Identifying context‐specific genetic variants and molecular pathways associated with resilience to Alzheimer’s disease in the induced immune response

Abstract

AbstractBackgroundNeurodegenerative pathologies consistent with Alzheimer’s disease (AD) are common in older adults even among those without cognitive symptoms. Genome‐wide association studies (GWAS) have identified loci associated with better‐than‐predicted cognitive performance for a given level of neuropathology, described as resilience to AD symptoms. Transcriptome‐wide association studies (TWAS) provide powerful mechanistic insights bridging the association between loci and phenotype by implicating genes. We hypothesize that genetic variants influence resilience phenotypes by altering the function and response of monocytes, one of the premier immune cells involved in neuroinflammation. Moving to test this hypothesis, we have developed monocyte TWAS reference panels based on expression from a naïve state and following in vitro stimulations which can reveal important associations only seen in an inflammatory context.MethodsGenetic data of monocytes produced by Fairfax et. al 2014 were obtained and SNPs imputed on the Michigan Imputation Server using samples available on the Haplotype Reference Consortium. Plink 1.9 was used for standard quality control. Corresponding monocyte expression data was downloaded from ArrayExpress, and a custom script was used to extract probes not overlapping with regions containing common SNPs (MAF > 0.05) and mapping to single genes. Cis‐eQTL analysis was then performed using the MatrixeQTL R package, and final gene expression prediction panels constructed by fitting elastic‐net regularized regression models using the PredictDB pipeline.ResultsOur pipeline has been validated through showing concordance between our results and those of the Fairfax group with respect to the rs1179625 SNP and its context‐specific direction of effect on the gene expression of HIP1. Further, genotype imputation enabled the identification of thousands of additional eQTLs and response‐eQTL’s (re‐eQTL’s) across the genome—illustrating the importance of studying these cells in an appropriate environment. TWAS analyses of their collective impact on resilience phenotypes are ongoing.ConclusionWe expand the available tissues and cell types for TWAS of AD by generating reference panels that account for the dynamic biology of monocytes in different states. These panels enable analyses that may have specific importance for cognitive resilience, and may provide concrete biological mechanisms as to how some individuals can manifest the neuropathology of AD and yet remain asymptomatic.