gTDT

gTDT performs gene-based or group-wise transmission/disequilibrium tests (TDT) to detect associations of rare genetic variants in family-based sequencing studies.

Key Features:

• Robustness Against Population Stratification: Uses family-based transmission tests to control for population stratification and admixture, reducing spurious associations.
• Haplotype-Based Framework: Constructs haplotypes by transmission when possible and aggregates signals at the haplotype level, accounting for linkage disequilibrium among variants.
• Flexibility Across Genetic Models: Supports six genetic models (M1–M6), including additive, dominant, and compound heterozygous (recessive) models.
• Increased Analytical Power and Type I Error Control: Simulation studies demonstrate correct type I error control under investigated models, including with population stratification, and higher power than single-marker TDT.
• Application to Trio Exome Data: Applied to autism exome sequencing data from 118 trios, identifying candidate genes with compound heterozygous rare variants.
• Implementation: Implemented in C++.

Scientific Applications:

• Rare Variant Association Studies in Family-Based Sequencing: Detects gene- or group-level associations of rare variants using family-based designs.
• Detection of Compound Heterozygous Effects: Identifies compound heterozygous rare variant associations, as demonstrated in autism trio exome analysis.

Methodology:

Performs gene- or group-wise TDT using a haplotype-based framework that constructs haplotypes by transmission when possible, evaluates six genetic models (M1–M6), and was assessed by simulation studies for type I error control and power; implemented in C++.