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Journal Articles Nature Year : 2020

Transcript expression-aware annotation improves rare variant interpretation

Beryl Cummings , Konrad Karczewski , Jack Kosmicki , Eleanor Seaby , Nicholas Watts , Moriel Singer-Berk , Jonathan Mudge , Juha Karjalainen , F. Kyle Satterstrom , Anne O’donnell-Luria , Timothy Poterba , Cotton Seed , Matthew Solomonson , Jessica Alföldi , Jessica Alföldi , Irina Armean , Eric Banks , Louis Bergelson , Kristian Cibulskis , Ryan Collins , Kristen Connolly , Miguel Covarrubias , Beryl Cummings , Mark Daly , Stacey Donnelly , Yossi Farjoun , Steven Ferriera , Laurent Francioli , Stacey Gabriel , Laura Gauthier , Jeff Gentry , Namrata Gupta , Thibault Jeandet , Diane Kaplan , Konrad Karczewski , Kristen Laricchia , Christopher Llanwarne , Eric Minikel , Ruchi Munshi , Benjamin Neale , Sam Novod , Anne O’donnell-Luria , Nikelle Petrillo , Timothy Poterba , David Roazen , Valentin Ruano-Rubio , Andrea Saltzman , Kaitlin Samocha , Molly Schleicher , Cotton Seed , Matthew Solomonson , Jose Soto , Grace Tiao , Kathleen Tibbetts , Charlotte Tolonen , Christopher Vittal , Gordon Wade , Arcturus Wang , Qingbo Wang , James Ware , Nicholas Watts , Ben Weisburd , Nicola Whiffin , Carlos Salinas , Tariq Ahmad , Christine Albert , Diego Ardissino , Gil Atzmon , John Barnard , Laurent Beaugerie , Emelia Benjamin , Michael Boehnke , Lori Bonnycastle , Erwin Bottinger , Donald Bowden , Matthew Bown , John Chambers , Juliana Chan , Daniel Chasman , Judy Cho , Mina Chung , Bruce Cohen , Adolfo Correa , Dana Dabelea , Mark Daly , Dawood Darbar , Ravindranath Duggirala , Josée Dupuis , Patrick Ellinor , Roberto Elosua , Jeanette Erdmann , Tõnu Esko , Martti Färkkilä , Jose Florez , Andre Franke , Gad Getz , Benjamin Glaser , Stephen Glatt , David Goldstein , Clicerio Gonzalez , Leif Groop , Christopher Haiman , Craig Hanis , Matthew Harms , Mikko Hiltunen , Matti Holi , Christina Hultman , Mikko Kallela , Jaakko Kaprio , Sekar Kathiresan , Bong-Jo Kim , Young Jin Kim , George Kirov , Jaspal Kooner , Seppo Koskinen , Harlan Krumholz , Subra Kugathasan , Soo Heon Kwak , Markku Laakso , Terho Lehtimäki , Ruth Loos , Steven Lubitz , Ronald Ma , Daniel Macarthur , Jaume Marrugat , Kari Mattila , Steven Mccarroll , Mark Mccarthy , Dermot Mcgovern , Ruth Mcpherson , James Meigs , Olle Melander , Andres Metspalu , Benjamin Neale , Peter Nilsson , Michael O’donovan , Dost Ongur , Lorena Orozco , Michael Owen , Colin Palmer , Aarno Palotie , Kyong Soo Park , Carlos Pato , Ann Pulver , Nazneen Rahman , Anne Remes , John Rioux , Samuli Ripatti , Dan Roden , Danish Saleheen , Veikko Salomaa , Nilesh Samani , Jeremiah Scharf , Heribert Schunkert , Moore Shoemaker , Pamela Sklar , Hilkka Soininen , Harry Sokol (1) , Tim Spector , Patrick Sullivan , Jaana Suvisaari , E. Shyong Tai , Yik Ying Teo , Tuomi Tiinamaija , Ming Tsuang , Dan Turner , Teresa Tusie-Luna , Erkki Vartiainen , Marquis Vawter , James Ware , Hugh Watkins , Rinse Weersma , Maija Wessman , James Wilson , Ramnik Xavier , Mark Daly , Daniel Macarthur
Beryl Cummings
Konrad Karczewski
Jack Kosmicki
  • Function : Author
Eleanor Seaby
  • Function : Author
Nicholas Watts
  • Function : Author
Moriel Singer-Berk
  • Function : Author
Jonathan Mudge
  • Function : Author
Juha Karjalainen
  • Function : Author
F. Kyle Satterstrom
Anne O’donnell-Luria
Timothy Poterba
  • Function : Author
Cotton Seed
  • Function : Author
Matthew Solomonson
  • Function : Author
Jessica Alföldi
Jessica Alföldi
  • Function : Author
Irina Armean
  • Function : Author
Eric Banks
  • Function : Author
Louis Bergelson
  • Function : Author
Kristian Cibulskis
  • Function : Author
Ryan Collins
  • Function : Author
Kristen Connolly
  • Function : Author
Miguel Covarrubias
  • Function : Author
Beryl Cummings
  • Function : Author
Mark Daly
  • Function : Author
Stacey Donnelly
  • Function : Author
Yossi Farjoun
  • Function : Author
Steven Ferriera
  • Function : Author
Laurent Francioli
  • Function : Author
Stacey Gabriel
  • Function : Author
Laura Gauthier
  • Function : Author
Jeff Gentry
  • Function : Author
Namrata Gupta
  • Function : Author
Thibault Jeandet
  • Function : Author
Diane Kaplan
  • Function : Author
Konrad Karczewski
  • Function : Author
Kristen Laricchia
  • Function : Author
Christopher Llanwarne
  • Function : Author
Eric Minikel
  • Function : Author
Ruchi Munshi
  • Function : Author
Benjamin Neale
  • Function : Author
Sam Novod
  • Function : Author
Anne O’donnell-Luria
  • Function : Author
Nikelle Petrillo
  • Function : Author
Timothy Poterba
  • Function : Author
David Roazen
  • Function : Author
Valentin Ruano-Rubio
  • Function : Author
Andrea Saltzman
  • Function : Author
Kaitlin Samocha
  • Function : Author
Molly Schleicher
  • Function : Author
Cotton Seed
  • Function : Author
Matthew Solomonson
  • Function : Author
Jose Soto
  • Function : Author
Grace Tiao
  • Function : Author
Kathleen Tibbetts
  • Function : Author
Charlotte Tolonen
  • Function : Author
Christopher Vittal
  • Function : Author
Gordon Wade
  • Function : Author
Arcturus Wang
  • Function : Author
Qingbo Wang
  • Function : Author
James Ware
  • Function : Author
Nicholas Watts
  • Function : Author
Ben Weisburd
  • Function : Author
Nicola Whiffin
  • Function : Author
Carlos Salinas
  • Function : Author
Tariq Ahmad
  • Function : Author
Christine Albert
  • Function : Author
Diego Ardissino
  • Function : Author
Gil Atzmon
  • Function : Author
John Barnard
  • Function : Author
Laurent Beaugerie
  • Function : Author
Emelia Benjamin
  • Function : Author
Michael Boehnke
  • Function : Author
Lori Bonnycastle
  • Function : Author
Erwin Bottinger
  • Function : Author
Donald Bowden
  • Function : Author
Matthew Bown
  • Function : Author
John Chambers
  • Function : Author
Juliana Chan
  • Function : Author
Daniel Chasman
  • Function : Author
Judy Cho
  • Function : Author
Mina Chung
  • Function : Author
Bruce Cohen
  • Function : Author
Adolfo Correa
  • Function : Author
Dana Dabelea
  • Function : Author
Mark Daly
  • Function : Author
Dawood Darbar
  • Function : Author
Ravindranath Duggirala
  • Function : Author
Josée Dupuis
  • Function : Author
Patrick Ellinor
  • Function : Author
Roberto Elosua
  • Function : Author
Jeanette Erdmann
  • Function : Author
Tõnu Esko
  • Function : Author
Martti Färkkilä
  • Function : Author
Jose Florez
  • Function : Author
Andre Franke
  • Function : Author
Gad Getz
  • Function : Author
Benjamin Glaser
  • Function : Author
Stephen Glatt
  • Function : Author
David Goldstein
  • Function : Author
Clicerio Gonzalez
  • Function : Author
Leif Groop
  • Function : Author
Christopher Haiman
  • Function : Author
Craig Hanis
  • Function : Author
Matthew Harms
  • Function : Author
Mikko Hiltunen
  • Function : Author
Matti Holi
  • Function : Author
Christina Hultman
  • Function : Author
Mikko Kallela
  • Function : Author
Jaakko Kaprio
  • Function : Author
Sekar Kathiresan
  • Function : Author
Bong-Jo Kim
  • Function : Author
Young Jin Kim
  • Function : Author
George Kirov
  • Function : Author
Jaspal Kooner
  • Function : Author
Seppo Koskinen
  • Function : Author
Harlan Krumholz
  • Function : Author
Subra Kugathasan
  • Function : Author
Soo Heon Kwak
  • Function : Author
Markku Laakso
  • Function : Author
Terho Lehtimäki
  • Function : Author
Ruth Loos
  • Function : Author
Steven Lubitz
  • Function : Author
Ronald Ma
  • Function : Author
Daniel Macarthur
  • Function : Author
Jaume Marrugat
  • Function : Author
Kari Mattila
  • Function : Author
Steven Mccarroll
  • Function : Author
Mark Mccarthy
  • Function : Author
Dermot Mcgovern
  • Function : Author
Ruth Mcpherson
  • Function : Author
James Meigs
  • Function : Author
Olle Melander
  • Function : Author
Andres Metspalu
  • Function : Author
Benjamin Neale
  • Function : Author
Peter Nilsson
  • Function : Author
Michael O’donovan
  • Function : Author
Dost Ongur
  • Function : Author
Lorena Orozco
  • Function : Author
Michael Owen
  • Function : Author
Colin Palmer
  • Function : Author
Aarno Palotie
  • Function : Author
Kyong Soo Park
  • Function : Author
Carlos Pato
  • Function : Author
Ann Pulver
  • Function : Author
Nazneen Rahman
  • Function : Author
Anne Remes
  • Function : Author
John Rioux
  • Function : Author
Samuli Ripatti
  • Function : Author
Dan Roden
  • Function : Author
Danish Saleheen
  • Function : Author
Veikko Salomaa
  • Function : Author
Nilesh Samani
  • Function : Author
Jeremiah Scharf
  • Function : Author
Heribert Schunkert
  • Function : Author
Moore Shoemaker
  • Function : Author
Pamela Sklar
  • Function : Author
Hilkka Soininen
  • Function : Author
Tim Spector
  • Function : Author
Patrick Sullivan
  • Function : Author
Jaana Suvisaari
  • Function : Author
E. Shyong Tai
  • Function : Author
Yik Ying Teo
  • Function : Author
Tuomi Tiinamaija
  • Function : Author
Ming Tsuang
  • Function : Author
Dan Turner
  • Function : Author
Teresa Tusie-Luna
  • Function : Author
Erkki Vartiainen
  • Function : Author
Marquis Vawter
  • Function : Author
James Ware
  • Function : Author
Hugh Watkins
  • Function : Author
Rinse Weersma
  • Function : Author
Maija Wessman
  • Function : Author
James Wilson
  • Function : Author
Ramnik Xavier
  • Function : Author
Mark Daly
Daniel Macarthur

Abstract

Abstract The acceleration of DNA sequencing in samples from patients and population studies has resulted in extensive catalogues of human genetic variation, but the interpretation of rare genetic variants remains problematic. A notable example of this challenge is the existence of disruptive variants in dosage-sensitive disease genes, even in apparently healthy individuals. Here, by manual curation of putative loss-of-function (pLoF) variants in haploinsufficient disease genes in the Genome Aggregation Database (gnomAD) 1 , we show that one explanation for this paradox involves alternative splicing of mRNA, which allows exons of a gene to be expressed at varying levels across different cell types. Currently, no existing annotation tool systematically incorporates information about exon expression into the interpretation of variants. We develop a transcript-level annotation metric known as the ‘proportion expressed across transcripts’, which quantifies isoform expression for variants. We calculate this metric using 11,706 tissue samples from the Genotype Tissue Expression (GTEx) project 2 and show that it can differentiate between weakly and highly evolutionarily conserved exons, a proxy for functional importance. We demonstrate that expression-based annotation selectively filters 22.8% of falsely annotated pLoF variants found in haploinsufficient disease genes in gnomAD, while removing less than 4% of high-confidence pathogenic variants in the same genes. Finally, we apply our expression filter to the analysis of de novo variants in patients with autism spectrum disorder and intellectual disability or developmental disorders to show that pLoF variants in weakly expressed regions have similar effect sizes to those of synonymous variants, whereas pLoF variants in highly expressed exons are most strongly enriched among cases. Our annotation is fast, flexible and generalizable, making it possible for any variant file to be annotated with any isoform expression dataset, and will be valuable for the genetic diagnosis of rare diseases, the analysis of rare variant burden in complex disorders, and the curation and prioritization of variants in recall-by-genotype studies.
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Dates and versions

hal-04007031 , version 1 (27-02-2023)

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Cite

Beryl Cummings, Konrad Karczewski, Jack Kosmicki, Eleanor Seaby, Nicholas Watts, et al.. Transcript expression-aware annotation improves rare variant interpretation. Nature, 2020, 581 (7809), pp.452-458. ⟨10.1038/s41586-020-2329-2⟩. ⟨hal-04007031⟩
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