Abstract
BackgroundSimultaneous consideration of two neuropathological traits related to Alzheimer’s disease (AD) has not been attempted in a genome-wide association study.MethodsWe conducted genome-wide pleiotropy analyses using association summary statistics from the Beecham et al. study (PLoS Genet 10:e1004606, 2014) for AD-related neuropathological traits, including neuritic plaque (NP), neurofibrillary tangle (NFT), and cerebral amyloid angiopathy (CAA). Significant findings were further examined by expression quantitative trait locus and differentially expressed gene analyses in AD vs. control brains using gene expression data.ResultsGenome-wide significant pleiotropic associations were observed for the joint model of NP and NFT (NP + NFT) with the single-nucleotide polymorphism (SNP) rs34487851 upstream of C2orf40 (alias ECRG4, P = 2.4 × 10−8) and for the joint model of NFT and CAA (NFT + CAA) with the HDAC9 SNP rs79524815 (P = 1.1 × 10−8). Gene-based testing revealed study-wide significant associations (P ≤ 2.0 × 10−6) for the NFT + CAA outcome with adjacent genes TRAPPC12, TRAPPC12-AS1, and ADI1. Risk alleles of proxy SNPs for rs79524815 were associated with significantly lower expression of HDAC9 in the brain (P = 3.0 × 10−3), and HDAC9 was significantly downregulated in subjects with AD compared with control subjects in the prefrontal (P = 7.9 × 10−3) and visual (P = 5.6 × 10−4) cortices.ConclusionsOur findings suggest that pleiotropy analysis is a useful approach to identifying novel genetic associations with complex diseases and their endophenotypes. Functional studies are needed to determine whether ECRG4 or HDAC9 is plausible as a therapeutic target.
Highlights
Simultaneous consideration of two neuropathological traits related to Alzheimer’s disease (AD) has not been attempted in a genome-wide association study
Bivariate genome-wide association study (GWAS) results There was no inflation in P values for the GWAS of the three neuropathological traits analyzed individually or as joint outcomes (Additional file 1: Figure S1)
Three of the previously established AD loci—BIN1, HLA region, and PICALM—were moderately associated (P < 10−4) in the pleiotropy analysis for neuritic plaque (NP) and neurofibrillary tangle (NFT) at a significance level of at least one order of magnitude smaller compared with the results from univariate analyses (Additional file 1: Table S2)
Summary
Simultaneous consideration of two neuropathological traits related to Alzheimer’s disease (AD) has not been attempted in a genome-wide association study. Alzheimer’s disease (AD) is the most common type of dementia in persons aged 65 years and older [1, 2]. It is characterized primarily by the appearance of both neuritic plaques (NPs) containing oligomers of β-. We hypothesized that additional novel associations could be identified in models allowing a genetic variant to influence more than one trait (i.e., pleiotropy). We performed genome-wide pleiotropy analyses of joint models of NP, NFT, and CAA using summary data from the previous study [6]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
