Genome Wide Analysis Across Alzheimer’s Disease Endophenotypes: Main Effects and Stage Specific Interactions

ABSTRACT 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-β, 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.