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

Abstract

IntroductionGenetic association analysis of key Alzheimers disease (AD) endophenotypes may provide insight into molecular mechanisms and genetic contributions. MethodsMajor AD endophenotypes based on the A/T/N (Amyloid-{beta}, Tau, and Neurodegeneration) biomarkers and cognitive performance were selected from Alzheimers 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. ResultsSixteen 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. DiscussionAn endophenotype approach identified novel genetic associations and new insights into the associations that may otherwise be missed using conventional case-control models.