A striking feature of Down syndrome (DS;trisomy 21;+21) is the wide range of severity, with strong inter-individual differences in its major features. These include cardiac defects, baseline cognitive function and age-related dementia, as well as several important phenotypes due to altered development and function of blood cells (e.g., childhood leukemias, anemia, autoimmune disorders, and susceptibility to infections). In most cases the genetic or epigenetic factors underlying this variation, and indeed the pathogenesis of the phenotypes themselves, remain largely unknown. Here we hypothesize that the relevant tissues in people with +21 may have accumulated altered patterns of DNA methylation on chromosome 21 and on other chromosomes, potentially affecting some or all of these phenotypes. We have substantial preliminary data supporting this hypothesis, from a profiling method that we developed called MSNP, and from a complementary platform, lllumina Infinium assays. In this highly interactive project we will carry out MSNP and lllumina Infinium assays on peripheral blood leukocyte (PBL) DNAs from people with DS spanning a wide range of ages, including a unique collection of the oldest old survivors, comparing the results with normal controls spanning the same age range. We will validate this epigenetic analysis with bisulfite Pyrosequencing, and correlate the methylation indices and SNP genotypes at the loci with strongest differential methylation with the severity of anemia, autoimmune disorders, and recurrent infections in more than 400 adults with DS. In parallel, we will carry out direct functional studies of the highest priority differentially methylated genes using cell culture and mouse models. While this project is focused on blood cell-related phenotypes, the data may additionally provide a proof-of-principle for future studies of altered DNA methylation in other major organs, including the brain, in this important chromosomal disorder.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD035897-26
Application #
8678958
Study Section
Special Emphasis Panel (ZHD1)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
26
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Hugo W. Moser Research Institute Kennedy Krieger
Department
Type
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Schupf, Nicole; Lee, Joseph H; Pang, Deborah et al. (2018) Epidemiology of estrogen and dementia in women with Down syndrome. Free Radic Biol Med 114:62-68
Babulal, Ganesh M; Quiroz, Yakeel T; Albensi, Benedict C et al. (2018) Perspectives on ethnic and racial disparities in Alzheimer's disease and related dementias: Update and areas of immediate need. Alzheimers Dement :
Lee, Joseph H; Lee, Annie J; Dang, Lam-Ha et al. (2017) Candidate gene analysis for Alzheimer's disease in adults with Down syndrome. Neurobiol Aging 56:150-158
Esbensen, Anna J; Hooper, Stephen R; Fidler, Deborah et al. (2017) Outcome Measures for Clinical Trials in Down Syndrome. Am J Intellect Dev Disabil 122:247-281
Do, Catherine; Xing, Zhuo; Yu, Y Eugene et al. (2017) Trans-acting epigenetic effects of chromosomal aneuploidies: lessons from Down syndrome and mouse models. Epigenomics 9:189-207
Jenkins, Edmund C; Ye, Lingling; Krinsky-McHale, Sharon J et al. (2016) Telomere longitudinal shortening as a biomarker for dementia status of adults with Down syndrome. Am J Med Genet B Neuropsychiatr Genet 171B:169-74
Mendioroz, Maite; Do, Catherine; Jiang, Xiaoling et al. (2015) Trans effects of chromosome aneuploidies on DNA methylation patterns in human Down syndrome and mouse models. Genome Biol 16:263
Schupf, Nicole; Lee, Annie; Park, Naeun et al. (2015) Candidate genes for Alzheimer's disease are associated with individual differences in plasma levels of beta amyloid peptides in adults with Down syndrome. Neurobiol Aging 36:2907.e1-10
Krinsky-McHale, Sharon J; Silverman, Wayne; Gordon, James et al. (2014) Vision deficits in adults with Down syndrome. J Appl Res Intellect Disabil 27:247-63
Hobbs, Charlotte A; Chowdhury, Shimul; Cleves, Mario A et al. (2014) Genetic epidemiology and nonsyndromic structural birth defects: from candidate genes to epigenetics. JAMA Pediatr 168:371-7

Showing the most recent 10 out of 73 publications