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. 2018 May 29:10:155.
doi: 10.3389/fnagi.2018.00155. eCollection 2018.

Associations of MAP2K3 Gene Variants With Superior Memory in SuperAgers

Matthew J Huentelman  1 , Ignazio S Piras  1 , Ashley L Siniard  1 , Matthew D De Both  1 , Ryan F Richholt  1 , Chris D Balak  1 , Pouya Jamshidi  2 , Eileen H Bigio  2   3 , Sandra Weintraub  2   4 , Emmaleigh T Loyer  2 , M-Marsel Mesulam  2   5 , Changiz Geula  2 , Emily J Rogalski  2   4
Affiliations

Associations of MAP2K3 Gene Variants With Superior Memory in SuperAgers

Matthew J Huentelman et al. Front Aging Neurosci. .

Abstract

Introduction: SuperAgers are adults age 80+ with episodic memory performance that is at least as good as that of average middle-aged adults. Understanding the biological determinants of SuperAging may have relevance to preventing age-related cognitive decline and dementia. This study aimed to identify associations between genetic variations and the SuperAging phenotype using Whole Exome Sequencing (WES). Methods: Sequence Kernel Association Combined (SKAT-C) test was conducted at the gene level including both rare and common variants in 56 SuperAgers and 22 cognitively-average controls from the Alzheimer's disease Neuroimaging Initiative (ADNI). Results: The SuperAging phenotype was associated with variants in the Mitogen-Activated Protein Kinase Kinase 3 (MAP2K3) gene. Three single nucleotide polymorphisms (SNPs) contributed to the significance (rs2363221 [intron 1], rs2230435 [exon 5], rs736103 [intron 7]). Conclusions: MAP2K3 resides in a biological pathway linked to memory. It is in a signaling cascade associated with beta-amyloid mediated apoptosis and has enriched expression in microglia. This preliminary work suggests MAP2K3 may represent a novel therapeutic target for age-related memory decline and perhaps Alzheimer's disease (AD).

Keywords: Alzheimer’s; Alzheimer’s dementia; Alzheimer’s disease (AD); aging; cognition; episodic memory; genetics; successful aging; whole exome sequencing.

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Figures

Figure 1
Figure 1
Manhattan plots showing the results of the Sequence Kernel Association Combined (SKAT-C) analysis between SuperAgers and Alzheimer’s disease neuroimaging initiative (ADNI) controls, without covariates (A) and with covariates (B) included in the model. The red line indicates the significance threshold after Bonferroni correction (p = 3.09E-06), whereas the blue line indicates the nominal significance threshold (p = 0.05). (C) Allele frequencies for the single nucleotidepolymorphisms (SNPs) in the Mitogen-Activated Protein Kinase Kinase 3 (MAP2K3) gene in SuperAging, Control and ExAC cohorts (European non-Finnish population sample).
See this image and copyright information in PMC

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