The Human Brainome: genome, transcriptome and proteome interaction in human cortex

Our hypothesis is that changes in gene and protein expression are crucial to the development of late onset Alzheimer’s disease. Previously we examined how DNA alleles control downstream expression of RNA transcripts and how those relationships are changed in late onset Alzheimer’s disease. We have now examined how proteins are incorporated into networks in two separate series and evaluated our outputs in two different cell lines. Our pipeline included the following steps: 1. Predicting expression quantitative trait loci, 2. Determining differential expression, 3. Analyzing networks of transcript and peptide relationships and 4. Validating effects in two separate cell lines. We performed all our analysis in two separate brain series to validate effects. Our two series included 345 samples in the first set (177 controls, 168 cases; age range 65-105; 58% female; KRONOSII cohort) and 409 samples in the replicate set (153 controls, 141 cases, 115 mild cognitive impairment; age range 66-107; 63% female; RUSH cohort). Our top target is Heat Shock Protein Family A Member 2 (HSPA2), which was identified as a key driver in our two datasets. HSPA2 was validated in two cell lines, with overexpression driving further elevation of Abeta40 and Abeta42 levels in amyloid precursor protein mutant cells as well as significant elevation of microtubule associated protein Tau (MAPT) and phospho-Tau in a modified neuroglioma line. This work further demonstrates that studying changes in gene and protein expression is crucial to understanding late onset disease and further nominates HSPA2 as a specific key regulator of late onset Alzheimer’s disease processes.