Abstract
BackgroundGenome-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.MethodsHuman 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.ResultsAltogether, 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.ConclusionsGenetic variants might play functional roles and suggest potential mechanisms in AD pathogenesis, which opens doors to uncover novel targets for AD treatment.
Highlights
Genome-wide association studies have identified more than 30 Alzheimer’s disease (AD) risk genes, the detailed mechanism through which all these genes are associated with AD pathogenesis remains unknown
The minor alleles of rs2526378 in BZRAP1-AS1 and rs12590654 in SLC24A4/RIN3 were associated with increased expression especially in temporal cortex (TCTX)/frontal cortex (FCTX) and FCTX, respectively, while the minor allele of rs3865444 in CD33 was associated with decreased expression in TCTX (Additional file 1: Figure S2)
We comprehensively analyze possible functional effects of the variants in top 30 non-APOE AD risk genes, based on whether (1) these variants are associated with altered expression levels and (2) the variants are associated with brain amyloidosis, tauopathy, and neurodegeneration
Summary
Genome-wide association studies have identified more than 30 Alzheimer’s disease (AD) risk genes, 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. The precise disease-associated mechanisms of the novel genetic variants identified in the recent GWAS metaanalysis remain unknown. We report a comprehensive analysis of the associations of the variants in the top 30 non-APOE AD risk genes from current large-scale GWAS studies of the transcript expression levels, and the pathological processes of brain amyloidosis, tauopathy, and neurodegeneration, using the baseline and follow-up data from AD-related CSF, PET, and MRI measures. Understanding the mechanisms by which these variants contribute to AD risk will lead to a better understanding of the disease-associated mechanisms and help uncover novel therapeutic avenues
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