Title : Silencer variants are key drivers of gene upregulation in alzheimer’s disease
Abstract:
Alzheimer’s disease (AD), particularly late-onset AD, stands as the most prevalent neurodegenerative disorder globally. Owing to its substantial heritability, genetic studies have emerged as indispensable for elucidating genes and biological pathways driving AD onset and progression. However, genetic and molecular mechanisms underlying AD remain poorly defined, largely due to the pronounced heterogeneity of AD and the intricate interactions among AD genetic factors. Notably, approximately 90% of AD-associated genetic variants reside in intronic and intergenic regions, yet their functional significance has remained largely uncharacterized.
To address this challenge, we developed a deep learning framework combining bulk and single-cell epigenomic data to evaluate the regulatory potential (i.e., silencing and activating strength) of noncoding AD variants in the dorsolateral prefrontal cortex (DLPFCs) and its major cell types. This model identified 1,457 silencer and 3,084 enhancer AD-associated variants in the DLPFC and binned them into silencer variants only (SL), enhancer variants only (EN), or both variant types (ENSL) classes. Each class exerts distinct cellular and molecular influences on AD pathogenesis. EN loci predominantly regulate housekeeping metabolic processes, whereas SL loci (including the genes MS4A6A, TREM2, USP6NL, HLA-D) are selectively linked to immune responses. Notably, 71% of these genes are significantly upregulated in AD and pro-inflammation-stimulated microglia. Furthermore, genes associated with SL loci are, in neuronal cells, often responsive to glutamate receptor antagonists (e.g, NBQX) and anti-inflammatory perturbagens (such as D-64131), the compound classes known for reducing the AD risk. ENSL loci, in contrast, are uniquely implicated in memory maintenance, neurofibrillary tangle assembly, and are also shared by other neurological disorders such as Parkinson’s disease and schizophrenia. Key genes in this class of loci, such as MAPT, CR1/2, and CLU, are frequently upregulated in AD subtypes with hyperphosphorylated tau aggregates.
Critically, our model can accurately predict the impact of regulatory variants, with an average Pearson correlation coefficient of 0.54 and a directional concordance rate of 70% between our predictions and experimental outcomes. This model identified rs636317 as a causal AD variant in the MS4A locus, distinguishing it from the 7bp-away allele-neutral variant rs636341. Similarly, rs7922621 was prioritized over its 54-bp-away allele-neutral rs7901634 in the TSPAN14 locus. Additional causal variants include rs6701713 in the CR1 locus, and rs28834970 and rs755951 in the PTK2B locus. Collectively, this work advances our understanding of the regulatory landscape of AD-associated genetic variants, providing a framework to explore their functional roles in the pathogenesis of this complex disease.
