Skip to main content

COVID-19 Resources

What people with cancer should know:

Guidance for cancer researchers:

Get the latest public health information from CDC:

Get the latest research information from NIH:

Grant Details

Grant Number: 2R01CA194393-05A1 Interpret this number
Primary Investigator: Lindstroem, Sara
Organization: University Of Washington
Project Title: Leveraging Cross-Cancer Shared Heritability to Better Understand the Genetic Architecture of Cancer
Fiscal Year: 2020


ABSTRACT Genome-wide association studies (GWAS) and transcriptome-wide association studies (TWAS) have identified hundreds of common, modest-effect alleles and genes associated with cancer risk, but much of cancer heritability remains unexplained. To date, most epidemiological studies of cancer focus on individual cancer types. We propose to leverage the shared heritability across cancers to conduct the largest cross-cancer GWAS and TWAS to date. To achieve our goal, we will use individual and summary GWAS data from 12 solid cancers (breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate and renal) based on more than 400,000 cases and 900,000 controls expanding our prior work with six new cancer sites and more than 100,000 new cancer cases. We will conduct overall and subset-based cross-cancer GWAS meta-analysis to identify novel cancer risk alleles (Aim 1a). We will also develop statistical methods that explicitly test for pleiotropic effects using summary statistics only and apply these to both known and novel cancer SNPs (Aim 1b). We will develop and apply methods for cross-cancer TWAS, leveraging the genetic regulation of gene expression in both tumor (TCGA) and normal (GTEx) tissue (Aim 2). Finally, we will use novel methods that leverage both GWAS summary statistics and individual-level data from dbGaP and UK Biobank, as well as functional annotation data from the ENCODE and the RoadMap Epigenomics projects to conduct in-depth heritability analysis of cancer. Specifically, we will model the relative effect sizes of risk alleles as a function of allele frequency and genomic annotation (Aim 3a), and for the first time assess the presence of dominance effects across multiple cancers (Aim 3b). The proposed Aims build on our previous success in using large GWAS summary statistics to establish and quantify the shared genetic contribution to multiple cancers. They also build on our proven track record for developing and applying statistical methods to conduct multi-phenotype association studies and heritability estimation. Our application is in response to PA-17-239: “Secondary Analysis and Integration of Existing Data to Elucidate the Genetic Architecture of Cancer Risk and Related Outcomes”. We have brought together investigators from 12 different cancer GWAS consortia, creating an unprecedented opportunity to identify novel cancer susceptibility loci. As part of the proposed research, we will develop a series of new statistical methods that can be broadly applied to other disease groups with a shared genetic basis. Completion of our Aims will lead to discovery of novel cancer risk alleles and identify shared pathways involved in tumor development across cancers. It will also inform the design and analysis of future sequencing studies to identify low- frequency and rare variants associated with cancer risk, by providing guidance on plausible effect sizes, required sample sizes and the genomic features most likely to harbor large-effect low-frequency variants.


Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.
Authors: Conti D.V. , Darst B.F. , Moss L.C. , Saunders E.J. , Sheng X. , Chou A. , Schumacher F.R. , Olama A.A.A. , Benlloch S. , Dadaev T. , et al. .
Source: Nature genetics, 2021 01; 53(1), p. 65-75.
EPub date: 2021-01-04.
PMID: 33398198
Related Citations

BATMAN: Fast and Accurate Integration of Single-Cell RNA-Seq Datasets via Minimum-Weight Matching.
Authors: Mandric I. , Hill B.L. , Freund M.K. , Thompson M. , Halperin E. .
Source: iScience, 2020-06-26; 23(6), p. 101185.
EPub date: 2020-05-20.
PMID: 32504875
Related Citations

Localizing Components of Shared Transethnic Genetic Architecture of Complex Traits from GWAS Summary Data.
Authors: Shi H. , Burch K.S. , Johnson R. , Freund M.K. , Kichaev G. , Mancuso N. , Manuel A.M. , Dong N. , Pasaniuc B. .
Source: American journal of human genetics, 2020-06-04; 106(6), p. 805-817.
EPub date: 2020-05-21.
PMID: 32442408
Related Citations

The Use Of Genetic Correlation And Mendelian Randomization Studies To Increase Our Understanding of Relationships Between Complex Traits.
Authors: Kraft P. , Chen H. , Lindström S. .
Source: Current epidemiology reports, 2020 Jun; 7(2), p. 104-112.
EPub date: 2020-05-16.
PMID: 33552841
Related Citations

Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.
Authors: Zhang H. , Ahearn T.U. , Lecarpentier J. , Barnes D. , Beesley J. , Qi G. , Jiang X. , O'Mara T.A. , Zhao N. , Bolla M.K. , et al. .
Source: Nature genetics, 2020 06; 52(6), p. 572-581.
EPub date: 2020-05-18.
PMID: 32424353
Related Citations

Genetic associations of breast and prostate cancer are enriched for regulatory elements identified in disease-related tissues.
Authors: Chen H. , Kichaev G. , Bien S.A. , MacDonald J.W. , Wang L. , Bammler T.K. , Auer P. , Pasaniuc B. , Lindström S. .
Source: Human genetics, 2019 Oct; 138(10), p. 1091-1104.
EPub date: 2019-06-22.
PMID: 31230194
Related Citations

Integrative analysis of Dupuytren's disease identifies novel risk locus and reveals a shared genetic etiology with BMI.
Authors: Major M. , Freund M.K. , Burch K.S. , Mancuso N. , Ng M. , Furniss D. , Pasaniuc B. , Ophoff R.A. .
Source: Genetic epidemiology, 2019 09; 43(6), p. 629-645.
EPub date: 2019-05-13.
PMID: 31087417
Related Citations

Accurate estimation of SNP-heritability from biobank-scale data irrespective of genetic architecture.
Authors: Hou K. , Burch K.S. , Majumdar A. , Shi H. , Mancuso N. , Wu Y. , Sankararaman S. , Pasaniuc B. .
Source: Nature genetics, 2019 08; 51(8), p. 1244-1251.
EPub date: 2019-07-29.
PMID: 31358995
Related Citations

Elevated Platelet Count Appears to Be Causally Associated with Increased Risk of Lung Cancer: A Mendelian Randomization Analysis.
Authors: Zhu Y. , Wei Y. , Zhang R. , Dong X. , Shen S. , Zhao Y. , Bai J. , Albanes D. , Caporaso N.E. , Landi M.T. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2019 05; 28(5), p. 935-942.
EPub date: 2019-01-30.
PMID: 30700444
Related Citations

Probabilistic fine-mapping of transcriptome-wide association studies.
Authors: Mancuso N. , Freund M.K. , Johnson R. , Shi H. , Kichaev G. , Gusev A. , Pasaniuc B. .
Source: Nature genetics, 2019 04; 51(4), p. 675-682.
EPub date: 2019-03-29.
PMID: 30926970
Related Citations

Shared heritability and functional enrichment across six solid cancers.
Authors: Jiang X. , Finucane H.K. , Schumacher F.R. , Schmit S.L. , Tyrer J.P. , Han Y. , Michailidou K. , Lesseur C. , Kuchenbaecker K.B. , Dennis J. , et al. .
Source: Nature communications, 2019-01-25; 10(1), p. 431.
EPub date: 2019-01-25.
PMID: 30683880
Related Citations

Author Correction: Large-scale transcriptome-wide association study identifies new prostate cancer risk regions.
Authors: Mancuso N. , Gayther S. , Gusev A. , Zheng W. , Penney K.L. , PRACTICAL consortium , Kote-Jarai Z. , Eeles R. , Freedman M. , Haiman C. , et al. .
Source: Nature communications, 2019-01-08; 10(1), p. 171.
EPub date: 2019-01-08.
PMID: 30622272
Related Citations

GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.
Authors: Franceschini N. , Giambartolomei C. , de Vries P.S. , Finan C. , Bis J.C. , Huntley R.P. , Lovering R.C. , Tajuddin S.M. , Winkler T.W. , Graff M. , et al. .
Source: Nature communications, 2018-12-03; 9(1), p. 5141.
EPub date: 2018-12-03.
PMID: 30510157
Related Citations

Distinguishing genetic correlation from causation across 52 diseases and complex traits.
Authors: O'Connor L.J. , Price A.L. .
Source: Nature genetics, 2018 12; 50(12), p. 1728-1734.
EPub date: 2018-10-29.
PMID: 30374074
Related Citations

Phenotype-Specific Enrichment of Mendelian Disorder Genes near GWAS Regions across 62 Complex Traits.
Authors: Freund M.K. , Burch K.S. , Shi H. , Mancuso N. , Kichaev G. , Garske K.M. , Pan D.Z. , Miao Z. , Mohlke K.L. , Laakso M. , et al. .
Source: American journal of human genetics, 2018-10-04; 103(4), p. 535-552.
PMID: 30290150
Related Citations

Large-scale transcriptome-wide association study identifies new prostate cancer risk regions.
Authors: Mancuso N. , Gayther S. , Gusev A. , Zheng W. , Penney K.L. , Kote-Jarai Z. , Eeles R. , Freedman M. , Haiman C. , Pasaniuc B. , et al. .
Source: Nature communications, 2018-10-04; 9(1), p. 4079.
EPub date: 2018-10-04.
PMID: 30287866
Related Citations

A Bayesian framework for multiple trait colocalization from summary association statistics.
Authors: Giambartolomei C. , Zhenli Liu J. , Zhang W. , Hauberg M. , Shi H. , Boocock J. , Pickrell J. , Jaffe A.E. , CommonMind Consortium , Pasaniuc B. , et al. .
Source: Bioinformatics (Oxford, England), 2018-08-01; 34(15), p. 2538-2545.
PMID: 29579179
Related Citations

A unifying framework for joint trait analysis under a non-infinitesimal model.
Authors: Johnson R. , Shi H. , Pasaniuc B. , Sankararaman S. .
Source: Bioinformatics (Oxford, England), 2018-07-01; 34(13), p. i195-i201.
PMID: 29949958
Related Citations

Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types.
Authors: Finucane H.K. , Reshef Y.A. , Anttila V. , Slowikowski K. , Gusev A. , Byrnes A. , Gazal S. , Loh P.R. , Lareau C. , Shoresh N. , et al. .
Source: Nature genetics, 2018 04; 50(4), p. 621-629.
EPub date: 2018-04-09.
PMID: 29632380
Related Citations

Placenta and appetite genes GDF15 and IGFBP7 are associated with hyperemesis gravidarum.
Authors: Fejzo M.S. , Sazonova O.V. , Sathirapongsasuti J.F. , Hallgrímsdóttir I.B. , Vacic V. , MacGibbon K.W. , Schoenberg F.P. , Mancuso N. , Slamon D.J. , Mullin P.M. , et al. .
Source: Nature communications, 2018-03-21; 9(1), p. 1178.
EPub date: 2018-03-21.
PMID: 29563502
Related Citations

Methods for fine-mapping with chromatin and expression data.
Authors: Roytman M. , Kichaev G. , Gusev A. , Pasaniuc B. .
Source: PLoS genetics, 2018 02; 14(2), p. e1007240.
EPub date: 2018-02-26.
PMID: 29481575
Related Citations

Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer.
Authors: Milne R.L. , Kuchenbaecker K.B. , Michailidou K. , Beesley J. , Kar S. , Lindström S. , Hui S. , Lemaçon A. , Soucy P. , Dennis J. , et al. .
Source: Nature genetics, 2017 Dec; 49(12), p. 1767-1778.
EPub date: 2017-10-23.
PMID: 29058716
Related Citations

Local Genetic Correlation Gives Insights into the Shared Genetic Architecture of Complex Traits.
Authors: Shi H. , Mancuso N. , Spendlove S. , Pasaniuc B. .
Source: American journal of human genetics, 2017-11-02; 101(5), p. 737-751.
PMID: 29100087
Related Citations

Association analysis identifies 65 new breast cancer risk loci.
Authors: Michailidou K. , Lindström S. , Dennis J. , Beesley J. , Hui S. , Kar S. , Lemaçon A. , Soucy P. , Glubb D. , Rostamianfar A. , et al. .
Source: Nature, 2017-11-02; 551(7678), p. 92-94.
EPub date: 2017-10-23.
PMID: 29059683
Related Citations

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 09; 26(9), p. 1427-1435.
EPub date: 2017-06-21.
PMID: 28637796
Related Citations

Improved methods for multi-trait fine mapping of pleiotropic risk loci.
Authors: Kichaev G. , Roytman M. , Johnson R. , Eskin E. , Lindström S. , Kraft P. , Pasaniuc B. .
Source: Bioinformatics (Oxford, England), 2017-01-15; 33(2), p. 248-255.
EPub date: 2016-09-22.
PMID: 27663501
Related Citations

Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation.
Authors: Gusev A. , Shi H. , Kichaev G. , Pomerantz M. , Li F. , Long H.W. , Ingles S.A. , Kittles R.A. , Strom S.S. , Rybicki B.A. , et al. .
Source: Nature communications, 2016-04-07; 7, p. 10979.
EPub date: 2016-04-07.
PMID: 27052111
Related Citations

Back to Top