Genetic association studies have been successful in identifying >1,000 genetic loci associated with complex disease traits in human populations. However, it remains a central challenge to interpret the vast amounts of data generated by GWAS studies towards an improved understanding of disease markers and, thus, mechanisms, which are critical for translating GWAS findings into genomic medicine applications enabling improvements in diagnostics, therapies, and outcomes. Recent efforts to incorporate prior biological information into GWAS analysis has greatly enhanced the interpretation of GWAS findings by providing biological frameworks for prioritizing associations, and for interpreting multiple associated loci within the contexts of biological networks and pathways. We recently demonstrated that position-specific evolutionary priors could be incorporated into analysis of GWAS results to prioritize variants that were more reproducible across studies. We propose to develop, investigate, and apply evolutionary informed integrative methods that embrace and leverage the genetic complexity of common disease. We hypothesize that position-specific evolutionary features can be incorporated into multiscale biological pathway and network analysis, and that evolutionary informed pathway and network analysis can be applied to existing GWAS and clinical data sets to identify mechanisms giving rise to complex disease phenotypes in populations and individuals. We propose to develop and evaluate these hypotheses through pursuit of the following specific aims: (1) Develop novel evolutionary-informed pathway and network analysis method for interpreting GWAS findings. (2) Apply novel methods to established GWAS and clinical data for T2D to elucidate disease mechanisms underlying the genetic architecture across populations. (3) Develop a public database and software tool to enable evolutionary informed network analysis of GWAS findings for the broader research community.

Public Health Relevance

Type 2 diabetes and other common diseases are characterized as having complex genetic architectures involving up to many hundreds or thousands of genetic factors. Genetic association studies are being performed to uncover these factors, but it remains challenging to use the result of these studies to learn more about the genetic basis of these diseases. We propose to develop and apply advanced evolutionary and integrative genomic methods to explore the existing genetic association data for type 2 diabetes and further elucidate the underlying genetic causes of disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK098242-01
Application #
8482670
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Mckeon, Catherine T
Project Start
2013-04-01
Project End
2017-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$431,460
Indirect Cost
$126,972
Name
Icahn School of Medicine at Mount Sinai
Department
Genetics
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Li, Li; Boland, Mary Regina; Miotto, Riccardo et al. (2016) Replicating Cardiovascular Condition-Birth Month Associations. Sci Rep 6:33166
Kidd, Brian A; Wroblewska, Aleksandra; Boland, Mary R et al. (2016) Mapping the effects of drugs on the immune system. Nat Biotechnol 34:47-54
Kuncheva, Zhana; Krishnan, Michelle L; Montana, Giovanni (2016) EXPLORING BRAIN TRANSCRIPTOMIC PATTERNS: A TOPOLOGICAL ANALYSIS USING SPATIAL EXPRESSION NETWORKS. Pac Symp Biocomput 22:70-81
Cohain, Ariella; Divaraniya, Aparna A; Zhu, Kuixi et al. (2016) EXPLORING THE REPRODUCIBILITY OF PROBABILISTIC CAUSAL MOLECULAR NETWORK MODELS. Pac Symp Biocomput 22:120-131
Karim, Sajjad; NourEldin, Hend Fakhri; Abusamra, Heba et al. (2016) e-GRASP: an integrated evolutionary and GRASP resource for exploring disease associations. BMC Genomics 17:770
Liu, Li; Tamura, Koichiro; Sanderford, Maxwell et al. (2016) A Molecular Evolutionary Reference for the Human Variome. Mol Biol Evol 33:245-54
Ruderfer, Douglas M; Charney, Alexander W; Readhead, Ben et al. (2016) Polygenic overlap between schizophrenia risk and antipsychotic response: a genomic medicine approach. Lancet Psychiatry 3:350-7
Readhead, B; Haure-Mirande, J-V; Zhang, B et al. (2016) Molecular systems evaluation of oligomerogenic APP(E693Q) and fibrillogenic APP(KM670/671NL)/PSEN1(Δexon9) mouse models identifies shared features with human Alzheimer's brain molecular pathology. Mol Psychiatry 21:1099-111
Hodos, Rachel A; Kidd, Brian A; Shameer, Khader et al. (2016) In silico methods for drug repurposing and pharmacology. Wiley Interdiscip Rev Syst Biol Med 8:186-210
Miotto, Riccardo; Li, Li; Kidd, Brian A et al. (2016) Deep Patient: An Unsupervised Representation to Predict the Future of Patients from the Electronic Health Records. Sci Rep 6:26094

Showing the most recent 10 out of 24 publications