Several genome-wide association studies (GWAS) for late-onset Alzheimer's disease (LOAD) have now been published. While all of these studies detected the association of APOE 54 with risk for LOAD only the two largest studies, with over 10,000 cases and controls provided genome-wide significant evidence for any novel loci. To develop larger datasets we and others have formed large collaborative groups, such as the Alzheimer's Disease Genetics Consortium (ADGC). We have also developed an innovative program using cerebrospinal fluid biomarker levels as endophenotypes for our genetic studies of LOAD. Our preliminary data demonstrate the power and novelty of this approach in identifying genes that alter biomarker levels and modify LOAD risk, age at onset or rate of disease progression. This endophenotype approach also has the advantage of pin-pointing specific biological hypotheses regarding the effects of associated variants that can be tested using simple cell culture assays. The goal of this proposal is to combine and analyze existing LOAD GWAS data, then use a novel approach that incorporates quantitative intermediate traits, re-sequencing, bioinformatics, expression and functional studies to facilitate the identification and characterization of genetic variants that modulate risk for LOAD, age at onset or rate of disease progression. To accomplish this we will 1) combine and analyze LOAD GWAS data, 2) use a novel method, the Genomic Information Network, to systematically incorporate biological information to prioritize single nucleotide polymorphisms (SNPs) for follow-up, 3) examine top SNPs from the LOAD GWAS for association with cerebrospinal fluid amyloid-beta and tau levels to establish specific hypotheses of mechanism, 4) use novel genetic and bioinformatic methods to identify putative causal variants from the replicated SNPs, 5) use re-sequencing to identify novel variants in the regions surrounding replicated SNPs, 6) examine the top hits for effects on gene expression. Finally, we will use information from these efforts to test specific amyloid-beta or tau related hypotheses for replicated SNPs in cell culture models. This proposal combines the unique resources and skills of our research team with the vast wealth of publicly available resources into a novel approach to the identification and characterization of genetic risk factors for LOAD.

Public Health Relevance

Alzheimer's disease is a very common neurodegenerative disease with no effective means of prevention or treatment. The goal of the present study is to identify genetic risk factors for Alzheimer's disease, which in the longer term may lead to novel drug targets and improved treatment/prevention of the disease. Alzheimer's disease is a very common neurodegenerative disease with no effective means of prevention or treatment. The goal of the present study is to identify genetic risk factors for Alzheimer's disease, which in the longer term may lead to novel drug targets and improved treatment/prevention of the disease.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AG035083-05
Application #
8717549
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Miller, Marilyn
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Karch, Celeste M; Goate, Alison M (2015) Alzheimer's disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry 77:43-51
Benitez, Bruno A; Jin, Sheng Chih; Guerreiro, Rita et al. (2014) Missense variant in TREML2 protects against Alzheimer's disease. Neurobiol Aging 35:1510.e19-26
Karch, Celeste M; Cruchaga, Carlos; Goate, Alison M (2014) Alzheimer's disease genetics: from the bench to the clinic. Neuron 83:11-26
Cruchaga, Carlos; Karch, Celeste M; Jin, Sheng Chih et al. (2014) Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease. Nature 505:550-4
Harari, Oscar; Cruchaga, Carlos; Kauwe, John S K et al. (2014) Phosphorylated tau-A?42 ratio as a continuous trait for biomarker discovery for early-stage Alzheimer's disease in multiplex immunoassay panels of cerebrospinal fluid. Biol Psychiatry 75:723-31
Jin, Sheng Chih; Benitez, Bruno A; Karch, Celeste M et al. (2014) Coding variants in TREM2 increase risk for Alzheimer's disease. Hum Mol Genet 23:5838-46
Harms, Matthew; Benitez, Bruno A; Cairns, Nigel et al. (2013) C9orf72 hexanucleotide repeat expansions in clinical Alzheimer disease. JAMA Neurol 70:736-41
Cruchaga, Carlos; Kauwe, John S K; Harari, Oscar et al. (2013) GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer's disease. Neuron 78:256-68
Benitez, Bruno A; Karch, Celeste M; Cai, Yefei et al. (2013) The PSEN1, p.E318G variant increases the risk of Alzheimer's disease in APOE-?4 carriers. PLoS Genet 9:e1003685
Karch, Celeste M; Jeng, Amanda T; Skorupa, Tara et al. (2013) Novel progranulin variants do not disrupt progranulin secretion and cleavage. Neurobiol Aging 34:2538-40

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