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In bioRxiv : the preprint server for biology

Background : Genome-wide association studies have found many genetic risk variants associated with Alzheimer's disease (AD). However, how these risk variants affect deeper phenotypes such as disease progression and immune response remains elusive. Also, our understanding of cellular and molecular mechanisms from disease risk variants to various phenotypes is still limited. To address these problems, we performed integrative multi-omics analysis from genotype, transcriptomics, and epigenomics for revealing gene regulatory mechanisms from disease variants to AD phenotypes.

Method : First, we cluster gene co-expression networks and identify gene modules for various AD phenotypes given population gene expression data. Next, we predict the transcription factors (TFs) that significantly regulate the genes in each module and the AD risk variants (e.g., SNPs) interrupting the TF binding sites on the regulatory elements. Finally, we construct a full gene regulatory network linking SNPs, interrupted TFs, and regulatory elements to target genes for each phenotype. This network thus provides mechanistic insights of gene regulation from disease risk variants to AD phenotypes.

Results : We applied our analysis to predict the gene regulatory networks in three major AD-relevant regions: hippocampus, dorsolateral prefrontal cortex (DLPFC), and lateral temporal lobe (LTL). These region networks provide a comprehensive functional genomic map linking AD SNPs to TFs and regulatory elements to target genes for various AD phenotypes. Comparative analyses further revealed cross-region-conserved and region-specific regulatory networks. For instance, AD SNPs rs13404184 and rs61068452 disrupt the bindings of TF SPI1 that regulates AD gene INPP5D in the hippocampus and lateral temporal lobe. However, SNP rs117863556 interrupts the bindings of TF REST to regulate GAB2 in the DLPFC only. Furthermore, driven by recent discoveries between AD and Covid-19, we found that many genes from our networks regulating Covid-19 pathways are also significantly differentially expressed in severe Covid patients (ICU), suggesting potential regulatory connections between AD and Covid. Thus, we used the machine learning models to predict severe Covid and prioritized highly predictive genes as AD-Covid genes. We also used Decision Curve Analysis to show that our AD-Covid genes outperform known Covid-19 genes for predicting Covid severity and deciding to send patients to ICU or not. In short, our results provide a deeper understanding of the interplay among multi-omics, brain regions, and AD phenotypes, including disease progression and Covid response. Our analysis is open-source available at .

Khullar Saniya, Wang Daifeng