| Title: | A deep catalogue of protein-coding variation in 983,578 individuals |
| Journal: | Nature |
| Published: | 20 May 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/38768635/ |
| DOI: | https://doi.org/10.1038/s41586-024-07556-0 |
Publication 12040
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
Abstract
Rare coding variants that substantially affect function provide insights into the biology of a gene1-3. However, ascertaining the frequency of such variants requires large sample sizes4-8. Here we present a catalogue of human protein-coding variation, derived from exome sequencing of 983,578 individuals across diverse populations. In total, 23% of the Regeneron Genetics Center Million Exome (RGC-ME) data come from individuals of African, East Asian, Indigenous American, Middle Eastern and South Asian ancestry. The catalogue includes more than 10.4 million missense and 1.1 million predicted loss-of-function (pLOF) variants. We identify individuals with rare biallelic pLOF variants in 4,848 genes, 1,751 of which have not been previously reported. From precise quantitative estimates of selection against heterozygous loss of function (LOF), we identify 3,988 LOF-intolerant genes, including 86 that were previously assessed as tolerant and 1,153 that lack established disease annotation. We also define regions of missense depletion at high resolution. Notably, 1,482 genes have regions that are depleted of missense variants despite being tolerant of pLOF variants. Finally, we estimate that 3% of individuals have a clinically actionable genetic variant, and that 11,773 variants reported in ClinVar with unknown significance are likely to be deleterious cryptic splice sites. To facilitate variant interpretation and genetics-informed precision medicine, we make this resource of coding variation from the RGC-ME dataset publicly accessible through a variant allele frequency browser.</p>
263 Authors
- Gonçalo Abecasis
- Giovanni Coppola
- Andrew Deubler
- Aris Economides
- Adolfo Ferrando
- Luca A. Lotta
- Alan Shuldiner
- Katherine Siminovitch
- Christina Beechert
- Erin D. Brian
- Laura M. Cremona
- Hang Du
- Caitlin Forsythe
- Zhenhua Gu
- Kristy Guevara
- Michael Lattari
- Kia Manoochehri
- Prathyusha Challa
- Manasi Pradhan
- Raymond Reynoso
- Ricardo Schiavo
- Maria Sotiropoulos Padilla
- Chenggu Wang
- Sarah E. Wolf
- Amelia Averitt
- Nilanjana Banerjee
- Dadong Li
- Sameer Malhotra
- Justin Mower
- Mudasar Sarwar
- Jeffrey C. Staples
- Sean Yu
- Aaron Zhang
- Andrew Bunyea
- Krishna Pawan Punuru
- Sanjay Sreeram
- Gisu Eom
- Benjamin Sultan
- Rouel Lanche
- Vrushali Mahajan
- Eliot Austin
- Sean O'Keeffe
- Razvan Panea
- Tommy Polanco
- Ayesha Rasool
- Lance Zhang
- Evan Edelstein
- Ju Guan
- Olga Krasheninina
- Samantha Zarate
- Adam J. Mansfield
- Evan K. Maxwell
- Kathie Sun
- Manuel Allen Revez Ferreira
- Kathy Burch
- Adrian Campos
- Lei Chen
- Sam Choi
- Amy Damask
- Sheila Gaynor
- Benjamin Geraghty
- Arkopravo Ghosh
- Salvador Romero Martinez
- Christopher Gillies
- Lauren Gurski
- Joseph Herman
- Eric Jorgenson
- Michael Kessler
- Jack Kosmicki
- Nan Lin
- Adam Locke
- Priyanka Nakka
- Karl Landheer
- Olivier Delaneau
- Maya Ghoussaini
- Joelle Mbatchou
- Arden Moscati
- Aditeya Pandey
- Anita Pandit
- Charles Paulding
- Jonathan Ross
- Carlo Sidore
- Eli Stahl
- Maria Suciu
- Peter VandeHaar
- Sailaja Vedantam
- Scott Vrieze
- Jingning Zhang
- Rujin Wang
- Kuan-Han Wu
- Bin Ye
- Blair Zhang
- Andrey Ziyatdinov
- Yuxin Zou
- Kyoko Watanabe
- Mira Tang
- Brian Hobbs
- Jon Silver
- William Palmer
- Rita Guerreiro
- Amit Joshi
- Antoine Baldassari
- Cristen Willer
- Sarah Graham
- Ernst Mayerhofer
- Mary Haas
- Niek Verweij
- George Hindy
- Tanima De
- Parsa Akbari
- Luanluan Sun
- Olukayode Sosina
- Arthur Gilly
- Peter Dornbos
- Juan Rodriguez-Flores
- Moeen Riaz
- Gannie Tzoneva
- Momodou W. Jallow
- Anna Alkelai
- Ariane Ayer
- Veera Rajagopal
- Vijay Kumar
- Jacqueline Otto
- Neelroop Parikshak
- Aysegul Guvenek
- Jose Bras
- Silvia Alvarez
- Jessie Brown
- Jing He
- Hossein Khiabanian
- Joana Revez
- Kimberly Skead
- Valentina Zavala
- Lyndon J. Mitnaul
- Marcus B. Jones
- Esteban Chen
- Michelle G. LeBlanc
- Jason Mighty
- Nirupama Nishtala
- Nadia Rana
- Jennifer Rico-Varela
- Jaimee Hernandez
- Alison Fenney
- Randi Schwartz
- Jody Hankins
- Samuel Hart
- Ann Perez-Beals
- Gina Solari
- Johannie Rivera-Picart
- Michelle Pagan
- Sunilbe Siceron
- David Gwynne
- Jerome I. Rotter
- Robert Weinreb
- Jonathan L. Haines
- Margaret A. Pericak-Vance
- Dwight Stambolian
- Nir Barzilai
- Yousin Suh
- Zhengdong Zhang
- Elliot Hong
- Braxton Mitchell
- Nicholas B. Blackburn
- Simon Broadley
- Marzena J. Fabis-Pedrini
- Vilija G. Jokubaitis
- Allan G. Kermode
- Trevor J. Kilpatrick
- Jeanette Lechner-Scott
- Stephen Leslie
- Bennet J. McComish
- Allan Motyer
- Grant P. Parnell
- Rodney J. Scott
- Bruce V. Taylor
- Justin P. Rubio
- Danish Saleheen
- Ken Kaufman
- Leah Kottyan
- Lisa Martin
- Marc E. Rothenberg
- Abdullah Ali
- Azra Raza
- Jonathan Cohen
- Adam Glassman
- William E. Kraus
- Christopher B. Newgard
- Svati H. Shah
- Jamie Craig
- Alex Hewitt
- Naga Chalasani
- Tatiana Foroud
- Suthat Liangpunsakul
- Nancy J. Cox
- Eileen Dolan
- Omar El-Charif
- Lois B. Travis
- Heather Wheeler
- Eric Gamazon
- Lori Sakoda
- John Witte
- Kostantinos Lazaridis
- Adam Buchanan
- David J. Carey
- Christa L. Martin
- Michelle N. Meyer
- Kyle Retterer
- David Rolston
- Nirmala Akula
- Emily Besançon
- Sevilla D. Detera-Wadleigh
- Layla Kassem
- Francis J. McMahon
- Thomas G. Schulze
- Adam Gordon
- Maureen Smith
- John Varga
- Yuki Bradford
- Scott Damrauer
- Stephanie DerOhannessian
- Theodore Drivas
- Scott Dudek
- Joseph Dunn
- Ned Haubein
- Renae Judy
- Yi-An Ko
- Colleen Morse Kripke
- Meghan Livingstone
- Nawar Naseer
- Kyle P. Nerz
- Afiya Poindexter
- Marjorie Risman
- Salma Santos
- Giorgio Sirugo
- Julia Stephanowski
- Teo Tran
- Fred Vadivieso
- Anurag Verma
- Shefali S. Verma
- JoEllen Weaver
- Colin Wollack
- Daniel J. Rader
- Marylyn Ritchie
- Joan O'Brien
- Erwin Bottinger
- Judy Cho
- S. Louis Bridges
- Robert Kimberly
- Marlena Fejzo
- Richard A. Spritz
- James T. Elder
- Rajan P. Nair
- Philip Stuart
- Lam C. Tsoi
- Robert Dent
- Ruth McPherson
- Brendan Keating
- Erin E. Kershaw
- Georgios Papachristou
- David C. Whitcomb
- Shervin Assassi
- Maureen D. Mayes
- Eric D. Austin
1 Application
| Application ID | Title |
|---|---|
| 26041 | Large-Scale Sequencing in the UK Biobank to Facilitate Gene Discovery, Genome Sciences, and Precision Medicine |
Enabling scientific discoveries that improve human health