Characterising the loss-of-function impact of 5’ untranslated region variants in whole genome sequence data from 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 (gnomAD) Production Team, Alföldi Jessica , 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 , Francioli Laurent , Gabriel Stacey , Gauthier Laura D. , Gentry Jeff , Gupta Namrata , Jeandet Thibault , Kaplan Diane , Karczewski Konrad J. , Laricchia Kristen M. , Llanwarne Christopher , Minikel Eric V. , Munshi Ruchi , Neale Benjamin M , Novod Sam , O’Donnell-Luria Anne H. , 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 , Ware James S , Watts Nicholas A , Weisburd Ben , Whiffin Nicola ,   Genome Aggregation Database (gnomAD) Consortium, Salinas Carlos A Aguilar , 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. , MacArthur Daniel G. , 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 , Soko 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 , Ware James S , Watkins Hugh , Weersma Rinse K , Wessman Maija , Wilson James G. , Xavier Ramnik J. , Cook Stuart A , Barton Paul J R , MacArthur Daniel G , Ware James S 
Published: February 2019

Upstream open reading frames (uORFs) are important tissue-specific cis-regulators of protein translation. Although isolated case reports have shown that variants that create or disrupt uORFs can cause disease, genetic sequencing approaches typically focus on protein-coding regions and ignore these variants. Here, we describe a systematic genome-wide study of variants that create and disrupt human uORFs, and explore their role in human disease using 15,708 whole genome sequences collected by the Genome Aggregation Database (gnomAD) project. We show that 14,897 variants that create new start codons upstream of the canonical coding sequence (CDS), and 2,406 variants disrupting the stop site of existing uORFs, are under strong negative selection. Furthermore, variants creating uORFs that overlap the CDS show signals of selection equivalent to coding loss-of-function variants, and uORF-perturbing variants are under strong selection when arising upstream of known disease genes and genes intolerant to loss-of-function variants. Finally, we identify specific genes where perturbation of uORFs is likely to represent an important disease mechanism, and report a novel uORF frameshift variant upstream of NF2 in families with neurofibromatosis. Our results highlight uORF-perturbing variants as an important and under-recognised functional class that can contribute to penetrant human disease, and demonstrate the power of large-scale population sequencing data to study the deleteriousness of specific classes of non-coding variants.