Genotype-based association test for general pedigrees: the genotype-PDT.
Many family-based tests of linkage disequilibrium (LD) are based on counts of alleles rather than genotypes. However, allele-based tests may not detect interactions among alleles at a single locus that are apparent when examining associations with genotypes. Family-based tests of LD based on genotypes have been developed, but they are typically valid as tests of association only in families with a single affected individual. To take advantage of families with multiple affected individuals, we propose the genotype-pedigree disequilibrium test (geno-PDT) to test for LD between marker locus genotypes and disease. Unlike previous tests for genotypic association, the geno-PDT is valid in general pedigrees. Simulations to compare the power of the allele-based PDT and geno-PDT reveal that under an additive model, the allele-based PDT is more powerful, but that the geno-PDT can have greater power when the genetic model is recessive or dominant. Perhaps the most important property of the geno-PDT is the ability to test for association with particular genotypes, which can reveal underlying patterns of association at the genotypic level. These genotype-specific tests can be used to suggest possible underlying genetic models that are consistent with the pattern of genotypic association. This is illustrated through an application to a candidate gene analysis of the MLLT3 gene in families with Alzheimer disease. The geno-PDT approach for testing genotypes in general family data provides a useful tool for identifying genes in complex disease, and partitioning individual genotype contributions will help to dissect the influence of genotype on risk.
Martin
E R
ER
Center for Human Genetics, Duke University Medical Center, Durham, NC 27710, USA. eden.martin@duke.edu
Bass
M P
MP
Gilbert
J R
JR
Pericak-Vance
M A
MA
Hauser
E R
ER
D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics; D003198:Computer Simulation; D003627:Data Interpretation, Statistical; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008957:Models, Genetic; D015233:Models, Statistical; D010375:Pedigree; D013223:Statistics as Topic