This competitive renewal grant application seeks to continue a collaboration that used genome-wide association data in large, prospective epidemiological cohorts, the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE), with >2-6 decades of risk factor, dementia, AD, MRI and cognitive endophenotype data in >30,000 persons to identify new genes/loci underlying the risk of Alzheimer's disease (AD). It produced >50 publications, helped identify 9 novel loci for AD (BIN1 & EPHA1 first reached genome-wide significance in a CHARGE-lead publication), and 8 for AD endophenotypes. CHARGE helped found the International Genomics of Alzheimer Project (IGAP) and established collaborations with >25 cohorts/ consortia such as the Enhancing Neuro Imaging through Meta-Analysis (ENIGMA) consortium. However, genes identified to date collectively explain <35% of the observed AD heritability of 60-80%. The missing heritability could be partly explained by multiple low-frequency or rare genetic variants that can be detected cost-effectively via analysis of exome chip (EC) data now available in the original CHARGE and in 4 additional cohorts (the CHARGE-Plus sample: n=45,910, ~4058 with AD). In this application we propose the following:
Aim 1 : To use EC data to search for rare genetic variants related to incident clinical AD, and to AD endophenotypes. We have shown that GWAS of AD endophenotypes, e.g. hippocampal & total brain volumes, verbal memory can identify novel loci implicated in brain aging, and biological pathways underlying AD. We propose to use EC data to search for rare variants related to these established AD endophenotypes.
Aim 2 : To understand preclinical AD, the stage of early pathological changes 1-2 decades before clinical AD, during which AD is likely most amenable to intervention, we propose GWAS and EC analyses of emerging novel, sensitive MRI endophenotypes, cognitive and circulating biomarker (plasma ?-amyloid and clusterin) data in the entire CHARGE-Plus and in younger cohorts aged 30-65 years.
Aim 3 : To better understand the biology, epidemiological and public health significance of the identified genes we will study gene-gene interactions between known and novel loci, and gene-environment interactions both targeted (interaction of loci from Aims 1&2 with midlife cholesterol and BMI), and genome-wide. The CHARGE cohorts, with premorbid data on mid-life exposure to a wide-range of environmental covariates, are uniquely positioned to study such interactions and permit analyses of other covariates when indicated.
Aim 4 : Finally, we will explore the biology of the identified variants using bio-informatics annotation databases created in CHARGE, available systemic and brain mRNA, miRNA, methylation data (n~8000 & 750, respectively), hippocampal neuronal expression in autopsy brains and in Drosophila tau & ?-amyloid models. We seek modest analytic resources to leverage existing phenotypic and genotypic data worth millions, to discover new AD genes and potentially novel prevention and treatment approaches for AD.

Public Health Relevance

Alzheimer's disease (AD) is a major public health burden with no known prevention or treatment, but identifying new AD genes can uncover new biological pathways leading to novel treatments. We assembled an international collaboration of cohort studies and searched for common genetic variants causing AD leading to the identification of 9 novel genes for AD, 8 for MRI and cognitive function markers of AD; we propose to expand our studies to seek rare genetic variants for AD using exome chip data on 45,000 persons, 4000 with AD. We will also explore the genetics of preclinical AD in the 40,000 without clinical disease by studying newer, sensitive MRI markers and gene-environment interactions and study the expression in humans and function in Drosophila for the novel genes we find.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
4R01AG033193-07
Application #
9093680
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Miller, Marilyn
Project Start
2009-02-01
Project End
2017-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
7
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Boston University
Department
Neurology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
Jian, Xueqiu; Satizabal, Claudia L; Smith, Albert V et al. (2018) Exome Chip Analysis Identifies Low-Frequency and Rare Variants in MRPL38 for White Matter Hyperintensities on Brain Magnetic Resonance Imaging. Stroke 49:1812-1819
Tynkkynen, Juho; Chouraki, Vincent; van der Lee, Sven J et al. (2018) Association of branched-chain amino acids and other circulating metabolites with risk of incident dementia and Alzheimer's disease: A prospective study in eight cohorts. Alzheimers Dement 14:723-733
Roostaei, Tina; Felsky, Daniel; Nazeri, Arash et al. (2018) Genetic influence of plasma homocysteine on Alzheimer's disease. Neurobiol Aging 62:243.e7-243.e14
Davies, Gail; Lam, Max; Harris, Sarah E et al. (2018) Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. Nat Commun 9:2098
Girdhar, Kiran; Hoffman, Gabriel E; Jiang, Yan et al. (2018) Cell-specific histone modification maps in the human frontal lobe link schizophrenia risk to the neuronal epigenome. Nat Neurosci 21:1126-1136
Kunutsor, Setor K; Laukkanen, Jari A; Burgess, Stephen (2018) Genetically elevated gamma-glutamyltransferase and Alzheimer's disease. Exp Gerontol 106:61-66
Nordestgaard, Liv Tybjærg; Tybjærg-Hansen, Anne; Rasmussen, Katrine Laura et al. (2018) Genetic variation in clusterin and risk of dementia and ischemic vascular disease in the general population: cohort studies and meta-analyses of 362,338 individuals. BMC Med 16:39
Blue, Elizabeth E; Bis, Joshua C; Dorschner, Michael O et al. (2018) Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer's Disease Sequencing Project. Dement Geriatr Cogn Disord 45:1-17
Nafikov, Rafael A; Nato Jr, Alejandro Q; Sohi, Harkirat et al. (2018) Analysis of pedigree data in populations with multiple ancestries: Strategies for dealing with admixture in Caribbean Hispanic families from the ADSP. Genet Epidemiol 42:500-515
Blue, E E; Yu, C-E; Thornton, T A et al. (2018) Variants regulating ZBTB4 are associated with age-at-onset of Alzheimer's disease. Genes Brain Behav 17:e12429

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