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- Title
Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer’s disease.
- Authors
Chung, Jaeyoon; Zhang, Xiaoling; Allen, Mariet; Wang, Xue; Ma, Yiyi; Beecham, Gary; Montine, Thomas J.; Younkin, Steven G.; Dickson, Dennis W.; Golde, Todd E.; Price, Nathan D.; Ertekin-Taner, Nilüfer; Lunetta, Kathryn L.; Mez, Jesse; Alzheimer’s Disease Genetics Consortium; Mayeux, Richard; Haines, Jonathan L.; Pericak-Vance, Margaret A.; Schellenberg, Gerard; Jun, Gyungah R.
- Abstract
Background: Simultaneous consideration of two neuropathological traits related to Alzheimer’s disease (AD) has not been attempted in a genome-wide association study. Methods: We conducted genome-wide pleiotropy analyses using association summary statistics from the <italic>Beecham et al</italic>. 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. Results: Genome-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 <italic>C2orf40</italic> (alias <italic>ECRG4</italic>, <italic>P</italic> = 2.4 × 10−8) and for the joint model of NFT and CAA (NFT + CAA) with the <italic>HDAC9</italic> SNP rs79524815 (<italic>P</italic> = 1.1 × 10−8). Gene-based testing revealed study-wide significant associations (<italic>P</italic> ≤ 2.0 × 10−6) for the NFT + CAA outcome with adjacent genes <italic>TRAPPC12</italic>, <italic>TRAPPC12-AS1</italic>, and <italic>ADI1</italic>. Risk alleles of proxy SNPs for rs79524815 were associated with significantly lower expression of <italic>HDAC9</italic> in the brain (<italic>P</italic> = 3.0 × 10−3), and <italic>HDAC9</italic> was significantly downregulated in subjects with AD compared with control subjects in the prefrontal (<italic>P</italic> = 7.9 × 10−3) and visual (<italic>P</italic> = 5.6 × 10−4) cortices. Conclusions: Our 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 <italic>ECRG4</italic> or <italic>HDAC9</italic> is plausible as a therapeutic target.
- Subjects
ALZHEIMER'S disease treatment; CEREBRAL amyloid angiopathy; SINGLE nucleotide polymorphisms; NEUROFIBRILLARY tangles; QUANTITATIVE research; GENE expression
- Publication
Alzheimer's Research & Therapy, 2018, Vol 10, p1
- ISSN
1758-9193
- Publication type
Article
- DOI
10.1186/s13195-018-0349-z