title: Retrospective Binary-Trait Association Test Elucidates Genetic Architecture of Crohn Disease.
abstract: In genetic association testing, failure to properly control for population structure can lead to severely inflated type 1 error and power loss. Meanwhile, adjustment for relevant covariates is often desirable and sometimes necessary to protect against spurious association and to improve power. Many recent methods to account for population structure and covariates are based on linear mixed models (LMMs), which are primarily designed for quantitative traits. For binary traits, however, LMM is a misspecified model and can lead to deteriorated performance. We propose CARAT, a binary-trait association testing approach based on a mixed-effects quasi-likelihood framework, which exploits the dichotomous nature of the trait and achieves computational efficiency through estimating equations. We show in simulation studies that CARAT consistently outperforms existing methods and maintains high power in a wide range of population structure settings and trait models. Furthermore, CARAT is based on a retrospective approach, which is robust to misspecification of the phenotype model. We apply our approach to a genome-wide analysis of Crohn disease, in which we replicate association with 17 previously identified regions. Moreover, our analysis on 5p13.1, an extensively reported region of association, shows evidence for the presence of multiple independent association signals in the region. This example shows how CARAT can leverage known disease risk factors to shed light on the genetic architecture of complex traits.
authors.affiliation: Department of Statistics, Oregon State University, Corvallis, OR 97331, USA.
authors.forename: Duo
authors.initials: D
authors.lastname: Jiang
authors.affiliation: Department of Statistics, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhong
authors.affiliation: Department of Statistics, University of Chicago, Chicago, IL 60637, USA; Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA. Electronic address: mcpeek@uchicago.edu.
authors.forename: Mary Sara
authors.initials: MS
authors.lastname: McPeek
mesh_terms: D000328:Adult; D003424:Crohn Disease / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D044382:Population Groups / Q000235:genetics; D019655:Quantitative Trait, Heritable; D012189:Retrospective Studies; D055815:Young Adult
references.citation: Genet Epidemiol. 2010 Nov;34(7):769-71; author reply 772
references.pmid: 20878718
references.citation: Nature. 2001 May 31;411(6837):603-6
references.pmid: 11385577
references.citation: Nat Genet. 2007 Feb;39(2):207-11
references.pmid: 17200669
references.citation: Nature. 2008 Apr 3;452(7187):537-8
references.pmid: 18385720
references.citation: Nature. 2007 Jun 7;447(7145):661-78
references.pmid: 17554300
references.citation: Nat Genet. 2007 Jul;39(7):830-2
references.pmid: 17554261
references.citation: Nat Genet. 2006 Aug;38(8):904-9
references.pmid: 16862161
references.citation: Hum Mol Genet. 2005 May 15;14(10):1245-50
references.pmid: 15790594
references.citation: Biometrics. 1986 Mar;42(1):121-30
references.pmid: 3719049
references.citation: Genetica. 1995;96(1-2):3-12
references.pmid: 7607457
references.citation: Inflamm Bowel Dis. 2012 Dec;18(12):2277-87
references.pmid: 22411504
references.citation: Nature. 2012 Nov 1;491(7422):56-65
references.pmid: 23128226
references.citation: Nat Genet. 2012 Jul 22;44(8):955-9
references.pmid: 22820512
references.citation: Am J Hum Genet. 2015 May 7;96(5):720-30
references.pmid: 25892111
references.citation: Nat Genet. 2014 Feb;46(2):100-6
references.pmid: 24473328
references.citation: Am J Hum Genet. 2010 Feb 12;86(2):172-84
references.pmid: 20137780
references.citation: Nat Genet. 2012 Jun 17;44(7):821-4
references.pmid: 22706312
references.citation: Nat Methods. 2011 Sep 04;8(10):833-5
references.pmid: 21892150
references.citation: Nat Genet. 2008 Aug;40(8):955-62
references.pmid: 18587394
references.citation: Nature. 2001 May 31;411(6837):599-603
references.pmid: 11385576
references.citation: Nat Methods. 2015 Apr;12(4):332-4
references.pmid: 25664543
references.citation: Genet Epidemiol. 2010 Dec;34(8):816-34
references.pmid: 21058334
references.citation: Annu Rev Genomics Hum Genet. 2009;10:387-406
references.pmid: 19715440
references.citation: Nat Genet. 2010 Apr;42(4):348-54
references.pmid: 20208533
references.citation: Nat Genet. 2012 Feb 05;44(3):243-6
references.pmid: 22306651
references.citation: Am J Hum Genet. 2011 Dec 9;89(6):798-805
references.pmid: 22152681
references.citation: Bioinformatics. 2015 Mar 1;31(5):782-4
references.pmid: 25338720
references.citation: Nat Genet. 2015 May;47(5):550-4
references.pmid: 25822090
references.citation: PLoS Genet. 2012;8(3):e1002559
references.pmid: 22412388
references.citation: PLoS One. 2007 Sep 05;2(9):e819
references.pmid: 17786191
references.citation: Inflamm Bowel Dis. 2008 Aug;14(8):1118-24
references.pmid: 18338763
references.citation: PLoS One. 2007 Aug 08;2(8):e691
references.pmid: 17684544
references.citation: Nat Genet. 2010 Apr;42(4):355-60
references.pmid: 20208535
references.citation: PLoS One. 2009 Dec 01;4(12):e7928
references.pmid: 19956572
references.citation: J Hum Genet. 2007;52(7):575-583
references.pmid: 17534574
references.citation: Science. 2006 Dec 1;314(5804):1461-3
references.pmid: 17068223
references.citation: PLoS Genet. 2007 Apr 20;3(4):e58
references.pmid: 17447842
references.citation: Nat Genet. 2006 Feb;38(2):203-8
references.pmid: 16380716
references.citation: Genet Epidemiol. 2010 Jan;34(1):51-9
references.pmid: 19455578
references.citation: Nat Rev Genet. 2013 Apr;14(4):300
references.pmid: 23438871