A joint association test for multiple SNPs in genetic case-control studies.
For a dense set of genetic markers such as single nucleotide polymorphisms (SNPs) on high linkage disequilibrium within a small candidate region, a haplotype-based approach for testing association between a disease phenotype and the set of markers is attractive in reducing the data complexity and increasing the statistical power. However, due to unknown status of the underlying disease variant, a comprehensive association test may require consideration of various combinations of the SNPs, which often leads to severe multiple testing problems. In this paper, we propose a latent variable approach to test for association of multiple tightly linked SNPs in case-control studies. First, we introduce a latent variable into the penetrance model to characterize a putative disease susceptible locus (DSL) that may consist of a marker allele, a haplotype from a subset of the markers, or an allele at a putative locus between the markers. Next, through using of a retrospective likelihood to adjust for the case-control sampling ascertainment and appropriately handle the Hardy-Weinberg equilibrium constraint, we develop an expectation-maximization (EM)-based algorithm to fit the penetrance model and estimate the joint haplotype frequencies of the DSL and markers simultaneously. With the latent variable to describe a flexible role of the DSL, the likelihood ratio statistic can then provide a joint association test for the set of markers without requiring an adjustment for testing of multiple haplotypes. Our simulation results also reveal that the latent variable approach may have improved power under certain scenarios comparing with classical haplotype association methods.
Wang
Tao
T
Division of Biostatistics, Department of Population Health, Medical College of Wisconsin, Milwaukee, Wisconsin 53226-0509, USA. taowang@mcw.edu
Jacob
Howard
H
Ghosh
Soumitra
S
Wang
Xujing
X
Zeng
Zhao-Bang
ZB
D000465:Algorithms; D000483:Alleles; D016022:Case-Control Studies; D005787:Gene Frequency; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D016013:Likelihood Functions; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008957:Models, Genetic; D015233:Models, Statistical; D017720:Molecular Epidemiology / Q000706:statistics & numerical data*; D020641:Polymorphism, Single Nucleotide
D005819:Genetic Markers
Am J Hum Genet. 2002 Feb;70(2):425-34
11791212
Genet Epidemiol. 2004 Dec;27(4):321-33
15368617
Hum Hered. 2003;55(1):56-65
12890927
Am J Hum Genet. 2003 Dec;73(6):1316-29
14631556
Genet Epidemiol. 2007 Jul;31(5):365-75
17326099
Am J Hum Genet. 2004 Oct;75(4):561-70
15290652
Genet Epidemiol. 2007 Jul;31(5):383-95
17410554
Hum Hered. 2002;53(2):79-91
12037407
Diabetes Care. 1998 Jun;21(6):949-58
9614613
Hum Hered. 2003;55(4):179-90
14566096
Stat Med. 2005 Nov 15;24(21):3289-310
16206241
Genet Epidemiol. 2005 Sep;29(2):108-27
16080203
Mol Biol Evol. 1995 Sep;12(5):921-7
7476138
Ann Hum Genet. 2006 Jul;70(Pt 4):506-23
16759182
Genet Epidemiol. 2004 Dec;27(4):348-64
15543638
Genetics. 1994 Apr;136(4):1457-68
8013918