80 Genome-wide association study of visual memory and spatial organization in a community setting: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium

Objectives/Goals: Poor visual memory and perceptual organization task performance predicts cognitive decline and is sensitive to dementia severity. No genome-wide association study (GWAS) has assessed the genomic basis of cognitive visual-spatial phenotypes. We aimed to identify common genetic variants associated with visual memory and spatial organization. Methods/Study Population: We included dementia- and stroke-free participants aged 45 years or older from up to seven cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, who performed cognitive tasks assessing delayed visual memory (e.g., Benton Visual Retention Test (BVRT, n = 10,934) and visual reproductions (VR, n = 5,527)) or spatial organization (i.e., Hooper Visual Organization Test (HVOT, n = 5,024)). Each cohort used linear regression models to relate common genetic variants imputed to the 1000 Genomes panel to each cognitive phenotype, adjusting for age, sex, population stratification, and education. Summary statistics for the BVRT were meta-analyzed using METAL. Combined GWAS was used for a joint analysis of all traits. Results/Anticipated Results: We identified a genome-wide significant variant related to BVRT performance located near the TSHZ3 gene (rs10425277, p = 6.76×10–9). TSHZ3 is important for the development and function of cortical projecting neurons and may be implicated in Alzheimer’s disease progression by repressing CASP4 transcription. Multitrait analyses, including BVRT, VR, and HVOT, identified two additional variants of interest in SMYD3 gene (rs10802275, p = 5.58×10–7) and near ZFPM2 (rs2957459, p = 2.03×10–7), both of which are overexpressed in the brain and have important implications for neurodevelopment. SMYD3 may be directly involved in synaptic dysfunction and has been shown to be upregulated in the prefrontal cortex of Alzheimer’s disease patients. Discussion/Significance of Impact: Our findings suggest that variants related to visual memory and spatial organization are involved in neurodevelopmental and degenerative pathways. This GWAS adds to the growing body of GWAS literature on the genetic basis of cognitive function. Additional analyses are underway to replicate these findings and extend functional annotation.