Genome Wide Analysis Across Alzheimer's Disease Endophenotypes: Main Effects and Stage Specific Interactions
Introduction: Genetic association analysis of key Alzheimer's disease (AD) endophenotypes may provide insight into molecular mechanisms and genetic contributions. Methods: Major AD endophenotypes based on the A/T/N (Amyloid-beta, Tau, and Neurodegeneration) biomarkers and cognitive performance were selected from Alzheimer's Disease Neuroimaging Initiative (ADNI) in up to 1,565 subjects. Genome-wide association analysis of quantitative phenotypes was performed using a main SNP effect and a SNP by Diagnosis interaction (SNPxDX) model to identify stage specific genetic effects. Results: Sixteen novel or replicated loci were identified in the main effect model, with six (SRSF10, MAPT, XKR3, KIAA1671, ZNF826P, and LOC100507506) meeting study significance thresholds with the A/T/N biomarkers. The SNPxDX model identified three study significant genetic loci (BACH2, EP300, PACRG-AS1) associated with a neuroprotective effect in later AD stage endophenotypes. Discussion: An endophenotype approach identified novel genetic associations and new insights into the associations that may otherwise be missed using conventional case-control models.