John SK Kauwe - US grants

DESCRIPTION (provided by applicant): Recent observations in Alzheimer's disease suggest that factors, which influence the relationship between pathological features in the brain and clinical symptoms, play a significant role in the disease process. First, more than 25% of non-demented, elderly individuals have brain pathology that is indistinguishable from known Alzheimer's disease individuals. Second, among those with a clinical diagnosis of disease there are clearly fast progressors and slow progressors. We will perform a genome-wide screen for relationship loci (rQTL) that modify the known relationship (correlation) between cerebrospinal fluid A¿42 levels and case/control status, thus screening for loci that explain the observation of non-demented individuals with Alzheimer's disease pathology. With slight adjustments to our models we can also screen for loci, which modify the known relationship between cerebrospinal fluid A¿42 levels and tau levels, and may explain the variation in the rate of progression of disease. For these analyses we have assembled over 2,000 samples with cerebrospinal fluid biomarker measurements, clinical evaluations, and whole-genome marker data for discovery and nearly 1000 samples with cerebrospinal fluid biomarker measurements and clinical evaluations for replication (genotyping to be completed as part of this proposal). We will then test the replicated variants for association with risk and rate of progression of Alzheimer's disease in approximately 20,000 cases and 30,000 controls (over 1900 of which have longitudinal measurements of disease progression). As demonstrated by our preliminary analyses, this promising approach will leverage the largest sample of its kind to identify genetic variation that is associated with Alzheimer's disease and Alzheimer's disease biomarkers via pleiotropic and interaction effects. This will provide insight into variation in important disease related processes such as protein aggregation and inflammatory and immune response. These findings are likely to be important for other protein aggregation and/or protein misfolding diseases. PUBLIC HEALTH RELEVANCE: The broad, long-term goal of our research is to solve the complex genetic architecture of Alzheimer's Disease, which will lead to better strategies for treatment and prevention of this devastating disease. In this proposal we will test hypotheses that genetic factors influence important clinical observations, such as the observation of Pleiotropic effects of APOE e4 on cerebrospinal fluid A¿ and tau levels, non-demented individuals with Alzheimer's disease pathology and variation in the rate of progression in clinically diagnosed Alzheimer's disease cases. We will use genome-wide marker data to detect loci that simultaneously affect cerebrospinal fluid amyloid beta and tau levels (pleiotropy), the relationships between Alzheimer's disease biomarkers (cerebrospinal fluid amyloid beta and tau) and Alzheimer's disease (referred to as rQTL), and gene-by-gene interactions. Identified loci are likely to affect both risk and/or progression of AD and will shed light on pathways connecting cerebrospinal fluid amyloid beta, tau, and Alzheimer's Disease.

DESCRIPTION (provided by applicant): Recent observations in Alzheimer's disease suggest that factors, which influence the relationship between pathological features in the brain and clinical symptoms, play a significant role in the disease process. First, more than 25% of non-demented, elderly individuals have brain pathology that is indistinguishable from known Alzheimer's disease individuals. Second, among those with a clinical diagnosis of disease there are clearly fast progressors and slow progressors. We will perform a genome-wide screen for relationship loci (rQTL) that modify the known relationship (correlation) between cerebrospinal fluid A?42 levels and case/control status, thus screening for loci that explain the observation of non-demented individuals with Alzheimer's disease pathology. With slight adjustments to our models we can also screen for loci, which modify the known relationship between cerebrospinal fluid A?42 levels and tau levels, and may explain the variation in the rate of progression of disease. For these analyses we have assembled over 2,000 samples with cerebrospinal fluid biomarker measurements, clinical evaluations, and whole-genome marker data for discovery and nearly 1000 samples with cerebrospinal fluid biomarker measurements and clinical evaluations for replication (genotyping to be completed as part of this proposal). We will then test the replicated variants for association with risk and rate of progression of Alzheimer's disease in approximately 20,000 cases and 30,000 controls (over 1900 of which have longitudinal measurements of disease progression). As demonstrated by our preliminary analyses, this promising approach will leverage the largest sample of its kind to identify genetic variation that is associated with Alzheimer's disease and Alzheimer's disease biomarkers via pleiotropic and interaction effects. This will provide insight into variation in important disease related processes such as protein aggregation and inflammatory and immune response. These findings are likely to be important for other protein aggregation and/or protein misfolding diseases.

DESCRIPTION (provided by applicant): Recent observations in Alzheimer's disease suggest that factors, which influence the relationship between pathological features in the brain and clinical symptoms, play a significant role in the disease process. First, more than 25% of non-demented, elderly individuals have brain pathology that is indistinguishable from known Alzheimer's disease individuals. Second, among those with a clinical diagnosis of disease there are clearly fast progressors and slow progressors. We will perform a genome-wide screen for relationship loci (rQTL) that modify the known relationship (correlation) between cerebrospinal fluid A?42 levels and case/control status, thus screening for loci that explain the observation of non-demented individuals with Alzheimer's disease pathology. With slight adjustments to our models we can also screen for loci, which modify the known relationship between cerebrospinal fluid A?42 levels and tau levels, and may explain the variation in the rate of progression of disease. For these analyses we have assembled over 2,000 samples with cerebrospinal fluid biomarker measurements, clinical evaluations, and whole-genome marker data for discovery and nearly 1000 samples with cerebrospinal fluid biomarker measurements and clinical evaluations for replication (genotyping to be completed as part of this proposal). We will then test the replicated variants for association with risk and rate of progression of Alzheimer's disease in approximately 20,000 cases and 30,000 controls (over 1900 of which have longitudinal measurements of disease progression). As demonstrated by our preliminary analyses, this promising approach will leverage the largest sample of its kind to identify genetic variation that is associated with Alzheimer's disease and Alzheimer's disease biomarkers via pleiotropic and interaction effects. This will provide insight into variation in important disease related processes such as protein aggregation and inflammatory and immune response. These findings are likely to be important for other protein aggregation and/or protein misfolding diseases.

Project Abstract Far too many people have personal experience with the destructive nature of Alzheimer's disease (AD). Despite significant progress identifying genetic risk factors and increased understanding of the inflammatory and immune response in AD etiology, our knowledge remains inadequate to develop effective preventions or cures. We have linked data and subjects from the Utah Population Database (medical records, death certificates, and genealogy for over 7 million subjects) and the Cache County Study on Memory in Aging (longitudinal cognitive assessment on over 5,000 subjects in Utah). These samples are an accurate representation of the general European American population, making findings from these data generalizable in that context. The combination of these studies enables the execution of an innovative design for gene discovery, and to evaluate the association between AD risk and resilience pedigrees, and key aspects of AD epidemiology, including socioeconomic status, cardiovascular disease, cancer and many others. We will first, conduct studies that leverage linkage and association to identify novel genetic risk factors. Second, we will use the UPDB to conduct powerful studies of measureable risk and resilience factors for AD. Third, we will collect additional samples from key pedigrees to enhance our study. And finally, all data associated with our effort will be harmonized and deposited into public databases. In summary our approach is carefully designed and well powered to provide new knowledge and facilitate efforts to develop a cure for AD. Specifically, we will augment the Cache County Study, an existing longitudinal cohort study, in an efficient and directed manner, including collecting and sequencing DNA samples from well-characterized cases and controls in the study. Using our unparalleled and powerful dataset and approach, we will explore trends in the risk of AD and their explanation via putative risk and protective factors. Our successful efforts will identify measurable risk and resilience factors for AD, enabling precision medicine by providing information for modifying risk in individuals and providing insights into those who will benefit most from therapeutic interventions. Finally, all data in from this proposal will be harmonized with relevant datasets and electronically archived in appropriate databases.

An award is made to Brigham Young University to purchase a PacBio Sequel Single-Molecule, Real-time (SMRT) Sequencer-the latest in single-molecule sequencing-to benefit faculty, undergraduate, and graduate student research and education at BYU and BYU-Hawaii, and to implement an outreach program designed to educate underrepresented minorities in science through BYU's deep connection into Polynesian cultures. BYU has one of the most vibrant undergraduate research programs in the world, involving students directly in research early in their education. BYU's undergraduate research program also includes concerted efforts to involve students from underrepresented minorities. Additionally, the BYU program has arranged an exciting collaboration with Pacific Heritage Academy in Salt Lake City to perform sequencing studies on species endemic to their native Hawaii. Having a PacBio Sequel System will make BYU a major SMRT sequencing and educational hub for faculty, graduate, undergraduate, and high school students in the intermountain west region of the United States

With new technologies such as the PacBio Sequel System, it is now possible to accomplish what was previously unfeasible. This new technology dramatically improves or enables researchers to: (1) construct more complete genomes, (2) identify large genetic mutations, and (3) resolve unknown aspects of gene expression, amongst many other exciting applications. Researchers across the intermountain west will have easy access to this breakthrough technology to advance genomic understanding from numerous non-model organisms, and to develop needed computational algorithms.

Project Abstract Far too many people have personal experience with the destructive nature of Alzheimer's disease (AD). Despite significant progress identifying genetic risk factors and increased understanding of the inflammatory and immune response in AD etiology, our knowledge remains inadequate to develop effective preventions or cures. We have linked data and subjects from the Utah Population Database (medical records, death certificates, and genealogy for over 7 million subjects) and the Cache County Study on Memory in Aging (longitudinal cognitive assessment on over 5,000 subjects in Utah). These samples are an accurate representation of the general European American population, making findings from these data generalizable in that context. The combination of these studies enables the execution of an innovative design for gene discovery, and to evaluate the association between AD risk and resilience pedigrees, and key aspects of AD epidemiology, including socioeconomic status, cardiovascular disease, cancer and many others. We will first, conduct studies that leverage linkage and association to identify novel genetic risk factors. Second, we will use the UPDB to conduct powerful studies of measurable risk and resilience factors for AD. Third, we will collect additional samples from key pedigrees to enhance our study. And finally, all data associated with our effort will be harmonized and deposited into public databases. In summary our approach is carefully designed and well powered to provide new knowledge and facilitate efforts to develop a cure for AD. Specifically, we will augment the Cache County Study, an existing longitudinal cohort study, in an efficient and directed manner, including collecting and sequencing DNA samples from well-characterized cases and controls in the study. Using our unparalleled and powerful dataset and approach, we will explore trends in the risk of AD and their explanation via putative risk and protective factors. Our successful efforts will identify measurable risk and resilience factors for AD, enabling precision medicine by providing information for modifying risk in individuals and providing insights into those who will benefit most from therapeutic interventions. Finally, all data in from this proposal will be harmonized with relevant datasets and electronically archived in appropriate databases.