Rare Variants Association Analysis in Large-Scale Sequencing Studies at the Single Locus Level

Xinge Jessie Jeng, Zhongyin J Daye, Wenbin Lu, Jung Ying Tzeng

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Genetic association analyses of rare variants in next-generation sequencing (NGS) studies are fundamentally challenging due to the presence of a very large number of candidate variants at extremely low minor allele frequencies. Recent developments often focus on pooling multiple variants to provide association analysis at the gene instead of the locus level. Nonetheless, pinpointing individual variants is a critical goal for genomic researches as such information can facilitate the precise delineation of molecular mechanisms and functions of genetic factors on diseases. Due to the extreme rarity of mutations and high-dimensionality, significances of causal variants cannot easily stand out from those of noncausal ones. Consequently, standard false-positive control procedures, such as the Bonferroni and false discovery rate (FDR), are often impractical to apply, as a majority of the causal variants can only be identified along with a few but unknown number of noncausal variants. To provide informative analysis of individual variants in large-scale sequencing studies, we propose the Adaptive False-Negative Control (AFNC) procedure that can include a large proportion of causal variants with high confidence by introducing a novel statistical inquiry to determine those variants that can be confidently dispatched as noncausal. The AFNC provides a general framework that can accommodate for a variety of models and significance tests. The procedure is computationally efficient and can adapt to the underlying proportion of causal variants and quality of significance rankings. Extensive simulation studies across a plethora of scenarios demonstrate that the AFNC is advantageous for identifying individual rare variants, whereas the Bonferroni and FDR are exceedingly over-conservative for rare variants association studies. In the analyses of the CoLaus dataset, AFNC has identified individual variants most responsible for gene-level significances. Moreover, single-variant results using the AFNC have been successfully applied to infer related genes with annotation information.

Original languageEnglish (US)
Article numbere1004993
JournalPLoS Computational Biology
Volume12
Issue number6
DOIs
StatePublished - Jun 1 2016

Fingerprint

Sequencing
Locus
loci
gene
Molecular Sequence Annotation
genes
Genes
Bonferroni
rarity
Gene Frequency
ranking
gene frequency
Gene
mutation
genomics
allele
Proportion
Mutation
Genetic Association
Significance Test

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Modeling and Simulation
  • Ecology
  • Molecular Biology
  • Genetics
  • Cellular and Molecular Neuroscience
  • Computational Theory and Mathematics

Cite this

Rare Variants Association Analysis in Large-Scale Sequencing Studies at the Single Locus Level. / Jeng, Xinge Jessie; Daye, Zhongyin J; Lu, Wenbin; Tzeng, Jung Ying.

In: PLoS Computational Biology, Vol. 12, No. 6, e1004993, 01.06.2016.

Research output: Contribution to journalArticle

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