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, Y; Felsky, D; Reyes-Dumeyer, D; Sariya, S; Rentería, MA; Ma, Y; Klein, H; Cosentino, S; De Jager, PL; Bennett, DA; Brickman, AM; Schellenberg, GD; Mayeux, R; Barral, S; CHAP, UKBB, ADNI, ROSMAP, LLFS, NIA-LOAD and ADGC consortia;
Year: 2022;  
Journal: Alzheimer's & Dementia: The Journal of the Alzheimer's Association;  
Volume: 18;  
Issue: 10;  

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.