O3‐11‐06: δ‐Catenin is genetically and biologically associated with cortical cataract and future Alzheimer's‐related structural and functional brain changes

Abstract

AD is a progressive disorder related to aging and is largely influenced by genetic factors with 60 to 80% heritability. Age-related cataract (ARC) and Alzheimer's disease (AD) are common in the general population and often co-occur among elderly persons. Multiple lines of evidence suggest common factors linking AD-associated pathology in the brain and lens. We estimated co-heritability of quantitative measures of ARC subtypes with AD-related brain MRI traits using 1,249 members of the Framingham Offspring Study. Next, we conducted genome-wide association study (GWAS) using 187,657 single nucleotide polymorphisms (SNPs) for the joint outcome (a bivariate model) of the most highly co-heritable cataract subtype and MRI trait. Lens specimens obtained from two autopsy-confirmed AD subjects and two non-AD controls were evaluated histopathologically. Effects of a functional mutation on cell morphology and amyloid β expression were studied in neuronal cell culture. Cortical cataract (CC), but not other cataract subtypes, was found to be co-heritable with future development of AD and with several MRI traits, especially temporal horn volume (THV, Ï□=0.24, P<10-4). GWAS of a joint outcome of CC and THV identified genome-wide significant association with CTNND2 SNPs rs17183619, rs13155993 and rs13170756 (P<2.6x10-7). These SNPs were also significantly associated with joint outcomes of CC and scores on highly heritable neuropsychological tests (5.7x10-9 < P < 3.7x10-6). We identified interaction of rs17183619 with APP SNP rs2096488 on CC (P=0.0015) and CC-THV (P=0.038). A rare CTNND2 missense mutation (G810R) 249 base pairs from rs17183619 altered δ-catenin localization and increased secreted amyloid-β1-42 in HEK293 cells. Immunohistopathological analysis revealed elevated expression of δ-catenin in epithelial and cortical regions of lenses from AD subjects compared to controls. Our findings suggest that genetic variation in the CTNND2 gene may underlie both cortical lens opacities in mid-life and the subsequent development of MRI and cognitive changes that presage the development of AD.