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.

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.