title: Cis-eQTL-based trans-ethnic meta-analysis reveals novel genes associated with breast cancer risk.
abstract: Breast cancer is the most common solid organ malignancy and the most frequent cause of cancer death among women worldwide. Previous research has yielded insights into its genetic etiology, but there remains a gap in the understanding of genetic factors that contribute to risk, and particularly in the biological mechanisms by which genetic variation modulates risk. The National Cancer Institute's "Up for a Challenge" (U4C) competition provided an opportunity to further elucidate the genetic basis of the disease. Our group leveraged the seven datasets made available by the U4C organizers and data from the publicly available UK Biobank cohort to examine associations between imputed gene expression and breast cancer risk. In particular, we used reference datasets describing the breast tissue and whole blood transcriptomes to impute expression levels in breast cancer cases and controls. In trans-ethnic meta-analyses of U4C and UK Biobank data, we found significant associations between breast cancer risk and the expression of RCCD1 (joint p-value: 3.6x10-06) and DHODH (p-value: 7.1x10-06) in breast tissue, as well as a suggestive association for ANKLE1 (p-value: 9.3x10-05). Expression of RCCD1 in whole blood was also suggestively associated with disease risk (p-value: 1.2x10-05), as were expression of ACAP1 (p-value: 1.9x10-05) and LRRC25 (p-value: 5.2x10-05). While genome-wide association studies (GWAS) have implicated RCCD1 and ANKLE1 in breast cancer risk, they have not identified the remaining three genes. Among the genetic variants that contributed to the predicted expression of the five genes, we found 23 nominally (p-value < 0.05) associated with breast cancer risk, among which 15 are not in high linkage disequilibrium with risk variants previously identified by GWAS. In summary, we used a transcriptome-based approach to investigate the genetic underpinnings of breast carcinogenesis. This approach provided an avenue for deciphering the functional relevance of genes and genetic variants involved in breast cancer.
authors.affiliation: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, United States of America.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Hoffman
authors.affiliation: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, United States of America.
authors.forename: Rebecca E
authors.identifier: http://orcid.org/0000-0003-0316-8303
authors.initials: RE
authors.lastname: Graff
authors.affiliation: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, United States of America.|Program in Biological and Medical Informatics, University of California San Francisco, San Francisco, CA, United States of America.
authors.forename: Nima C
authors.identifier: http://orcid.org/0000-0002-4296-7805
authors.initials: NC
authors.lastname: Emami
authors.affiliation: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, United States of America.
authors.forename: Caroline G
authors.initials: CG
authors.lastname: Tai
authors.affiliation: Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH, United States of America.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Passarelli
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, CA, United States of America.
authors.forename: Donglei
authors.initials: D
authors.lastname: Hu
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, CA, United States of America.
authors.forename: Scott
authors.initials: S
authors.lastname: Huntsman
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, CA, United States of America.
authors.forename: Dexter
authors.identifier: http://orcid.org/0000-0003-0990-4674
authors.initials: D
authors.lastname: Hadley
authors.affiliation: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, United States of America.
authors.forename: Lancelote
authors.identifier: http://orcid.org/0000-0003-4899-0261
authors.initials: L
authors.lastname: Leong
authors.affiliation: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, United States of America.
authors.forename: Arunabha
authors.identifier: http://orcid.org/0000-0002-5609-075X
authors.initials: A
authors.lastname: Majumdar
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, CA, United States of America.
authors.forename: Noah
authors.initials: N
authors.lastname: Zaitlen
authors.affiliation: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, United States of America.
authors.forename: Elad
authors.initials: E
authors.lastname: Ziv
authors.affiliation: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, United States of America.|Department of Urology, University of California San Francisco, San Francisco, CA, United States of America.|Institute for Human Genetics, University of California San Francisco, San Francisco, CA, United States of America.
authors.forename: John S
authors.initials: JS
authors.lastname: Witte
mesh_terms: D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000097:blood / Q000235:genetics*; D004720:Endonucleases / Q000097:blood / Q000235:genetics; D005006:Ethnicity; D005260:Female; D020690:GTPase-Activating Proteins / Q000097:blood / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008565:Membrane Proteins / Q000097:blood / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics*; D012307:Risk Factors; D059467:Transcriptome / Q000235:genetics
chemical_list: C507017:ACAP1 protein, human; D002352:Carrier Proteins; D020690:GTPase-Activating Proteins; D008565:Membrane Proteins; C000600473:RCCD1 protein, human; C579363:ANKLE1 protein, human; D004720:Endonucleases