Over the past few years genome-wide association studies (GWASs) have identified numerous genes associated with common human diseases. In these studies, genetic variation in thousands of individuals is collected and correlated with the disease status in these individuals. A challenging aspect of GWAS is that the collected individuals are related to each other by differing degrees. This can lead to spurious associations which are genes that appear to be associated with the disease, but in fact are an artifact of the relatedness between individuals. Several methods have been proposed to address this problem and are implemented in publicly available software packages. Environmental factors often interact with genetic variation to increase risk of disease. Identifying these interactions, referrd to as gene-by-environment (GxE) interactions, is now a major focus of research in both human studies and model organism studies. Discovering GxE interactions can provide insight into disease pathways, an understanding of the effect of environmental factors in disease, better risk prediction and personalized therapies. Model organisms such as mouse are ideal environments for studying GxE interactions because environmental exposures can be carefully controlled. Unfortunately, for the same reasons that relatedness can cause spurious associations in association studies, relatedness can cause spurious gene-by- environment interactions. In this proposal we propose to develop methodology that corrects for relatedness in studies that search for gene-by-environment interactions. The results of our project will be a set of methods that are can detect gene-by-environment interactions consistently even when the individuals in the study are related. These methods can then be widely used by many researchers involved in studies to discovery gene-by-environment interactions. We will apply our developed methods to the Minnesota Center for Twin and Family Research (MCTFR) data to investigate how gene-environment interplay influences the development of substance abuse (SA) and to mouse genetic studies investigating the genetic factors which influence response to high fat diet and susceptibility to heart failure. We will make implement our methods available to the research community through publicly available software packages and webserver resources.

Public Health Relevance

An individual's predisposition to disease depends on both genetic factors and environmental factors as well as the interaction of these genetic and environmental factors. Relatively little is known about these interactions and few of them have been discovered. This proposal is relevant to human health because it develops novel methods for discovering these types of interactions which can provide insight into the factors which contribute to disease leading to directions for new treatments and therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES022282-02
Application #
8728856
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Mcallister, Kimberly A
Project Start
2013-09-01
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Biostatistics & Other Math Sci
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Mangul, Serghei; Yang, Harry Taegyun; Strauli, Nicolas et al. (2018) ROP: dumpster diving in RNA-sequencing to find the source of 1 trillion reads across diverse adult human tissues. Genome Biol 19:36
Rahmani, Elior; Schweiger, Regev; Shenhav, Liat et al. (2018) BayesCCE: a Bayesian framework for estimating cell-type composition from DNA methylation without the need for methylation reference. Genome Biol 19:141
Kang, Eun Yong; Lee, Cue Hyunkyu; Furlotte, Nicholas A et al. (2018) An Association Mapping Framework To Account for Potential Sex Difference in Genetic Architectures. Genetics 209:685-698
Park, Danny S; Eskin, Itamar; Kang, Eun Yong et al. (2018) An ancestry-based approach for detecting interactions. Genet Epidemiol 42:49-63
Gamazon, Eric R; Segrè, Ayellet V; van de Bunt, Martijn et al. (2018) Using an atlas of gene regulation across 44 human tissues to inform complex disease- and trait-associated variation. Nat Genet 50:956-967
Olde Loohuis, Loes M; Mangul, Serghei; Ori, Anil P S et al. (2018) Transcriptome analysis in whole blood reveals increased microbial diversity in schizophrenia. Transl Psychiatry 8:96
Hormozdiari, Farhad; Zhu, Anthony; Kichaev, Gleb et al. (2017) Widespread Allelic Heterogeneity in Complex Traits. Am J Hum Genet 100:789-802
Bilow, Michael; Crespo, Fernando; Pan, Zhicheng et al. (2017) Simultaneous Modeling of Disease Status and Clinical Phenotypes To Increase Power in Genome-Wide Association Studies. Genetics 205:1041-1047
Rahmani, Elior; Zaitlen, Noah; Baran, Yael et al. (2017) Correcting for cell-type heterogeneity in DNA methylation: a comprehensive evaluation. Nat Methods 14:218-219
Duong, Dat; Gai, Lisa; Snir, Sagi et al. (2017) Applying meta-analysis to genotype-tissue expression data from multiple tissues to identify eQTLs and increase the number of eGenes. Bioinformatics 33:i67-i74

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