title: Application of a novel score test for genetic association incorporating gene-gene interaction suggests functionality for prostate cancer susceptibility regions.
abstract: OBJECTIVE
  We introduce an innovative multilocus test for disease association. It is an extension of an existing score test that gains power over alternative methods by incorporating a parsimonious one-degree-of-freedom model for interaction. We use our method in applications designed to detect interactions that generate hypotheses about the functionality of prostate cancer (PRCA) susceptibility regions.
  
  
  METHODS
  Our proposed score test is designed to gain additional power through the use of a retrospective likelihood that exploits an assumption of independence between unlinked loci in the underlying population. Its performance is validated through simulation. The method is used in conditional scans with data from stage II of the Cancer Genetic Markers of Susceptibility PRCA genome-wide association study.
  
  
  RESULTS
  Our proposed method increases power to detect susceptibility loci in diverse settings. It identified two high-ranking, biologically interesting interactions: (1) rs748120 of NR2C2 and subregions of 8q24 that contain independent susceptibility loci specific to PRCA and (2) rs4810671 of SULF2 and both JAZF1 and HNF1B that are associated with PRCA and type 2 diabetes.
  
  
  CONCLUSIONS
  Our score test is a promising multilocus tool for genetic epidemiology. The results of our applications suggest functionality for poorly understood PRCA susceptibility regions. They motivate replication study.
authors.affiliation: Epidemiology and Biostatistics Program, Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD 20852, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Ciampa
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.forename: Kevin
authors.initials: K
authors.lastname: Jacobs
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Thun
authors.forename: Susan
authors.initials: S
authors.lastname: Gapstur
authors.forename: Demetrius
authors.initials: D
authors.lastname: Albanes
authors.forename: Jarmo
authors.initials: J
authors.lastname: Virtamo
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Weinstein
authors.forename: Edward
authors.initials: E
authors.lastname: Giovannucci
authors.forename: Walter C
authors.initials: WC
authors.lastname: Willett
authors.forename: Geraldine
authors.initials: G
authors.lastname: Cancel-Tassin
authors.forename: Olivier
authors.initials: O
authors.lastname: Cussenot
authors.forename: Antoine
authors.initials: A
authors.lastname: Valeri
authors.forename: David
authors.initials: D
authors.lastname: Hunter
authors.forename: Robert
authors.initials: R
authors.lastname: Hoover
authors.forename: Gilles
authors.initials: G
authors.lastname: Thomas
authors.forename: Stephen
authors.initials: S
authors.lastname: Chanock
authors.forename: Chris
authors.initials: C
authors.lastname: Holmes
authors.forename: Nilanjan
authors.initials: N
authors.lastname: Chatterjee
mesh_terms: D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D004843:Epistasis, Genetic; D052138:Genes, Neoplasm / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D015894:Genome, Human / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D009367:Neoplasm Staging; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D012044:Regression Analysis
references.citation: Am J Hum Genet. 2010 Mar 12;86(3):331-42
references.pmid: 20206333
references.citation: Am J Epidemiol. 2009 Jan 15;169(2):219-26
references.pmid: 19022827
references.citation: Genome Res. 2003 Mar;13(3):413-21
references.pmid: 12618372
references.citation: Nat Genet. 2007 Aug;39(8):977-83
references.pmid: 17603485
references.citation: Nat Genet. 2010 Nov;42(11):985-90
references.pmid: 20953190
references.citation: J Pathol. 2010 Mar;220(4):452-60
references.pmid: 19960500
references.citation: Genetics. 1976 Feb;82(2):349-76
references.pmid: 1261797
references.citation: Acta Diabetol. 2010 Jun;47(2):87-95
references.pmid: 20376506
references.citation: Stat Med. 1997 Aug 15;16(15):1731-43
references.pmid: 9265696
references.citation: Cancer Prev Res (Phila). 2010 Mar;3(3):259-62
references.pmid: 20179295
references.citation: Diabetes Metab Res Rev. 2001 Nov-Dec;17(6):412-21
references.pmid: 11757076
references.citation: PLoS Genet. 2006 Sep 22;2(9):e157
references.pmid: 17002500
references.citation: Am J Hum Genet. 2003 Dec;73(6):1316-29
references.pmid: 14631556
references.citation: Genet Epidemiol. 2004 Nov;27(3):202-14
references.pmid: 15389929
references.citation: J Biol Chem. 2005 Dec 2;280(48):40066-73
references.pmid: 16192265
references.citation: PLoS One. 2007 Apr 25;2(4):e392
references.pmid: 17460759
references.citation: Diabetologia. 2008 Oct;51(10):1757-60
references.pmid: 18696045
references.citation: Cancer Lett. 2006 Jun 8;237(1):22-32
references.pmid: 16023783
references.citation: Nat Genet. 2008 Mar;40(3):310-5
references.pmid: 18264096
references.citation: Genet Epidemiol. 2007 Dec;31(8):894-909
references.pmid: 17654599
references.citation: Cancer Res. 2011 May 1;71(9):3287-95
references.pmid: 21372204
references.citation: Neoplasia. 2005 Nov;7(11):1001-10
references.pmid: 16331886
references.citation: Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):14724-9
references.pmid: 10611280
references.citation: Nat Genet. 2007 May;39(5):645-9
references.pmid: 17401363
references.citation: Diabetes Care. 2001 Apr;24(4):672-7
references.pmid: 11315829
references.citation: Biometrics. 2008 Sep;64(3):685-694
references.pmid: 18162111
references.citation: Am J Epidemiol. 2009 Feb 15;169(4):497-504
references.pmid: 19074774
references.citation: Mol Cancer. 2006 Mar 01;5:9
references.pmid: 16507112
references.citation: J Surg Res. 1999 Jan;81(1):42-7
references.pmid: 9889056
references.citation: J Biol Chem. 1999 Jun 4;274(23):16198-205
references.pmid: 10347174
references.citation: Front Biosci. 2001 Jul 01;6:D820-48
references.pmid: 11438443
references.citation: Nat Genet. 2005 Apr;37(4):413-7
references.pmid: 15793588
references.citation: Oncogene. 2008 Dec 4;27(57):7180-91
references.pmid: 18794802
references.citation: Nat Genet. 2005 Jan;37(1):77-83
references.pmid: 15592468
references.citation: Nat Genet. 2009 Oct;41(10):1055-7
references.pmid: 19767755
references.citation: Stat Med. 1994 Jan 30;13(2):153-62
references.pmid: 8122051
references.citation: Biostatistics. 2011 Jul;12(3):582-93
references.pmid: 21209154
references.citation: J Natl Cancer Inst. 2001 Oct 3;93(19):1484-91
references.pmid: 11584065
references.citation: Science. 2004 Feb 6;303(5659):808-13
references.pmid: 14764870
references.citation: Nature. 1999 Dec 2;402(6761 Suppl):C47-52
references.pmid: 10591225
references.citation: Annu Rev Nutr. 2002;22:139-66
references.pmid: 12055341
references.citation: Cancer Causes Control. 2006 Oct;17(8):1091-101
references.pmid: 16933060
references.citation: Evolution. 2002 Mar;56(3):642-53
references.pmid: 11989692
references.citation: Hepatology. 2008 Apr;47(4):1211-22
references.pmid: 18318435
references.citation: Am J Epidemiol. 1996 Aug 1;144(3):207-13
references.pmid: 8686689
references.citation: Diabetologia. 2006 Oct;49(10):2453-62
references.pmid: 16896944
references.citation: PLoS Genet. 2011 Mar;7(3):e1001338
references.pmid: 21437271
references.citation: Cancer Res. 1999 Sep 1;59(17):4216-8
references.pmid: 10485458
references.citation: Mol Cell Biol. 2008 Oct;28(19):5986-95
references.pmid: 18662995
references.citation: Oncogene. 2010 Feb 4;29(5):635-46
references.pmid: 19855436
references.citation: Am J Epidemiol. 2001 Oct 15;154(8):687-93
references.pmid: 11590080
references.citation: PLoS Genet. 2009 Aug;5(8):e1000597
references.pmid: 19680443
references.citation: Hum Hered. 2007;63(2):111-9
references.pmid: 17283440
references.citation: Endocr Relat Cancer. 2004 Dec;11(4):709-24
references.pmid: 15613447
references.citation: Hum Hered. 2010;69(3):193-201
references.pmid: 20203524
references.citation: Carcinogenesis. 2009 Aug;30(8):1372-9
references.pmid: 19528667
references.citation: J Natl Cancer Inst. 2008 Jul 2;100(13):962-6
references.pmid: 18577746
references.citation: Am J Hum Genet. 2006 Dec;79(6):1002-16
references.pmid: 17186459