UNC5C variants are associated with cerebral amyloid angiopathy

摘要

Objective: To determine whether common genetic variants in UNC5C , a recently identified late-onset Alzheimer disease (LOAD) dementia susceptibility gene, are associated with AD susceptibility or AD-related clinical/pathologic phenotypes. Methods: We used data from deceased individuals of European descent who participated in the Religious Orders Study or the Rush Memory and Aging Project (n = 1,288). We examined whether there were associations between single nucleotide polymorphisms (SNPs) within ±100 kb of the UNC5C gene and a diagnosis of AD dementia, global cognitive decline, a pathologic diagnosis of AD, β-amyloid load, neuritic plaque count, diffuse plaque count, paired helical filament tau density, neurofibrillary tangle count, and cerebral amyloid angiopathy (CAA) score. We also evaluated the relation of the CAA-associated variant and dorsolateral prefrontal cortex (DLPFC) UNC5C RNA expression. Secondary analyses were performed to examine the interaction of the CAA-associated SNP and known genetic risk factors of CAA as well as the association of the SNP with other cerebrovascular pathologies. Results: A set of UNC5C SNPs tagged by rs28660566T was associated with a higher CAA score ( p = 2.3 × 10?6): each additional rs28660566T allele was associated with a 0.60 point higher CAA score, which is equivalent to approximately 75% of the higher CAA score associated with each allele of APOE ε4. rs28660566T was weakly associated with lower UNC5C expression in the human DLPFC ( p = 0.036). Moreover, rs28660566T had a synergistic interaction with APOE ε4 on their association with higher CAA severity ( p = 0.027) and was associated with more severe arteriolosclerosis ( p = 0.0065). Conclusions: Targeted analysis of the UNC5C region uncovered a set of SNPs associated with CAA. A recent study reported the association of UNC5C T835M (rs137875858A), a rare coding variant in this netrin receptor implicated in axon guidance during development, 1 with late-onset Alzheimer disease (LOAD). 2 As we have shown in our study of the TREM locus, 3 multiple genetic variants in the same locus can have independent effects on disease susceptibility and could affect specific features of the disease. We, therefore, assessed whether common UNC5C variants influence AD-related cognitive and pathologic phenotypes in 2 large clinical pathologic cohort studies of aging and dementia. We found a set of UNC5C single nucleotide polymorphisms (SNPs) in a single linkage disequilibrium (LD) block linked to the severity of cerebral amyloid angiopathy (CAA), a disease of small cerebral arterioles caused by β-amyloid accumulation. 4 .