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

Rui Chen, Qiang Wei, Xiaowei Zhan, Xue Zhong, James S. Sutcliffe, Nancy J. Cox, Edwin H. Cook, Chun Li, Wei Chen, Bingshan Li

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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

Original languageEnglish (US)
Pages (from-to)1452-1459
Number of pages8
JournalBioinformatics
Volume31
Issue number9
DOIs
StatePublished - Nov 5 2014

Fingerprint

Haplotype
Genetic Models
Haplotypes
Stratification
Population
Exome
Linkage Disequilibrium
Sequencing
Medical Genetics
Autistic Disorder
Genes
Gene
Model
Type I error
Collapsing
Test Statistic
Eliminate
Flexibility
Power (Psychology)
Framework

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Computational Theory and Mathematics
  • Computer Science Applications
  • Computational Mathematics
  • Statistics and Probability

Cite this

A haplotype-based framework for group-wise transmission/disequilibrium tests for rare variant association analysis. / Chen, Rui; Wei, Qiang; Zhan, Xiaowei; Zhong, Xue; Sutcliffe, James S.; Cox, Nancy J.; Cook, Edwin H.; Li, Chun; Chen, Wei; Li, Bingshan.

In: Bioinformatics, Vol. 31, No. 9, 05.11.2014, p. 1452-1459.

Research output: Contribution to journalArticle

Chen, R, Wei, Q, Zhan, X, Zhong, X, Sutcliffe, JS, Cox, NJ, Cook, EH, Li, C, Chen, W & Li, B 2014, 'A haplotype-based framework for group-wise transmission/disequilibrium tests for rare variant association analysis', Bioinformatics, vol. 31, no. 9, pp. 1452-1459. https://doi.org/10.1093/bioinformatics/btu860
Chen, Rui ; Wei, Qiang ; Zhan, Xiaowei ; Zhong, Xue ; Sutcliffe, James S. ; Cox, Nancy J. ; Cook, Edwin H. ; Li, Chun ; Chen, Wei ; Li, Bingshan. / A haplotype-based framework for group-wise transmission/disequilibrium tests for rare variant association analysis. In: Bioinformatics. 2014 ; Vol. 31, No. 9. pp. 1452-1459.
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