Single-marker and two-marker association tests for unphased case-control genotype data, with a power comparison.
In case-control single nucleotide polymorphism (SNP) data, the allele frequency, Hardy Weinberg Disequilibrium, and linkage disequilibrium (LD) contrast tests are three distinct sources of information about genetic association. While all three tests are typically developed in a retrospective context, we show that prospective logistic regression models may be developed that correspond conceptually to the retrospective tests. This approach provides a flexible framework for conducting a systematic series of association analyses using unphased genotype data and any number of covariates. For a single stage study, two single-marker tests and four two-marker tests are discussed. The true association models are derived and they allow us to understand why a model with only a linear term will generally fit well for a SNP in weak LD with a causal SNP, whatever the disease model, but not for a SNP in high LD with a non-additive disease SNP. We investigate the power of the association tests using real LD parameters from chromosome 11 in the HapMap CEU population data. Among the single-marker tests, the allelic test has on average the most power in the case of an additive disease, but for dominant, recessive, and heterozygote disadvantage diseases, the genotypic test has the most power. Among the four two-marker tests, the Allelic-LD contrast test, which incorporates linear terms for two markers and their interaction term, provides the most reliable power overall for the cases studied. Therefore, our result supports incorporating an interaction term as well as linear terms in multi-marker tests.
Kim
Sulgi
S
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106-7281, USA.
Morris
Nathan J
NJ
Won
Sungho
S
Elston
Robert C
RC
D000483:Alleles; D016022:Case-Control Studies; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D003627:Data Interpretation, Statistical; D005787:Gene Frequency; D005819:Genetic Markers; D055106:Genome-Wide Association Study / Q000379:methods* / Q000706:statistics & numerical data; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008957:Models, Genetic; D015233:Models, Statistical; D019683:Penetrance; D020641:Polymorphism, Single Nucleotide
D005819:Genetic Markers