Dataset Information

Cross-Species Analyses Identify Dlgap2 as a Regulator of Age-Related Cognitive Decline and Alzheimer's Dementia.

ABSTRACT: Genetic mechanisms underlying age-related cognitive decline and dementia remain poorly understood. Here, we take advantage of the Diversity Outbred mouse population to utilize quantitative trait loci mapping and identify Dlgap2 as a positional candidate responsible for modifying working memory decline. To evaluate the translational relevance of this finding, we utilize longitudinal cognitive measures from human patients, RNA expression from post-mortem brain tissue, data from a genome-wide association study (GWAS) of Alzheimer's dementia (AD), and GWAS results in African Americans. We find an association between Dlgap2 and AD phenotypes at the variant, gene and protein expression, and methylation levels. Lower cortical DLGAP2 expression is observed in AD and is associated with more plaques and tangles at autopsy and faster cognitive decline. Results will inform future studies aimed at investigating the cross-species role of Dlgap2 in regulating cognitive decline and highlight the benefit of using genetically diverse mice to prioritize novel candidates.

SUBMITTER: Ouellette AR

PROVIDER: S-EPMC7502175 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Cross-Species Analyses Identify Dlgap2 as a Regulator of Age-Related Cognitive Decline and Alzheimer's Dementia.

Ouellette Andrew R AR Neuner Sarah M SM Dumitrescu Logan L Anderson Laura C LC Gatti Daniel M DM Mahoney Emily R ER Bubier Jason A JA Churchill Gary G Peters Luanne L Huentelman Matthew J MJ Herskowitz Jeremy H JH Yang Hyun-Sik HS Smith Alexandra N AN Reitz Christiane C Kunkle Brian W BW White Charles C CC De Jager Philip L PL Schneider Julie A JA Bennett David A DA Seyfried Nicholas T NT Chesler Elissa J EJ Hadad Niran N Hohman Timothy J TJ Kaczorowski Catherine C CC

Cell reports 20200901 9

Genetic mechanisms underlying age-related cognitive decline and dementia remain poorly understood. Here, we take advantage of the Diversity Outbred mouse population to utilize quantitative trait loci mapping and identify Dlgap2 as a positional candidate responsible for modifying working memory decline. To evaluate the translational relevance of this finding, we utilize longitudinal cognitive measures from human patients, RNA expression from post-mortem brain tissue, data from a genome-wide assoc ...[more]

PMID: 32877673

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Dataset Information

Cross-Species Analyses Identify Dlgap2 as a Regulator of Age-Related Cognitive Decline and Alzheimer's Dementia.

Publications

Cross-Species Analyses Identify Dlgap2 as a Regulator of Age-Related Cognitive Decline and Alzheimer's Dementia.

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