Genotype-based association test for general pedigrees: the genotype-PDT.

Area of Science:

• Genetics
• Biostatistics
• Complex Disease Research

Background:

• Family-based linkage disequilibrium (LD) tests often use allele counts, potentially missing locus interactions detectable with genotypes.
• Existing genotype-based tests are limited, typically valid only for families with a single affected individual.

Purpose of the Study:

• To introduce the genotype-pedigree disequilibrium test (geno-PDT) for testing LD between marker genotypes and disease in general pedigrees.
• To enable the analysis of families with multiple affected individuals, overcoming limitations of previous methods.

Main Methods:

• The proposed genotype-pedigree disequilibrium test (geno-PDT) is applied to general pedigrees.
• Simulations compare the power of the allele-based pedigree disequilibrium test (PDT) and the geno-PDT under various genetic models.
• The geno-PDT is applied to a candidate gene analysis for Alzheimer disease.

Main Results:

• The geno-PDT is valid in general pedigrees, accommodating families with multiple affected individuals.
• Under additive models, the allele-based PDT is more powerful; however, the geno-PDT shows greater power for recessive or dominant models.
• Genotype-specific tests within geno-PDT can reveal association patterns and suggest underlying genetic models.

Conclusions:

• The geno-PDT is a valuable tool for identifying genes associated with complex diseases using general family data.
• Partitioning individual genotype contributions aids in dissecting the influence of genotype on disease risk.
• The method was successfully illustrated in a candidate gene analysis for Alzheimer disease.