Meng-Shan Tan1,2, Yu-Xiang Yang3, Wei Xu2, Hui-Fu Wang2, Lin Tan2, Chuan-Tao Zuo4, Qiang Dong3, Lan Tan2, John Suckling5, Jin-Tai Yu6. 1. Department of Psychiatry, University of Cambridge, Cambridge, UK. 2. Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China. 3. Department of Neurology and Institute of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, 12th Wulumuqi Zhong Road, Shanghai, 200040, China. 4. PET Center, Huashan Hospital, Fudan University, Shanghai, China. 5. Department of Psychiatry, University of Cambridge, Cambridge, UK. js369@cam.ac.uk. 6. Department of Neurology and Institute of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, 12th Wulumuqi Zhong Road, Shanghai, 200040, China. jintai_yu@fudan.edu.cn.
Abstract
BACKGROUND: Genome-wide association studies have identified more than 30 Alzheimer's disease (AD) risk genes, although the detailed mechanism through which all these genes are associated with AD pathogenesis remains unknown. We comprehensively evaluate the roles of the variants in top 30 non-APOE AD risk genes, based on whether these variants were associated with altered mRNA transcript levels, as well as brain amyloidosis, tauopathy, and neurodegeneration. METHODS: Human brain gene expression data were obtained from the UK Brain Expression Consortium (UKBEC), while other data used in our study were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We examined the association of AD risk allele carrier status with the levels of gene expression in blood and brain regions and tested the association with brain amyloidosis, tauopathy, and neurodegeneration at baseline, using a multivariable linear regression model. Next, we analyzed the longitudinal effects of these variants on the change rates of pathology using a mixed effect model. RESULTS: Altogether, 27 variants were detected to be associated with the altered expression of 21 nearby genes in blood and brain regions. Eleven variants (especially novel variants in ADAM10, IGHV1-68, and SLC24A4/RIN3) were associated with brain amyloidosis, 7 variants (especially in INPP5D, PTK2B) with brain tauopathy, and 8 variants (especially in ECHDC3, HS3ST1) with brain neurodegeneration. Variants in ADAMTS1, BZRAP1-AS1, CELF1, CD2AP, and SLC24A4/RIN3 participated in more than one cerebral pathological process. CONCLUSIONS: Genetic variants might play functional roles and suggest potential mechanisms in AD pathogenesis, which opens doors to uncover novel targets for AD treatment.
BACKGROUND: Genome-wide association studies have identified more than 30 Alzheimer's disease (AD) risk genes, although the detailed mechanism through which all these genes are associated with AD pathogenesis remains unknown. We comprehensively evaluate the roles of the variants in top 30 non-APOE AD risk genes, based on whether these variants were associated with altered mRNA transcript levels, as well as brain amyloidosis, tauopathy, and neurodegeneration. METHODS:Human brain gene expression data were obtained from the UK Brain Expression Consortium (UKBEC), while other data used in our study were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We examined the association of AD risk allele carrier status with the levels of gene expression in blood and brain regions and tested the association with brain amyloidosis, tauopathy, and neurodegeneration at baseline, using a multivariable linear regression model. Next, we analyzed the longitudinal effects of these variants on the change rates of pathology using a mixed effect model. RESULTS: Altogether, 27 variants were detected to be associated with the altered expression of 21 nearby genes in blood and brain regions. Eleven variants (especially novel variants in ADAM10, IGHV1-68, and SLC24A4/RIN3) were associated with brain amyloidosis, 7 variants (especially in INPP5D, PTK2B) with brain tauopathy, and 8 variants (especially in ECHDC3, HS3ST1) with brain neurodegeneration. Variants in ADAMTS1, BZRAP1-AS1, CELF1, CD2AP, and SLC24A4/RIN3 participated in more than one cerebral pathological process. CONCLUSIONS: Genetic variants might play functional roles and suggest potential mechanisms in AD pathogenesis, which opens doors to uncover novel targets for AD treatment.
Entities:
Keywords:
Alzheimer disease; Amyloid; Gene expression; Neurodegeneration; Risk variants; Tau
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