Characterising the loss-of-function impact of 5’ untranslated region variants in 15,708 individuals
Authors: Whiffin Nicola , Karczewski Konrad J. , Zhang Xiaolei , Chothani Sonia , Smith Miriam J. , Evans D. Gareth , Roberts Angharad M. , Quaife Nicholas M. , Schafer Sebastian , Rackham Owen , Alföldi Jessica , O’Donnell-Luria Anne H. , Francioli Laurent C. ,   Genome Aggregation Database Production Team, Armean Irina M. , Banks Eric , Bergelson Louis , Cibulskis Kristian , Collins Ryan L. , Connolly Kristen M. , Covarrubias Miguel , Cummings Beryl , Daly Mark J. , Donnelly Stacey , Farjoun Yossi , Ferriera Steven , Gabriel Stacey , Gauthier Laura D. , Gentry Jeff , Gupta Namrata , Jeandet Thibault , Kaplan Diane , Laricchia Kristen M. , Llanwarne Christopher , Minikel Eric V. , Munshi Ruchi , Neale Benjamin M. , Novod Sam , Petrillo Nikelle , Poterba Timothy , Roazen David , Ruano-Rubio Valentin , Saltzman Andrea , Samocha Kaitlin E. , Schleicher Molly , Seed Cotton , Solomonson Matthew , Soto Jose , Tiao Grace , Tibbetts Kathleen , Tolonen Charlotte , Vittal Christopher , Wade Gordon , Wang Arcturus , Wang Qingbo , Watts Nicholas A. , Weisburd Ben ,   Genome Aggregation Database Consortium, Aguilar Salinas Carlos A. , Ahmad Tariq , Albert Christine M. , Ardissino Diego , Atzmon Gil , Barnard John , Beaugerie Laurent , Benjamin Emelia J. , Boehnke Michael , Bonnycastle Lori L. , Bottinger Erwin P. , Bowden Donald W. , Bown Matthew J. , Chambers John C. , Chan Juliana C. , Chasman Daniel , Cho Judy , Chung Mina K. , Cohen Bruce , Correa Adolfo , Dabelea Dana , Daly Mark J. , Darbar Dawood , Duggirala Ravindranath , Dupuis Josée , Ellinor Patrick T. , Elosua Roberto , Erdmann Jeanette , Esko Tõnu , Färkkilä Martti , Florez Jose , Franke Andre , Getz Gad , Glaser Benjamin , Glatt Stephen J. , Goldstein David , Gonzalez Clicerio , Groop Leif , Haiman Christopher , Hanis Craig , Harms Matthew , Hiltunen Mikko , Holi Matti M. , Hultman Christina M. , Kallela Mikko , Kaprio Jaakko , Kathiresan Sekar , Kim Bong-Jo , Kim Young Jin , Kirov George , Kooner Jaspal , Koskinen Seppo , Krumholz Harlan M. , Kugathasan Subra , Kwak Soo Heon , Laakso Markku , Lehtimäki Terho , Loos Ruth J. F. , Lubitz Steven A. , Ma Ronald C. W. , Marrugat Jaume , Mattila Kari M. , McCarroll Steven , McCarthy Mark I. , McGovern Dermot , McPherson Ruth , Meigs James B. , Melander Olle , Metspalu Andres , Neale Benjamin M. , Nilsson Peter M. , O’Donovan Michael C. , Ongur Dost , Orozco Lorena , Owen Michael J. , Palmer Colin N. A. , Palotie Aarno , Park Kyong Soo , Pato Carlos , Pulver Ann E. , Rahman Nazneen , Remes Anne M. , Rioux John D. , Ripatti Samuli , Roden Dan M. , Saleheen Danish , Salomaa Veikko , Samani Nilesh J. , Scharf Jeremiah , Schunkert Heribert , Shoemaker Moore B. , Sklar Pamela , Soininen Hilkka , Sokol Harry , Spector Tim , Sullivan Patrick F. , Suvisaari Jaana , Tai E. Shyong , Teo Yik Ying , Tiinamaija Tuomi , Tsuang Ming , Turner Dan , Tusie-Luna Teresa , Vartiainen Erkki , Watkins Hugh , Weersma Rinse K. , Wessman Maija , Wilson James G. , Xavier Ramnik J. , Vawter Marquis P. , Cook Stuart A. , Barton Paul J. R. , MacArthur Daniel G. , Ware James S. 
Published: May 2020

Upstream open reading frames (uORFs) are tissue-specific cis-regulators of protein translation. Isolated reports have shown that variants that create or disrupt uORFs can cause disease. Here, in a systematic genome-wide study using 15,708 whole genome sequences, we show that variants that create new upstream start codons, and variants disrupting stop sites of existing uORFs, are under strong negative selection. This selection signal is significantly stronger for variants arising upstream of genes intolerant to loss-of-function variants. Furthermore, variants creating uORFs that overlap the coding sequence show signals of selection equivalent to coding missense variants. Finally, we identify specific genes where modification of uORFs likely represents an important disease mechanism, and report a novel uORF frameshift variant upstream of NF2 in neurofibromatosis. Our results highlight uORF-perturbing variants as an under-recognised functional class that contribute to penetrant human disease, and demonstrate the power of large-scale population sequencing data in studying non-coding variant classes.