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Integration of GWAS and brain transcriptomic analyses in a multiethnic sample of 35,245 older adults identifies DCDC2 gene as predictor of episodic memory maintenance
Author(s) -
Gao Yizhe,
Felsky Daniel,
ReyesDumeyer Dolly,
Sariya Sanjeev,
Rentería Miguel Arce,
Ma Yiyi,
Klein HansUlrich,
Cosentino Stephanie,
De Jager Philip L.,
Bennett David A.,
Brickman Adam M.,
Schellenberg Gerard D.,
Mayeux Richard,
Barral Sandra
Publication year - 2022
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.12524
Subject(s) - episodic memory , genome wide association study , apolipoprotein e , prefrontal cortex , psychology , transcriptome , neuroscience , biology , medicine , disease , gene , genetics , single nucleotide polymorphism , gene expression , cognition , genotype
Abstract Identifying genes underlying memory function will help characterize cognitively resilient and high‐risk declining subpopulations contributing to precision medicine strategies. We estimated episodic memory trajectories in 35,245 ethnically diverse older adults representing eight independent cohorts. We conducted apolipoprotein E ( APOE )‐stratified genome‐wide association study (GWAS) analyses and combined individual cohorts’ results via meta‐analysis. Three independent transcriptomics datasets were used to further interpret GWAS signals. We identified DCDC2 gene significantly associated with episodic memory (Pmeta = 3.3 x 10 ‐8 ) among non‐carriers of APOE ε4 (N = 24,941). Brain transcriptomics revealed an association between episodic memory maintenance and (1) increased dorsolateral prefrontal cortex DCDC2 expression ( P = 3.8 x 10 ‐4 ) and (2) lower burden of pathological Alzheimer's disease (AD) hallmarks (paired helical fragment tau P = .003, and amyloid beta load P = .008). Additional transcriptomics results comparing AD and cognitively healthy brain samples showed a downregulation of DCDC2 levels in superior temporal gyrus ( P = .007) and inferior frontal gyrus ( P = .013). Our work identified DCDC2 gene as a novel predictor of memory maintenance.