title: Variants at IRX4 as prostate cancer expression quantitative trait loci.
abstract: Genome-wide association studies (GWAS) have identified numerous prostate cancer-associated risk loci. Some variants at these loci may be regulatory and influence expression of nearby genes. Such loci are known as cis-expression quantitative trait loci (cis-eQTL). As cis-eQTLs are highly tissue-specific, we asked if GWAS-identified prostate cancer risk loci are cis-eQTLs in human prostate tumor tissues. We investigated 50 prostate cancer samples for their genotype at 59 prostate cancer risk-associated single-nucleotide polymorphisms (SNPs) and performed cis-eQTL analysis of transcripts from paired primary tumors within two megabase windows. We tested 586 transcript-genotype associations, of which 27 were significant (false discovery rate ≤10%). An equivalent eQTL analysis of the same prostate cancer risk loci in lymphoblastoid cell lines did not result in any significant associations. The top-ranked cis-eQTL involved the IRX4 (Iroquois homeobox protein 4) transcript and rs12653946, tagged by rs10866528 in our study (P=4.91 × 10(-5)). Replication studies, linkage disequilibrium, and imputation analyses highlight population specificity at this locus. We independently validated IRX4 as a potential prostate cancer risk gene through cis-eQTL analysis of prostate cancer risk variants. Cis-eQTL analysis in relevant tissues, even with a small sample size, can be a powerful method to expedite functional follow-up of GWAS.
authors.affiliation: 1] Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA [2] Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Wasay M
authors.initials: WM
authors.lastname: Hussain
authors.affiliation: 1] Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA [2] Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Vijai
authors.affiliation: 1] Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA [2] Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Offit
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
authors.affiliation: 1] Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY, USA [2] Centre for Integrative Biology, CIBIO, University of Trento, Trento, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Demichelis
authors.affiliation: 1] Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA [2] Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Klein
mesh_terms: D002874:Chromosome Mapping; D015972:Gene Expression Regulation, Neoplastic; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics*; D040641:Quantitative Trait Loci
chemical_list: D005819:Genetic Markers; D018398:Homeodomain Proteins; C485533:IRX4 protein, human
references.citation: Cancer Epidemiol Biomarkers Prev. 2010 Aug;19(8):2035-42
references.pmid: 20696662
references.citation: Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9362-7
references.pmid: 19474294
references.citation: Nat Genet. 2010 Sep;42(9):751-4
references.pmid: 20676098
references.citation: Nat Genet. 2007 May;39(5):645-9
references.pmid: 17401363
references.citation: BMC Med Genet. 2007 Sep 19;8 Suppl 1:S6
references.pmid: 17903305
references.citation: Cancer Epidemiol Biomarkers Prev. 2012 Jan;21(1):212-6
references.pmid: 22056501
references.citation: Nat Rev Genet. 2010 Jul;11(7):499-511
references.pmid: 20517342
references.citation: Nature. 2007 Oct 18;449(7164):851-61
references.pmid: 17943122
references.citation: PLoS Genet. 2010 Nov 11;6(11):e1001204
references.pmid: 21085629
references.citation: PLoS Genet. 2010 Apr 01;6(4):e1000888
references.pmid: 20369019
references.citation: Nat Genet. 2012 May 20;44(6):685-9
references.pmid: 22610119
references.citation: Proc Natl Acad Sci U S A. 2012 Jul 10;109(28):11252-7
references.pmid: 22730461
references.citation: Nucleic Acids Res. 2010 Jun;38(10):3275-86
references.pmid: 20156996
references.citation: Nat Genet. 2009 Oct;41(10):1122-6
references.pmid: 19767754
references.citation: Nat Genet. 2007 May;39(5):638-44
references.pmid: 17401364
references.citation: Nature. 2010 Oct 28;467(7319):1061-73
references.pmid: 20981092
references.citation: Mol Cell Biol. 2001 Mar;21(5):1730-6
references.pmid: 11238910
references.citation: Genome Res. 2011 Jan;21(1):56-67
references.pmid: 21036922
references.citation: Bioinformatics. 2011 Jan 15;27(2):281-3
references.pmid: 21134889
references.citation: PLoS Genet. 2011 May;7(5):e1001387
references.pmid: 21637779
references.citation: Nature. 2004 Aug 12;430(7001):743-7
references.pmid: 15269782
references.citation: Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6686-91
references.pmid: 22496589
references.citation: Nat Genet. 2007 May;39(5):631-7
references.pmid: 17401366
references.citation: Nature. 2010 Sep 2;467(7311):52-8
references.pmid: 20811451
references.citation: PLoS Genet. 2011 Feb 03;7(2):e1002003
references.pmid: 21304890
references.citation: Nat Genet. 2008 Mar;40(3):310-5
references.pmid: 18264096
references.citation: PLoS Genet. 2009 Jun;5(6):e1000529
references.pmid: 19543373
references.citation: PLoS One. 2012;7(5):e37866
references.pmid: 22662242
references.citation: Nat Genet. 2007 Aug;39(8):977-83
references.pmid: 17603485
references.citation: Sci Transl Med. 2010 Dec 15;2(62):62ra92
references.pmid: 21160077
references.citation: Nat Genet. 2008 Mar;40(3):281-3
references.pmid: 18264098
references.citation: Cancer Epidemiol Biomarkers Prev. 2010 Jan;19(1):229-39
references.pmid: 20056642
references.citation: Carcinogenesis. 2012 Feb;33(2):356-60
references.pmid: 22114074
references.citation: Nat Genet. 2007 Oct;39(10):1217-24
references.pmid: 17873874
references.citation: Br J Cancer. 2011 Sep 6;105(6):864-9
references.pmid: 21829199
references.citation: Hum Mol Genet. 2009 Apr 1;18(7):1368-75
references.pmid: 19153072
references.citation: PLoS One. 2010 May 18;5(5):e10693
references.pmid: 20502693
references.citation: Hum Mol Genet. 2012 May 1;21(9):2076-85
references.pmid: 22323358
references.citation: PLoS One. 2011 Mar 29;6(3):e17539
references.pmid: 21479260
references.citation: Genes Cancer. 2010 Jun;1(6):555-9
references.pmid: 21779458
references.citation: Nat Genet. 2008 Mar;40(3):316-21
references.pmid: 18264097
references.citation: Science. 2012 Sep 7;337(6099):1190-5
references.pmid: 22955828
references.citation: Am J Hum Genet. 2007 Sep;81(3):559-75
references.pmid: 17701901
references.citation: Science. 1999 Feb 19;283(5405):1161-4
references.pmid: 10024241
references.citation: Bioinformatics. 2010 Sep 15;26(18):2336-7
references.pmid: 20634204
references.citation: Cancer Res. 2009 Jan 1;69(1):10-5
references.pmid: 19117981
references.citation: Am J Epidemiol. 2011 Dec 15;174(12):1391-5
references.pmid: 22085625
references.citation: Nature. 2003 Mar 20;422(6929):297-302
references.pmid: 12646919
references.citation: Nat Genet. 2003 Mar;33(3):422-5
references.pmid: 12567189
references.citation: Hum Mol Genet. 2011 Oct 1;20(19):3867-75
references.pmid: 21743057
references.citation: Science. 2009 Sep 4;325(5945):1246-50
references.pmid: 19644074
references.citation: Nat Genet. 2009 Oct;41(10):1116-21
references.pmid: 19767753