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

Alzheimer disease (AD) polygenic risk scores (ADPRS) built from cell-type (ct) specific genetic variants can be used to infer cell-type contributions to AD. We derived two ct-ADPRSs using variants near single-nuclei RNA-seq (snRNA) derived cell-type specific genes or on single-nuclei ATAC-seq (snATAC) derived cell-type specific accessible chromatin regions. We generated a multi-omic ct-ADPRS for eight neuron subtypes using both single-nuclei datasets. SnATAC-derived ct-ADPRSs demonstrated considerably lower correlations among cell types (average r = 0.071) than snRNA-derived ct-ADPRSs (average r = 0.19), indicating their heightened cell-type specificity. The association of these ct-ADPRSs with AD endophenotypes was evaluated using logistic and linear regression models. Tau tangle burden was associated with astrocyte (AST) ct-ADPRS derived from snATAC (β=0.82, FDR=0.0013) and snRNA (β=0.60, FDR=0.045) as well as microglia (MIC) ct-ADPRS from both (snATAC: β=0.75, FDR=0.0047) (snRNA: β=0.63, FDR=0.028). AST ct-ADPRS was significantly associated with Mini-Mental State Examination score only when derived from snATAC data (β=-0.82, FDR=0.011). SST expressing GABAergic neuron ADPRS was strongly associated ct-ADPRS with neuritic plaque burden (β=0.087, FDR=0.0014) and the only neuron subtype ct-ADPRS significantly associated with AD endophenotypes. We investigated 1954 SNPs contributing to this ct-ADPRS and found the strongest association with variants upstream of the neuropeptide Y gene, NPY, particularly rs3940268 (β=-0.13, P = 8.2x10^-5). This association is significant even after adjusting for diffuse plaque (β=-0.12, P = 1.5x10^-4) or neurofibrillary tangle burden (β=-0.08, P = 3.9x10^-3). NPY was expressed in a small subset of neurons, and these findings suggest its strong impact on the association of SST+ GABAergic neurons with early AD pathology.