DIFFERENTIAL EXPRESSION OF POLYGENIC RISK IN CEREBROSPINAL FLUID PROTEOMIC MEASURES IN ALZHEIMER’S DISEASE

Abstract

Genetic factors play a major role in Alzheimer's disease (AD) pathology, but through which biological mechanisms these factors contribute to AD remains elusive. Cerebrospinal fluid (CSF) proteomic studies have demonstrated disrupted biological processes in AD. Using a CSF proteomic approach, we examined the contribution of the genetic predisposition for AD to these biological processes. We selected 250 subjects (AD/MCI/normal cognition=61/116/73, age 75±7 years, 39%female) from the Alzheimer's disease Neuroimaging Initiative (ADNI). We calculated fourteen polygenic risk scores for AD (PGRS-AD) with increasing significance thresholds (range p=1e-30-p=0.5) using IGAP GWAS summary statistics. Associations between PGRS-AD and 412 CSF protein(s)(fragments) were examined using linear regression, adjusted for age and sex. Analyses were repeated adjusting for APOE-ε4 carrier status. We further performed hierarchical clustering analysis on proteins with at least one nominal significant PGRS-AD association (puncorrected<0.05), to determine how CSF proteins were associated with different PGRS thresholds. Enrichment analysis on PGRS-AD associated CSF proteins was performed using STRINGv10, including KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways and Gene Ontology (GO) databases. Fifty-six (13%) protein(s)(fragments) were associated with at least one PGRS-AD score (n=56 proteins; pFDR<0.05, n=199 proteins; puncorrected<0.05) (Figure 1). Using hierarchical clustering analysis, we identified three patterns of genetic correlations with CSF expression profiles. Cluster 1 proteins (n=69, 34%) were correlated with highly significant variants (pIGAP<1.00e-03) and seemed to be involved in Aβ pathology, and showed enrichment for complement and coagulation cascades. Cluster 2 proteins (n=19, 10%) were more polygenic (range pIGAP=0.01-0.05) and appeared to be involved in neuronal injury - but showed no enrichment for specific biological processes. Cluster 3 proteins (n=112, 56%) had a strong polygenic pattern of inheritance (pIGAP>0.1), and were enriched for cytokine-cytokine interactions and cell adhesion molecules.