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Grant Details

Grant Number: 5R01CA189532-04 Interpret this number
Primary Investigator: Hsu, Li
Organization: Fred Hutchinson Cancer Research Center
Project Title: Methods for Integrating Functional Data Into Complex Disease Genetic Analyses
Fiscal Year: 2018
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Abstract

? DESCRIPTION (provided by applicant): Recent developments in The Human Genome Project and breakthroughs in different types of high throughput technologies have changed how researchers approach complex diseases by moving toward cross- disciplinary studies, collecting data on all facets of disease. The objective of this application is to develop efficient statistica and computational approaches to integrating genetics, genomics and epidemiologic data for understanding the interplay of genetics and environment in complex diseases, with the long-term goal of devising personalized strategies to prevent and treat these diseases. Genome-wide association studies have identified thousands of trait associated genetic variants, and provided valuable insights into the genetic architecture of these traits. However, most variants identified so far confer relatively small increments in risk, and explain only a small proportion o heritability, leading many to question how the remaining 'missing' heritability can be explained. This application addresses this 'missing' heritability from several aspects: rare variant association analysis, gene-environment interaction, and heritability estimation beyond additive genetic effects. Accordingly, we propose the following specific aims. Aim 1 is to develop methods for integrating functional information into rare variants association analysis. To achieve this goal, Aim 1 includes developing databases of tissue-specific functional annotation and constructing regulatory expression networks (eQTL) from public data generated from large collaborative projects such as the Encyclopedia of DNA Elements and the Genotype Tissue Expression. The theoretical properties of the rare variants analysis will also be studied to devise powerful tests in consideration of genomic features such as linkage disequilibrium and sparse signals. Aim 2 is to develop methods for rare variants gene-environment interaction (GxE) that incorporates functional information. Efficient and versatile screening strategies will also be developed for genome-wide discovery of GxE. Even though this aim is focused on GxE, the methods are also applicable to gene-gene interaction (GxG). Aim 3 is to develop methods for estimating heritability that incorporates GxE and GxG to understand the complex interplay between genetic susceptibility and environment The proposed work is motivated by a large consortium on colorectal cancer, which has over 40,000 participants from well-characterized studies with detailed data on both environmental risk factors and GWAS and whole genome sequencing data. The developed methods will be applied to the consortium to gain new insights in colorectal cancer and demonstrate the feasibility of the methods. Since the methods are applicable to other complex diseases and traits, R-based open source software will be developed and submitted to the Comprehensive R Archive Network for broad dissemination.

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Publications

Diagnostics of Pleiotropy in Mendelian Randomization Studies: Global and Individual Tests for Direct Effects.
Authors: Dai J.Y. , Peters U. , Wang X. , Kocarnik J. , Chang-Claude J. , Slattery M.L. , Chan A. , Lemire M. , Berndt S.I. , Casey G. , et al. .
Source: American Journal Of Epidemiology, 2018-09-05 00:00:00.0; , .
EPub date: 2018-09-05 00:00:00.0.
PMID: 30188971
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Joint skeleton estimation of multiple directed acyclic graphs for heterogeneous population.
Authors: Liu J. , Sun W. , Liu Y. .
Source: Biometrics, 2018-08-06 00:00:00.0; , .
EPub date: 2018-08-06 00:00:00.0.
PMID: 30081434
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Characterizing functional consequences of DNA copy number alterations in breast and ovarian tumors by spaceMap.
Authors: Conley C.J. , Ozbek U. , Wang P. , Peng J. .
Source: Journal Of Genetics And Genomics = Yi Chuan Xue Bao, 2018-07-20 00:00:00.0; 45(7), p. 361-371.
EPub date: 2018-07-26 00:00:00.0.
PMID: 30057342
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Mendelian randomisation study of age at menarche and age at menopause and the risk of colorectal cancer.
Authors: Neumeyer S. , Banbury B.L. , Arndt V. , Berndt S.I. , Bezieau S. , Bien S.A. , Buchanan D.D. , Butterbach K. , Caan B.J. , Campbell P.T. , et al. .
Source: British Journal Of Cancer, 2018 Jun; 118(12), p. 1639-1647.
EPub date: 2018-05-24 00:00:00.0.
PMID: 29795306
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A Mixed-Effects Model for Powerful Association Tests in Integrative Functional Genomics.
Authors: Su Y.R. , Di C. , Bien S. , Huang L. , Dong X. , Abecasis G. , Berndt S. , Bezieau S. , Brenner H. , Caan B. , et al. .
Source: American Journal Of Human Genetics, 2018-05-03 00:00:00.0; 102(5), p. 904-919.
PMID: 29727690
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The association between copy number aberration, DNA methylation and gene expression in tumor samples.
Authors: Sun W. , Bunn P. , Jin C. , Little P. , Zhabotynsky V. , Perou C.M. , Hayes D.N. , Chen M. , Lin D.Y. .
Source: Nucleic Acids Research, 2018-04-06 00:00:00.0; 46(6), p. 3009-3018.
PMID: 29529299
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Multivariate association analysis with somatic mutation data.
Authors: He Q. , Liu Y. , Peters U. , Hsu L. .
Source: Biometrics, 2018 Mar; 74(1), p. 176-184.
EPub date: 2017-07-19 00:00:00.0.
PMID: 28722765
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Joint Analysis of Strain and Parent-of-Origin Effects for Recombinant Inbred Intercrosses Generated from Multiparent Populations with the Collaborative Cross as an Example.
Authors: Liu Y. , Xiong S. , Sun W. , Zou F. .
Source: G3 (bethesda, Md.), 2018-02-02 00:00:00.0; 8(2), p. 599-605.
EPub date: 2018-02-02 00:00:00.0.
PMID: 29255115
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Incorporation of Biological Knowledge Into the Study of Gene-Environment Interactions.
Authors: Ritchie M.D. , Davis J.R. , Aschard H. , Battle A. , Conti D. , Du M. , Eskin E. , Fallin M.D. , Hsu L. , Kraft P. , et al. .
Source: American Journal Of Epidemiology, 2017-10-01 00:00:00.0; 186(7), p. 771-777.
PMID: 28978191
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Update on the State of the Science for Analytical Methods for Gene-Environment Interactions.
Authors: Gauderman W.J. , Mukherjee B. , Aschard H. , Hsu L. , Lewinger J.P. , Patel C.J. , Witte J.S. , Amos C. , Tai C.G. , Conti D. , et al. .
Source: American Journal Of Epidemiology, 2017-10-01 00:00:00.0; 186(7), p. 762-770.
PMID: 28978192
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Current Challenges and New Opportunities for Gene-Environment Interaction Studies of Complex Diseases.
Authors: McAllister K. , Mechanic L.E. , Amos C. , Aschard H. , Blair I.A. , Chatterjee N. , Conti D. , Gauderman W.J. , Hsu L. , Hutter C.M. , et al. .
Source: American Journal Of Epidemiology, 2017-10-01 00:00:00.0; 186(7), p. 753-761.
PMID: 28978193
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A new method to study the change of miRNA-mRNA interactions due to environmental exposures.
Authors: Petralia F. , Aushev V.N. , Gopalakrishnan K. , Kappil M. , W Khin N. , Chen J. , Teitelbaum S.L. , Wang P. .
Source: Bioinformatics (oxford, England), 2017-07-15 00:00:00.0; 33(14), p. i199-i207.
PMID: 28881990
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Quantifying the genetic correlation between multiple cancer types.
Authors: Lindström S. , Finucane H. , Bulik-Sullivan B. , Schumacher F.R. , Amos C.I. , Hung R.J. , Rand K. , Gruber S.B. , Conti D. , Permuth J.B. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2017-06-21 00:00:00.0; , .
EPub date: 2017-06-21 00:00:00.0.
PMID: 28637796
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Hypothesis testing in functional linear models.
Authors: Su Y.R. , Di C.Z. , Hsu L. .
Source: Biometrics, 2017-03-10 00:00:00.0; , .
EPub date: 2017-03-10 00:00:00.0.
PMID: 28295175
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On Estimation Of Time-dependent Attributable Fraction From Population-based Case-control Studies
Authors: Zhao W. , Chen Y.Q. , Hsu L. .
Source: Biometrics, 2017-01-18 00:00:00.0; , .
PMID: 28099992
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Heritability Estimation using a Regularized Regression Approach (HERRA): Applicable to continuous, dichotomous or age-at-onset outcome.
Authors: Gorfine M. , Berndt S.I. , Chang-Claude J. , Hoffmeister M. , Le Marchand L. , Potter J. , Slattery M.L. , Keret N. , Peters U. , Hsu L. .
Source: Plos One, 2017; 12(8), p. e0181269.
EPub date: 2017-08-16 00:00:00.0.
PMID: 28813438
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Enrichment of colorectal cancer associations in functional regions: Insight for using epigenomics data in the analysis of whole genome sequence-imputed GWAS data.
Authors: Bien S.A. , Auer P.L. , Harrison T.A. , Qu C. , Connolly C.M. , Greenside P.G. , Chen S. , Berndt S.I. , Bézieau S. , Kang H.M. , et al. .
Source: Plos One, 2017; 12(11), p. e0186518.
EPub date: 2017-11-21 00:00:00.0.
PMID: 29161273
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A Unified Powerful Set-based Test For Sequencing Data Analysis Of Gxe Interactions
Authors: Su Y.R. , Di C.Z. , Hsu L. , Genetics and Epidemiology of Colorectal Cancer Consortium .
Source: Biostatistics (oxford, England), 2016-07-28 00:00:00.0; , .
PMID: 27474101
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A Fully Nonparametric Estimator Of The Marginal Survival Function Based On Case-control Clustered Age-at-onset Data
Authors: Gorfine M. , Bordo N. , Hsu L. .
Source: Biostatistics (oxford, England), 2016-07-19 00:00:00.0; , .
PMID: 27436674
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