Characterising the loss-of-function impact of 5’ untranslated region variants in whole genome sequence data from 15,708 individuals
Whiffin N., Karczewski KJ., Zhang X., Chothani S., Smith MJ., Evans DG., Roberts AM., Quaife NM., Schafer S., Rackham O., Alföldi J., O’Donnell-Luria AH., Francioli LC., Alföldi J., Armean IM., Banks E., Bergelson L., Cibulskis K., Collins RL., Connolly KM., Covarrubias M., Cummings B., Daly MJ., Donnelly S., Farjoun Y., Ferriera S., Francioli L., Gabriel S., Gauthier LD., Gentry J., Gupta N., Jeandet T., Kaplan D., Karczewski KJ., Laricchia KM., Llanwarne C., Minikel EV., Munshi R., Neale BM., Novod S., O’Donnell-Luria AH., Petrillo N., Poterba T., Roazen D., Ruano-Rubio V., Saltzman A., Samocha KE., Schleicher M., Seed C., Solomonson M., Soto J., Tiao G., Tibbetts K., Tolonen C., Vittal C., Wade G., Wang A., Wang Q., Ware JS., Watts NA., Weisburd B., Whiffin N., Salinas CAA., Ahmad T., Albert CM., Ardissino D., Atzmon G., Barnard J., Beaugerie L., Benjamin EJ., Boehnke M., Bonnycastle LL., Bottinger EP., Bowden DW., Bown MJ., Chambers JC., Chan JC., Chasman D., Cho J., Chung MK., Cohen B., Correa A., Dabelea D., Daly MJ., Darbar D., Duggirala R., Dupuis J., Ellinor PT., Elosua R., Erdmann J., Esko T., Färkkilä M., Florez J., Franke A., Getz G., Glaser B., Glatt SJ., Goldstein D., Gonzalez C., Groop L., Haiman C., Hanis C., Harms M., Hiltunen M., Holi MM., Hultman CM., Kallela M., Kaprio J., Kathiresan S., Kim B-J., Kim YJ., Kirov G., Kooner J., Koskinen S., Krumholz HM., Kugathasan S., Kwak SH., Laakso M., Lehtimäki T., Loos RJF., Lubitz SA., Ma RCW., MacArthur DG., Marrugat J., Mattila KM., McCarroll S., McCarthy MI., McGovern D., McPherson R., Meigs JB., Melander O., Metspalu A., Neale BM., Nilsson PM., O’Donovan MC., Ongur D., Orozco L., Owen MJ., Palmer CNA., Palotie A., Park KS., Pato C., Pulver AE., Rahman N., Remes AM., Rioux JD., Ripatti S., Roden DM., Saleheen D., Salomaa V., Samani NJ., Scharf J., Schunkert H., Shoemaker MB., Sklar P., Soininen H., Soko H., Spector T., Sullivan PF., Suvisaari J., Tai ES., Teo YY., Tiinamaija T., Tsuang M., Turner D., Tusie-Luna T., Vartiainen E., Ware JS., Watkins H., Weersma RK., Wessman M., Wilson JG., Xavier RJ., Cook SA., Barton PJR., MacArthur DG., Ware JS.
<jats:title>Abstract</jats:title><jats:p>Upstream open reading frames (uORFs) are important tissue-specific <jats:italic>cis</jats:italic>-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 <jats:italic>NF2</jats:italic> 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.</jats:p>