Basic Science and Pathogenesis.

Area of Science:

• Genetics
• Neuroscience
• Bioinformatics

Background:

• The Alzheimer's Disease Sequencing Project Phenotype Harmonization Consortium (ADSP-PHC) provided harmonized cognitive data from 12 studies.
• Whole genome sequencing (WGS) data enabled genomic analyses of Alzheimer's disease (AD) related endophenotypes.

Purpose of the Study:

• To identify genetic factors influencing cognitive function through genome-wide analyses.
• To investigate associations of common and rare variants with baseline memory scores.

Main Methods:

• Selected 9,698 ADSP participants with mild cognitive impairment or normal cognition and WGS data.
• Conducted genome-wide association studies (GWAS) for common variants and used STAARpipeline for rare variants.
• Applied three models to account for study heterogeneity and adjusted for covariates including APOE status.

Main Results:

• Genomic inflation factors (λ) were reduced by accounting for study heterogeneity, with Model_3 achieving λ=1.01.
• APOE status was consistently associated with baseline memory score across all models.
• A common variant (rs36110370) near GOLPH3 showed a consistent association with lower memory scores (p < 3x10^-8).
• Rare noncoding variants in TOMM40 were associated with baseline memory score.

Conclusions:

• Modeling study-specific variance effectively addressed residual structure in harmonized memory scores.
• The variant rs36110370 demonstrated a consistent association with memory, though not always genome-wide significant.
• Ongoing analyses will examine language and executive function scores from the ADSP PHC.