GENOME-WIDE ASSOCIATION STUDY OF ALZHEIMER DISEASE ENDOPHENOTYPES AT PRECLINICAL AND MCI STAGES

Genetic associations for endophenotypes of Alzheimer's disease (AD) in cognitive stages preceding Alzheimer disease have not been thoroughly evaluated. We conducted genome-wide association studies using brain hippocampal volume (HPV), logical memory test scores (LMT), and cerebrospinal fluid (CSF) levels of amyloid β42 and total/phosphorylated tau (t-/p-Tau) in 305 clinically normal (CN), 581 mild cognitive impairment (MCI), and 190 AD subjects in the Alzheimer's Disease Neuroimaging Initiative study. Differential expression profiles of the top ranked genes were evaluated using 50 AD and 21 control brains for AD status and neurofibrillary tangle pathology (Braak stages) using RNA sequencing (RNA-seq) data from Eisai Brain Bank. Enriched pathways of the top ranked genes were determined by cell-type specific co-expression network analysis using single cell RNA-seq data from the GEO database. In CN subjects, study-wide significant associations (SWS, p<8.33x10-9) were identified for t-Tau with SNPs near SRRM4 (best SNP: rs10775009, P=1.59x10-9) and C14orf79 (rs2819438, P=4.58x10-9), and for HPV with SNPs between PDGFRL and MTUS1 (rs4921790, P=1.38x10-9). In MCI subjects, SWS association was found with SNPs near ZNF804B for LMT-delayed recall (best SNP: rs73705514, P=2.27x10-9). Bioinformatic analysis revealed that subjects with risk alleles of SNPs in high LD with rs4921790 had significantly higher expression level of MTUS1 in brain (best SNP: rs10089607, P = 4.2x10-6 in caudate). MTUS1 was significantly up-regulated in AD compared to normal brain (P=8.2x10-3) and the expression level of MTUS1 was significantly associated with increased Braak stage (P=6.8x10-4). Analysis of cell-type specific expression profiles in single cell RNA-Seq data showed that MTUS1 is expressed mainly in neurons and oligodendrocytes. Gene network analysis showed that MTUS1 is co-expressed with MAPT in a microtubule and postsynaptic density network. We identified association of several genes not previously identified in AD genetic studies with AD-related endophenotypes in cognitively normal and MCI subjects. One of these loci, MTUS1, encodes angiotensin II interacting proteins which co-localizes with microtubules and regulates neuronal differentiation and neurite outgrowth. Our findings provide further insight about AD-related mechanisms prior to onset of AD symptoms and potential targets for early intervention.