A haplotype-based framework for group-wise transmission/disequilibrium tests for rare variant association analysis

摘要: Motivation: A major focus of current sequencing studies for human genetics is to identify rare variants associated with complex diseases. Aside from reduced power detecting variants, controlling population stratification particularly challenging variants. Transmission/disequilibrium tests (TDT) based on family designs are robust and admixture, therefore provide an effective approach variant association eliminate spurious associations. To increase analysis, gene-based collapsing methods become standard approaches analyzing Existing that extend this strategy in families usually combine TDT statistics at individual lack the flexibility incorporating other genetic models. Results: In study, we describe a haplotype-based framework group-wise (gTDT) flexible encompass variety models such as additive, dominant compound heterozygous (CH) (i.e. recessive) well interactions. Unlike existing methods, gTDT constructs haplotypes by transmission when possible inherently takes into account linkage disequilibrium among Through extensive simulations showed type I error was correctly controlled under all investigated, remained true presence stratification. Under models, increased compared single marker TDT. Application autism exome data 118 trios identified potentially interesting candidate genes CH variants. Availability implementation: We implemented C++ source code detailed usage available authors’ website (https://medschool.vanderbilt.edu/cgg). Contact: ude.tlibrednav@il.nahsgnib or ude.phc@nehc.iew Supplementary information: Supplementary Bioinformatics online.