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.
|Brent, Robert J (2018) Estimating the monetary benefits of medicare eligibility for reducing the symptoms of dementia. Appl Econ 50:6327-6340|
|Burke, Shanna L; Maramaldi, Peter; Cadet, Tamara et al. (2018) Decreasing hazards of Alzheimer's disease with the use of antidepressants: mitigating the risk of depression and apolipoprotein E. Int J Geriatr Psychiatry 33:200-211|
|Sahoo, Aradhana; Bejanin, Alexandre; Murray, Melissa E et al. (2018) TDP-43 and Alzheimer's Disease Pathologic Subtype in Non-Amnestic Alzheimer's Disease Dementia. J Alzheimers Dis 64:1227-1233|
|Qian, Winnie; Fischer, Corinne E; Schweizer, Tom A et al. (2018) Association Between Psychosis Phenotype and APOE Genotype on the Clinical Profiles of Alzheimer's Disease. Curr Alzheimer Res 15:187-194|
|Pakhomov, Serguei V S; Eberly, Lynn E; Knopman, David S (2018) Recurrent perseverations on semantic verbal fluency tasks as an early marker of cognitive impairment. J Clin Exp Neuropsychol 40:832-840|
|Kang, Silvia S; Ebbert, Mark T W; Baker, Kelsey E et al. (2018) Microglial translational profiling reveals a convergent APOE pathway from aging, amyloid, and tau. J Exp Med 215:2235-2245|
|Sakae, Nobutaka; Bieniek, Kevin F; Zhang, Yong-Jie et al. (2018) Poly-GR dipeptide repeat polymers correlate with neurodegeneration and Clinicopathological subtypes in C9ORF72-related brain disease. Acta Neuropathol Commun 6:63|
|Gallagher, Damien; Kiss, Alex; Lanctot, Krista et al. (2018) Depression and Risk of Alzheimer Dementia: A Longitudinal Analysis to Determine Predictors of Increased Risk among Older Adults with Depression. Am J Geriatr Psychiatry 26:819-827|
|Deming, Yuetiva; Dumitrescu, Logan; Barnes, Lisa L et al. (2018) Sex-specific genetic predictors of Alzheimer's disease biomarkers. Acta Neuropathol 136:857-872|
|Haaksma, Miriam L; Calderón-Larrañaga, Amaia; Olde Rikkert, Marcel G M et al. (2018) Cognitive and functional progression in Alzheimer disease: A prediction model of latent classes. Int J Geriatr Psychiatry 33:1057-1064|
Showing the most recent 10 out of 1014 publications