Genome-wide interaction analysis of pathological hallmarks in Alzheimer's disease.

Genome-wide association studies have identified many loci associated with Alzheimer's dementia. However, these variants only explain part of the heritability of Alzheimer's disease (AD). As genetic epistasis can be a major contributor to the "missing heritability" of AD, we conducted genome-wide epistasis screening for AD pathologies in 2 independent cohorts. First, we performed a genome-wide epistasis study of AD-related brain pathologies (N max = 1318) in ROS/MAP. Candidate interactions were validated using cerebrospinal fluid biomarkers of AD in ADNI (N max = 1128). Further functional analysis tested the association of candidate interactions with neuroimaging phenotypes. For tau and amyloid-β pathology, we identified 2803 and 464 candidate SNP-SNP interactions, respectively. Associations of candidate SNP-SNP interactions with brain volume and white matter changes from neuroimages provides additional insights into their molecular functions. Transcriptional analysis supported possible gene-gene interactions identified by statistical screening through their co-expression in the brain. In summary, we outlined an exhaustive epistasis analysis to identify novel genetic interactions with potential roles in AD pathologies. We further delved into the functional relevance of candidate interactions by association with neuroimaging phenotypes and analysis of co-expression between corresponding gene pairs. • Genetic interactions help explain the "missing heritability" in Alzheimer's disease. • We conducted a genome-wide epistasis analysis for Alzheimer's disease pathologies. • The epistasis signals were replicated in independent data. • Transcriptome analysis supported the interactions (such as INPP4B / RBFOX1 interaction). • Association with neuroimages provides insights into molecular functions of interactions. [ABSTRACT FROM AUTHOR]