title: Deconvoluting complex tissues for expression quantitative trait locus-based analyses.
abstract: Breast cancer genome-wide association studies have pinpointed dozens of variants associated with breast cancer pathogenesis. The majority of risk variants, however, are located outside of known protein-coding regions. Therefore, identifying which genes the risk variants are acting through presents an important challenge. Variants that are associated with mRNA transcript levels are referred to as expression quantitative trait loci (eQTLs). Many studies have demonstrated that eQTL-based strategies provide a direct way to connect a trait-associated locus with its candidate target gene. Performing eQTL-based analyses in human samples is complicated because of the heterogeneous nature of human tissue. We addressed this issue by devising a method to computationally infer the fraction of cell types in normal human breast tissues. We then applied this method to 13 known breast cancer risk loci, which we hypothesized were eQTLs. For each risk locus, we took all known transcripts within a 2 Mb interval and performed an eQTL analysis in 100 reduction mammoplasty cases. A total of 18 significant associations were discovered (eight in the epithelial compartment and 10 in the stromal compartment). This study highlights the ability to perform large-scale eQTL studies in heterogeneous tissues.
authors: Department of Medical Oncology, The Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, MA 02215, USA.
authors: Ji-Heui
authors: JH
authors: Seo
authors: Qiyuan
authors: Q
authors: Li
authors: Aquila
authors: A
authors: Fatima
authors: Aron
authors: A
authors: Eklund
authors: Zoltan
authors: Z
authors: Szallasi
authors: Kornelia
authors: K
authors: Polyak
authors: Andrea L
authors: AL
authors: Richardson
authors: Matthew L
authors: ML
authors: Freedman
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D001940:Breast / Q000166:cytology* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D019295:Computational Biology / Q000379:methods; D004848:Epithelium / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D018740:Genetic Heterogeneity; D005819:Genetic Markers; D006801:Humans; D016462:Mammaplasty; D011237:Predictive Value of Tests; D040641:Quantitative Trait Loci; D012307:Risk Factors; D059467:Transcriptome
chemical_list: D005819:Genetic Markers
keywords: breast cancer risk single nucleotide polymorphisms; expression quantitative trait locus; heterogeneous tissue
references: Nature. 2008 Mar 27;452(7186):423-8
references: 18344981
references: PLoS One. 2012;7(8):e41695
references: 22912676
references: Nat Rev Genet. 2009 Mar;10(3):184-94
references: 19223927
references: Cell. 2013 Jan 31;152(3):633-41
references: 23374354
references: Nat Genet. 2011 Jun;43(6):561-4
references: 21572415
references: J Biol Chem. 2005 Aug 19;280(33):29625-36
references: 15985428
references: Cancer Genet Cytogenet. 2010 Mar;197(2):193-4
references: 20193855
references: Lancet. 2005 Feb 19-25;365(9460):671-9
references: 15721472
references: Breast Cancer Res. 2011 Jul 18;13(4):R72
references: 21767389
references: Genome Res. 2010 Dec;20(12):1730-9
references: 21045080
references: Nature. 2010 Aug 5;466(7307):714-9
references: 20686566
references: Mol Cell Endocrinol. 2001 Jan 22;171(1-2):137-49
references: 11165022
references: Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10370-5
references: 12934019
references: Carcinogenesis. 2002 Nov;23(11):1885-95
references: 12419837
references: Cancer Res. 2004 Oct 15;64(20):7610-7
references: 15492289
references: Proc Natl Acad Sci U S A. 2012 Jul 10;109(28):11252-7
references: 22730461
references: PLoS Biol. 2008 May 6;6(5):e108
references: 18462018
references: Nat Methods. 2010 Apr;7(4):287-9
references: 20208531
references: Nature. 2008 Mar 27;452(7186):429-35
references: 18344982
references: Science. 2012 Sep 7;337(6099):1190-5
references: 22955828
references: PLoS One. 2012;7(2):e30477
references: 22363440
references: Cancer Res. 2006 May 15;66(10):5330-7
references: 16707459
references: PLoS Genet. 2010 Nov 11;6(11):e1001204
references: 21085629
references: Bioinformatics. 2001;17 Suppl 1:S279-87
references: 11473019
references: PLoS One. 2011;6(8):e23480
references: 21912597
references: PLoS Genet. 2010 Apr 01;6(4):e1000888
references: 20369019
references: BMC Cancer. 2004 Jun 22;4:27
references: 15212687