Multi-omic derived cell-type specific Alzheimer disease polygenic risk scores

Area of Science:

• Neuroscience
• Genetics
• Computational Biology

Background:

• Alzheimer disease (AD) pathogenesis involves complex genetic factors influencing various cell types in the brain.
• Polygenic risk scores (PRS) are valuable tools for dissecting genetic contributions to complex diseases.
• Cell-type specific PRS (ct-PRS) can offer higher resolution in understanding disease mechanisms.

Purpose of the Study:

• To develop and compare cell-type specific Alzheimer disease polygenic risk scores (ct-ADPRSs) using single-nuclei RNA-seq (snRNA) and single-nuclei ATAC-seq (snATAC) data.
• To investigate the cell-type specificity of these ct-ADPRSs.
• To associate ct-ADPRSs with AD endophenotypes, including tau tangle burden, neuritic plaque burden, and cognitive scores.

Main Methods:

• Derived ct-ADPRSs utilizing genetic variants near cell-type specific genes from snRNA and accessible chromatin regions from snATAC.
• Generated a multi-omic ct-ADPRS for eight neuron subtypes.
• Assessed cell-type specificity by calculating correlations among ct-ADPRSs.
• Evaluated associations with AD endophenotypes using logistic and linear regression models.

Main Results:

• snATAC-derived ct-ADPRSs exhibited significantly lower inter-cell-type correlations (average r=0.071) compared to snRNA-derived ct-ADPRSs (average r=0.19), indicating superior cell-type specificity.
• Tau tangle burden associated with astrocyte (AST) and microglia (MIC) ct-ADPRSs from both snATAC and snRNA.
• AST ct-ADPRS from snATAC uniquely associated with Mini-Mental State Examination score.
• SST+ GABAergic neuron ct-ADPRS strongly associated with neuritic plaque burden and was the only neuron subtype ct-ADPRS significantly linked to AD endophenotypes.
• Variants upstream of the Neuropeptide Y (NPY) gene, particularly rs3940268, showed the strongest association with the SST+ GABAergic neuron ct-ADPRS.

Conclusions:

• snATAC-derived ct-ADPRSs provide enhanced cell-type specificity for dissecting AD genetic architecture.
• Specific cell types, including astrocytes, microglia, and SST+ GABAergic neurons, play distinct roles in AD pathology.
• Genetic variants near the NPY gene may significantly influence AD risk through their impact on SST+ GABAergic neurons.