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Identification of putative causal loci in whole-genome sequencing data via knockoff statistics.

Abstract
The analysis of whole-genome sequencing studies is challenging due to the large number of rare variants in noncoding regions and the lack of natural units for testing. We propose a statistical method to detect and localize rare and common risk variants in whole-genome sequencing studies based on a recently developed knockoff framework. It can (1) prioritize causal variants over associations due to linkage disequilibrium thereby improving interpretability; (2) help distinguish the signal due to rare variants from shadow effects of significant common variants nearby; (3) integrate multiple knockoffs for improved power, stability, and reproducibility; and (4) flexibly incorporate state-of-the-art and future association tests to achieve the benefits proposed here. In applications to whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP) and COPDGene samples from NHLBI Trans-Omics for Precision Medicine (TOPMed) Program we show that our method compared with conventional association tests can lead to substantially more discoveries.
AuthorsZihuai He, Linxi Liu, Chen Wang, Yann Le Guen, Justin Lee, Stephanie Gogarten, Fred Lu, Stephen Montgomery, Hua Tang, Edwin K Silverman, Michael H Cho, Michael Greicius, Iuliana Ionita-Laza
JournalNature communications (Nat Commun) Vol. 12 Issue 1 Pg. 3152 (05 25 2021) ISSN: 2041-1723 [Electronic] England
PMID34035245 (Publication Type: Evaluation Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
Topics
  • Algorithms
  • Causality
  • Computer Simulation
  • Data Interpretation, Statistical
  • Datasets as Topic
  • Genetic Loci
  • Genetic Predisposition to Disease
  • Genome, Human
  • Genome-Wide Association Study (methods)
  • Humans
  • Linkage Disequilibrium
  • Markov Chains
  • Models, Genetic
  • Polymorphism, Single Nucleotide
  • Reproducibility of Results
  • Whole Genome Sequencing (methods)

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