s participants as carriers of 1, 2, or no copies of APOE-e4 of the Selective Reminding Test (Buschke and Fuld, 1974) and the allele. recognition component of the Benton Visual Retention Test (Benton, 1955). The composite measure of memory was computed 3. Results as the average of the standardized individual memory tests from the last cognitive assessment (Siedlecki et al., 2008). Our analysis The strongest genetic association with episodic memory per- was restricted to the White subsample consisting of 436 cognitively formance was observed for intronic SNP rs2526690 in CREBBP, fi healthy elderly individuals. Genome-wide genotyping was done reaching statistical signi cance after adjusting for multiple testing ¼ Â À4 using the Omni Express platform by Illumina. (pmeta 3.7 10 ). When comparing the estimates of the beta coefficient of the SNP based on the APOE-e4 status, the SNP effect 2.2. Statistical methods size appeared to be driven by the noncarriers of APOE-e4 allele (all subjects: b ¼ 0.20, standard error [SE] ¼ 0.07; APOE-e4 noncarriers b ¼ ¼ 2.2.1. Imputed genotype data 0.13, SE 0.08). fi To significantly improve the single-nucleotide polymorphism Although not reaching statistically signi cant thresholds, 3 (SNP) coverage of the genes analyzed based on the different additional SNPs in CREBBP (rsrs36099109, rs112455953, and genome-wide association studies platforms, we used the imputed rs112193373) showed nominal associations that were directionally genotype data available for each of the study cohorts. consistent across cohorts among individuals lacking the APOE-e4 ¼ ¼ ¼ Genome-wide imputation of allele dosages within each of the allele (pmeta 0.006, pmeta 0.001, and pmeta 0.002, respectively). study cohorts was performed using the worldwide reference panel Within CREB1 gene proximity (39-Kb upstream the gene), SNP (v3, released March 2012) from 1000 Genomes for imputation of rs72954151 was found nominally associated with episodic memory ¼ genotypes (build 37, http://www.1000genomes.org/announcements/ (pmeta 0.008) in the noncarriers of the APOE-e4 allele. SNP marker updated-integrated-phase-1-release-calls-2012-03-16) and the rs9660296 located
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