Leveraging ancestry to improve causal variant identification in exome sequencing for monogenic disorders

Robert Brown, Hane Lee, Ascia Eskin, Gleb Kichaev, Kirk E. Lohmueller, Bruno Reversade, Stanley F. Nelson, Bogdan Pasaniuc

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Recent breakthroughs in exome-sequencing technology have made possible the identification of many causal variants of monogenic disorders. Although extremely powerful when closely related individuals (eg, child and parents) are simultaneously sequenced, sequencing of a single case is often unsuccessful due to the large number of variants that need to be followed up for functional validation. Many approaches filter out common variants above a given frequency threshold (eg, 1%), and then prioritize the remaining variants according to their functional, structural and conservation properties. Here we present methods that leverage the genetic structure across different populations to improve filtering performance while accounting for the finite sample size of the reference panels. We show that leveraging genetic structure reduces the number of variants that need to be followed up by 16% in simulations and by up to 38% in empirical data of 20 exomes from individuals with monogenic disorders for which the causal variants are known.
Original languageEnglish (US)
Pages (from-to)113-119
Number of pages7
JournalEuropean Journal of Human Genetics
Volume24
Issue number1
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

Bibliographical note

Generated from Scopus record by KAUST IRTS on 2023-02-15

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