Alzheimer’s disease perturbs gene‐gene correlation networks across brain regions

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Abstract Background Functional imaging has revealed how Alzheimer’s disease (AD) disrupts functional connectivity between brain regions, but the molecular basis of such changes has been less explored1. Genomic studies can reveal molecular/gene biomarkers in AD, but they have mostly been confined to within‐region analyses2. Here, we perform inter‐region analysis to explore how synchronized activities across brain regions are disrupted by gene‐pair rewiring in AD. Method We retrieved data on 264 AD and 372 control human post‐mortem RNA‐seq samples from Mount Sinai Brain Bank dataset for four brain regions: frontal pole (FP), superior temporal gyrus (STG), parahippocampal gyrus (PHG), and inferior frontal gyrus (IFG)3. Considering two brain regions at a time, we identified all pairs of genes across the two regions whose correlation strength is significantly altered in the AD group relative to the Control group4 (Fig. 1). The network of such differentially correlated (DC) genes provides information complementary to known differentially expressed genes in AD, and probably reflects cell‐intrinsic changes5 since we adjust for cell compositional effects. Result We found extensive DC gene pair rewiring in AD between pairs of brain regions, the most prominent being the coupling of PHG with other brain regions. Our analyses revealed that each brain region mostly uses a unique set of genes while interacting with other brain regions. Decomposing the bipartite DC network into gene modules revealed that certain gene modules affected in AD were enriched for synaptic signaling and ion transport pathways, whereas several others were enriched for AD GWAS (Genome‐wide Association Studies) signals. A module enriched for AD GWAS signal is also enriched for NF‐κβ signaling pathway, a key mediator of brain inflammation in AD. Beyond modules, we also identified individual genes such as ZKSCAN1 (Zinc Finger with KRAB And SCAN Domains) acting as a hub gene for most of the inter‐region comparisons and were enriched for AD GWAS signal. Conclusion These findings provide novel insights into the network of pairwise gene relations underlying the functional connectivity between brain regions and highlights how disruption of different factors rewires this network in AD patients. 1. Science, 1241‐4,2015. 2. Genome Med., 104,2016. 3. Sci Data., 180185,2018. 4. BMC Res Notes., 54,2017. 5. Bioinformatics, 1584‐91,2015.

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