Late-onset Alzheimer's disease (LOAD) has a substantial genetic component estimated to be as high as 80%, much of which remains unexplained. Genome-wide association studies (GWAS) are emerging as a powerful approach in deciphering the genetic risk factors for common-complex diseases. We recently genotyped 318,237 single-nucleotide polymorphisms (SNPs) in 2,465 subjects from LOAD case-control series. Of these subjects, there are 200 pathologically confirmed ADs and 197 non-ADs with cerebellar RNA samples. We measured cerebellar mRNA levels of 12 AD candidate genes in these 200 autopsy-confirmed AD subjects. We extracted the c/s-SNP genotypes for these 12 candidate genes from the GWAS and performed associations utilizing their expression levels as endophenotypes. We identified 3 SNPs that associate significantly with IDE (insulin degrading enzyme) expression levels after correcting for multiple testing. One SNP had IDE expression level association at p=2.73 x 10""""""""8, which would be significant even at the genome-wide level. Minor allele carriers of all 3 SNPs had IDE expression levels 2.43-2.66 fold higher than the major homozygotes. Minor allele carriers of all 3 /DESNPs had protective odds ratio estimates, as expected biologically from their effects on IDE expression levels. These SNPs were in linkage disequilibrium with IDE SNPs residing in regions conserved between human and mouse. These results suggest the existence of functional IDE variants that modify risk of AD via effects on gene expression. Importantly, they provide strong proof of principle that use of expression levels as endophenotypes may be a powerful approach in the identification of disease susceptibility alleles in GWAS. Our 200 AD cases and 197 non-AD subjects with whole genome SNP genotypes and brain RNA provide a highly valuable resource to pursue whole genome expression analysis. Assessment of whole-genome SNP associations with expression levels will generate a valuable resource for mapping complex diseases. Our data will enable simultaneous assessment of whole-genome variation for their effects on gene expression and the AD phenotype. SNPs that associate with both AD and expression levels will be candidate susceptibility variants for AD with plausible regulatory effects. In this proposal our specific aims are: 1. To obtain whole transcriptome expression levels from subjects with whole genome SNP genotypes. 2. To perform GWAS of whole transcriptome expression levels. 3. To identify and validate variants that associate with both AD risk and gene expression levels. 4. To validate the /DESNP-expression and AD associations.
Alzheimer's disease (AD) is an epidemic that accounts for 60% of all dementias and affects an estimate of 13.5 million individuals worldwide. Understanding the underlying genetics of this common disease will help understand its formation, may provide advancement for its prevention as well as potential drug targets for its cure. Our proposed work is aimed at the discovery of AD susceptibility variants that work through regulation of gene expression using a genome-wide association study design.
|Raman, Mekala R; Shu, Yunhong; Lesnick, Timothy G et al. (2017) Regional T1 relaxation time constants in Ex vivo human brain: Longitudinal effects of formalin exposure. Magn Reson Med 77:774-778|
|Jun, Gyungah R; Chung, Jaeyoon; Mez, Jesse et al. (2017) Transethnic genome-wide scan identifies novel Alzheimer's disease loci. Alzheimers Dement 13:727-738|
|McCarter, Stuart J; St Louis, Erik K; Sandness, David J et al. (2017) Diagnostic REM sleep muscle activity thresholds in patients with idiopathic REM sleep behavior disorder with and without obstructive sleep apnea. Sleep Med 33:23-29|
|Rogers, Justin T; Liu, Chia-Chen; Zhao, Na et al. (2017) Subacute ibuprofen treatment rescues the synaptic and cognitive deficits in advanced-aged mice. Neurobiol Aging 53:112-121|
|Sanchez-Contreras, Monica; Heckman, Michael G; Tacik, Pawel et al. (2017) Study of LRRK2 variation in tauopathy: Progressive supranuclear palsy and corticobasal degeneration. Mov Disord 32:115-123|
|Pichler, Michael; Vemuri, Prashanthi; Rabinstein, Alejandro A et al. (2017) Prevalence and Natural History of Superficial Siderosis: A Population-Based Study. Stroke 48:3210-3214|
|Vemuri, Prashanthi; Lowe, Val J; Knopman, David S et al. (2017) Tau-PET uptake: Regional variation in average SUVR and impact of amyloid deposition. Alzheimers Dement (Amst) 6:21-30|
|Whitwell, Jennifer L; Lowe, Val J; Tosakulwong, Nirubol et al. (2017) [18 F]AV-1451 tau positron emission tomography in progressive supranuclear palsy. Mov Disord 32:124-133|
|Raman, Mekala R; Tosakulwong, Nirubol; Zuk, Samantha M et al. (2017) Influence of preeclampsia and late-life hypertension on MRI measures of cortical atrophy. J Hypertens 35:2479-2485|
|Tripodis, Yorghos; Alosco, Michael L; Zirogiannis, Nikolaos et al. (2017) The Effect of Traumatic Brain Injury History with Loss of Consciousness on Rate of Cognitive Decline Among Older Adults with Normal Cognition and Alzheimer's Disease Dementia. J Alzheimers Dis 59:251-263|
Showing the most recent 10 out of 900 publications