Characterising the loss-of-function impact of 5’ untranslated region variants in 15,708 individuals
Nicola Whiffin, Konrad J. Karczewski, Xiaolei Zhang, Sonia Chothani, Miriam J. Smith, D. Gareth Evans, Angharad M. Roberts, Nicholas M. Quaife, Sebastian Schäfer, Owen J. L. Rackham, Jessica Alföldi, Anne O’Donnell‐Luria, Laurent C. Francioli, Genome Aggregation Database Production Team, Irina M. Armean, Eric Banks, Louis Bergelson, Kristian Cibulskis, Ryan L. Collins, Kristen M. Connolly, Miguel Covarrubias, Beryl B. Cummings, Mark J. Daly, Stacey Donnelly, Yossi Farjoun, Steven Ferriera, Stacey Gabriel, Laura D. Gauthier, Jeff Gentry, Namrata Gupta, Thibault Jeandet, Diane Kaplan, Kristen M. Laricchia, Christopher Llanwarne, Eric Vallabh Minikel, Ruchi Munshi, Benjamin M. Neale, Sam Novod, Nikelle Petrillo, Timothy Poterba, David Roazen, Valentín Ruano-Rubio, Andrea Saltzman, Kaitlin E. Samocha, Molly Schleicher, Cotton Seed, Matthew Solomonson, José Soto, Grace Tiao, Kathleen Tibbetts, Charlotte Tolonen, Christopher Vittal, Gordon Wade, Arcturus Wang, Qingbo S. Wang, Nicholas A. Watts, Ben Weisburd, Carlos A. Aguilar‐Salinas, Tariq Ahmad, Christine M. Albert, Diego Ardissino, Gil Atzmon, John Barnard, Laurent Beaugerie, Emelia J. Benjamin, Michael Boehnke, Lori L. Bonnycastle, Erwin P. Böttinger, Donald W. Bowden, Matthew J. Bown, John C. Chambers, Juliana C.N. Chan, Daniel I. Chasman, Judy H. Cho, Mina K. Chung, Bruce M. Cohen, Adolfo Correa, Dana Dabelea, Mark J. Daly, Dawood Darbar, Ravindranath Duggirala, Josée Dupuis, Patrick T. Ellinor, Roberto Elosúa, Jeanette Erdmann, Tõnu Esko, Martti Färkkilâ, José C. Florez, André Franke, Gad Getz, Benjamin Gläser, Stephen J. Glatt, David Goldstein, Clicerio González, Leif Groop, Christopher Haiman, Craig L. Hanis, Matthew B. Harms, Mikko Hiltunen, Matti Holi
Abstract
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.