UNC5C variants are associated with cerebral amyloid angiopathy

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 rs28660566(T) was associated with a higher CAA score (p = 2.3 × 10(−6)): each additional rs28660566(T) 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. rs28660566(T) was weakly associated with lower UNC5C expression in the human DLPFC (p = 0.036). Moreover, rs28660566(T) 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.