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.




Genetic risk, health-associated lifestyle, and risk of early-onset total cancer and breast cancer.
Authors: Zhang Y. , Lindström S. , Kraft P. , Liu Y. .
Source: Journal Of The National Cancer Institute, 2025-01-01 00:00:00.0; 117(1), p. 40-48.
PMID: 39189966
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Isoform-level analyses of 6 cancers uncover extensive genetic risk mechanisms undetected at the gene-level.
Authors: Chang Y.H. , Head S.T. , Harrison T. , Yu Y. , Huff C.D. , Pasaniuc B. , Lindström S. , Bhattacharya A. .
Source: Medrxiv : The Preprint Server For Health Sciences, 2024-10-30 00:00:00.0; , .
EPub date: 2024-10-30 00:00:00.0.
PMID: 39574839
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NON-ADDITIVE EFFECTS OF COMMON GENETIC VARIANTS HAVE A NEGLIGENT CONTRIBUTION TO CANCER HERITABILITY.
Authors: Hammermeister Suger A. , Harrison T.A. , Henning B. , Turman C. , Kraft P. , Lindström S. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2024-07-17 00:00:00.0; , .
EPub date: 2024-07-17 00:00:00.0.
PMID: 39018351
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Source: Medrxiv : The Preprint Server For Health Sciences, 2024-04-06 00:00:00.0; , .
EPub date: 2024-04-06 00:00:00.0.
PMID: 38633776
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Genotype error due to low-coverage sequencing induces uncertainty in polygenic scoring.
Authors: Petter E. , Ding Y. , Hou K. , Bhattacharya A. , Gusev A. , Zaitlen N. , Pasaniuc B. .
Source: American Journal Of Human Genetics, 2023-08-03 00:00:00.0; 110(8), p. 1319-1329.
EPub date: 2023-07-24 00:00:00.0.
PMID: 37490908
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Relationship between ABO blood group alleles and pancreatic cancer is modulated by secretor (FUT2) genotype, but not Lewis antigen (FUT3) genotype.
Authors: Kim J. , Yuan C. , Amundadottir L.T. , Wolpin B.M. , Klein A.P. , Risch H.A. , Kraft P. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2023-06-21 00:00:00.0; , .
EPub date: 2023-06-21 00:00:00.0.
PMID: 37342060
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Authors: Palmer D.S. , Zhou W. , Abbott L. , Wigdor E.M. , Baya N. , Churchhouse C. , Seed C. , Poterba T. , King D. , Kanai M. , et al. .
Source: Science (new York, N.y.), 2023-03-31 00:00:00.0; 379(6639), p. 1341-1348.
EPub date: 2023-03-30 00:00:00.0.
PMID: 36996212
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Source: Journal Of The National Cancer Institute, 2023-03-17 00:00:00.0; , .
EPub date: 2023-03-17 00:00:00.0.
PMID: 36929942
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Authors: Liu Y. , Chen H. , Heine J. , Lindstrom S. , Turman C. , Warner E.T. , Winham S.J. , Vachon C.M. , Tamimi R.M. , Kraft P. , et al. .
Source: Breast Cancer Research : Bcr, 2022-11-07 00:00:00.0; 24(1), p. 76.
EPub date: 2022-11-07 00:00:00.0.
PMID: 36344993
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Source: Breast Cancer Research : Bcr, 2022-04-12 00:00:00.0; 24(1), p. 27.
EPub date: 2022-04-12 00:00:00.0.
PMID: 35414113
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Authors: Palmer D.S. , Howrigan D.P. , Chapman S.B. , Adolfsson R. , Bass N. , Blackwood D. , Boks M.P.M. , Chen C.Y. , Churchhouse C. , Corvin A.P. , et al. .
Source: Nature Genetics, 2022-04-11 00:00:00.0; , .
EPub date: 2022-04-11 00:00:00.0.
PMID: 35410376
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Somatic mutational profiles and germline polygenic risk scores in human cancer.
Authors: Liu Y. , Gusev A. , Heng Y.J. , Alexandrov L.B. , Kraft P. .
Source: Genome Medicine, 2022-02-11 00:00:00.0; 14(1), p. 14.
EPub date: 2022-02-11 00:00:00.0.
PMID: 35144655
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Estimation of regional polygenicity from GWAS provides insights into the genetic architecture of complex traits.
Authors: Johnson R. , Burch K.S. , Hou K. , Paciuc M. , Pasaniuc B. , Sankararaman S. .
Source: Plos Computational Biology, 2021 Oct; 17(10), p. e1009483.
EPub date: 2021-10-21 00:00:00.0.
PMID: 34673766
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Evaluating the estimation of genetic correlation and heritability using summary statistics.
Authors: Zhang J. , Schumacher F.R. .
Source: Molecular Genetics And Genomics : Mgg, 2021-09-29 00:00:00.0; , .
EPub date: 2021-09-29 00:00:00.0.
PMID: 34586498
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Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals.
Authors: Chen H. , Majumdar A. , Wang L. , Kar S. , Brown K.M. , Feng H. , Turman C. , Dennis J. , Easton D. , Michailidou K. , et al. .
Source: Hgg Advances, 2021-07-08 00:00:00.0; 2(3), .
EPub date: 2021-06-12 00:00:00.0.
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Multitrait transcriptome-wide association study (TWAS) tests.
Authors: Feng H. , Mancuso N. , Pasaniuc B. , Kraft P. .
Source: Genetic Epidemiology, 2021-06-03 00:00:00.0; , .
EPub date: 2021-06-03 00:00:00.0.
PMID: 34082479
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Leveraging eQTLs to identify individual-level tissue of interest for a complex trait.
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Source: Plos Computational Biology, 2021 May; 17(5), p. e1008915.
EPub date: 2021-05-21 00:00:00.0.
PMID: 34019542
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Source: Plos Genetics, 2021 Apr; 17(4), p. e1008973.
EPub date: 2021-04-08 00:00:00.0.
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Authors: Ziyatdinov A. , Kim J. , Prokopenko D. , Privé F. , Laporte F. , Loh P.R. , Kraft P. , Aschard H. .
Source: G3 (bethesda, Md.), 2021-03-18 00:00:00.0; , .
EPub date: 2021-03-18 00:00:00.0.
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EPub date: 2021-01-04 00:00:00.0.
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Source: Nature Genetics, 2020 06; 52(6), p. 572-581.
EPub date: 2020-05-18 00:00:00.0.
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EPub date: 2020-05-16 00:00:00.0.
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EPub date: 2020-05-20 00:00:00.0.
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Source: Nature Genetics, 2019 Aug; 51(8), p. 1244-1251.
EPub date: 2019-07-29 00:00:00.0.
PMID: 31358995
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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, 2019-06-22 00:00:00.0; , .
EPub date: 2019-06-22 00:00:00.0.
PMID: 31230194
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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, 2019-05-13 00:00:00.0; , .
EPub date: 2019-05-13 00:00:00.0.
PMID: 31087417
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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 May; 28(5), p. 935-942.
EPub date: 2019-01-30 00:00:00.0.
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Source: Nature Genetics, 2019 04; 51(4), p. 675-682.
EPub date: 2019-03-29 00:00:00.0.
PMID: 30926970
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Source: Nature Communications, 2019-01-25 00:00:00.0; 10(1), p. 431.
EPub date: 2019-01-25 00:00:00.0.
PMID: 30683880
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Source: Nature Communications, 2019-01-08 00:00:00.0; 10(1), p. 171.
EPub date: 2019-01-08 00:00:00.0.
PMID: 30622272
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EPub date: 2018-12-03 00:00:00.0.
PMID: 30510157
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Authors: O'Connor L.J. , Price A.L. .
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EPub date: 2018-10-04 00:00:00.0.
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PMID: 29579179
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Source: Nature Genetics, 2018 Apr; 50(4), p. 621-629.
EPub date: 2018-04-09 00:00:00.0.
PMID: 29632380
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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 00:00:00.0; 9(1), p. 1178.
EPub date: 2018-03-21 00:00:00.0.
PMID: 29563502
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Authors: Roytman M. , Kichaev G. , Gusev A. , Pasaniuc B. .
Source: Plos Genetics, 2018 02; 14(2), p. e1007240.
EPub date: 2018-02-26 00:00:00.0.
PMID: 29481575
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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 00:00:00.0.
PMID: 29058716
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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 00:00:00.0; 551(7678), p. 92-94.
EPub date: 2017-10-23 00:00:00.0.
PMID: 29059683
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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 00:00:00.0; 101(5), p. 737-751.
PMID: 29100087
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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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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 00:00:00.0; 33(2), p. 248-255.
EPub date: 2016-09-22 00:00:00.0.
PMID: 27663501
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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 00:00:00.0; 7, p. 10979.
EPub date: 2016-04-07 00:00:00.0.
PMID: 27052111
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