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@article{Whiffin:2019:10.1101/543504,
author = {Whiffin, N and Karczewski, KJ and Zhang, X and Chothani, S and Smith, MJ and Evans, DG and Roberts, AM and Quaife, NM and Schafer, S and Rackham, O and Alföldi, J and ODonnell-Luria, AH and Francioli, LC and Alföldi, J and Armean, IM and Banks, E and Bergelson, L and Cibulskis, K and Collins, RL and Connolly, KM and Covarrubias, M and Cummings, B and Daly, MJ and Donnelly, S and Farjoun, Y and Ferriera, S and Francioli, L and Gabriel, S and Gauthier, LD and Gentry, J and Gupta, N and Jeandet, T and Kaplan, D and Karczewski, KJ and Laricchia, KM and Llanwarne, C and Minikel, EV and Munshi, R and Neale, BM and Novod, S and ODonnell-Luria, AH and Petrillo, N and Poterba, T and Roazen, D and Ruano-Rubio, V and Saltzman, A and Samocha, KE and Schleicher, M and Seed, C and Solomonson, M and Soto, J and Tiao, G and Tibbetts, K and Tolonen, C and Vittal, C and Wade, G and Wang, A and Wang, Q and Ware, JS and Watts, NA and Weisburd, B and Whiffin, N and Salinas, CAA and Ahmad, T and Albert, CM },
doi = {10.1101/543504},
journal = {Nature Communications},
title = {Characterising the loss-of-function impact of 5’ untranslated region variants in whole genome sequence data from 15,708 individuals},
url = {http://dx.doi.org/10.1101/543504},
volume = {11},
year = {2019}
}

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TY  - JOUR
AB  - <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>
AU  - Whiffin,N
AU  - Karczewski,KJ
AU  - Zhang,X
AU  - Chothani,S
AU  - Smith,MJ
AU  - Evans,DG
AU  - Roberts,AM
AU  - Quaife,NM
AU  - Schafer,S
AU  - Rackham,O
AU  - Alföldi,J
AU  - ODonnell-Luria,AH
AU  - Francioli,LC
AU  - Alföldi,J
AU  - Armean,IM
AU  - Banks,E
AU  - Bergelson,L
AU  - Cibulskis,K
AU  - Collins,RL
AU  - Connolly,KM
AU  - Covarrubias,M
AU  - Cummings,B
AU  - Daly,MJ
AU  - Donnelly,S
AU  - Farjoun,Y
AU  - Ferriera,S
AU  - Francioli,L
AU  - Gabriel,S
AU  - Gauthier,LD
AU  - Gentry,J
AU  - Gupta,N
AU  - Jeandet,T
AU  - Kaplan,D
AU  - Karczewski,KJ
AU  - Laricchia,KM
AU  - Llanwarne,C
AU  - Minikel,EV
AU  - Munshi,R
AU  - Neale,BM
AU  - Novod,S
AU  - ODonnell-Luria,AH
AU  - Petrillo,N
AU  - Poterba,T
AU  - Roazen,D
AU  - Ruano-Rubio,V
AU  - Saltzman,A
AU  - Samocha,KE
AU  - Schleicher,M
AU  - Seed,C
AU  - Solomonson,M
AU  - Soto,J
AU  - Tiao,G
AU  - Tibbetts,K
AU  - Tolonen,C
AU  - Vittal,C
AU  - Wade,G
AU  - Wang,A
AU  - Wang,Q
AU  - Ware,JS
AU  - Watts,NA
AU  - Weisburd,B
AU  - Whiffin,N
AU  - Salinas,CAA
AU  - Ahmad,T
AU  - Albert,CM
AU  - Ardissino,D
AU  - Atzmon,G
AU  - Barnard,J
AU  - Beaugerie,L
AU  - Benjamin,EJ
AU  - Boehnke,M
AU  - Bonnycastle,LL
AU  - Bottinger,EP
AU  - Bowden,DW
AU  - Bown,MJ
AU  - Chambers,JC
AU  - Chan,JC
AU  - Chasman,D
AU  - Cho,J
AU  - Chung,MK
AU  - Cohen,B
AU  - Correa,A
AU  - Dabelea,D
AU  - Daly,MJ
AU  - Darbar,D
AU  - Duggirala,R
AU  - Dupuis,J
AU  - Ellinor,PT
AU  - Elosua,R
AU  - Erdmann,J
AU  - Esko,T
AU  - Färkkilä,M
AU  - Florez,J
AU  - Franke,A
AU  - Getz,G
AU  - Glaser,B
AU  - Glatt,SJ
AU  - Goldstein,D
AU  - Gonzalez,C
AU  - Groop,L
AU  - Haiman,C
AU  - Hanis,C
AU  - Harms,M
AU  - Hiltunen,M
AU  - Holi,MM
AU  - Hultman,CM
AU  - Kallela,M
AU  - Kaprio,J
AU  - Kathiresan,S
AU  - Kim,B-J
AU  - Kim,YJ
AU  - Kirov,G
AU  - Kooner,J
AU  - Koskinen,S
AU  - Krumholz,HM
AU  - Kugathasan,S
AU  - Kwak,SH
AU  - Laakso,M
AU  - Lehtimäki,T
AU  - Loos,RJF
AU  - Lubitz,SA
AU  - Ma,RCW
AU  - MacArthur,DG
AU  - Marrugat,J
AU  - Mattila,KM
AU  - McCarroll,S
AU  - McCarthy,MI
AU  - McGovern,D
AU  - McPherson,R
AU  - Meigs,JB
AU  - Melander,O
AU  - Metspalu,A
AU  - Neale,BM
AU  - Nilsson,PM
AU  - ODonovan,MC
AU  - Ongur,D
AU  - Orozco,L
AU  - Owen,MJ
AU  - Palmer,CNA
AU  - Palotie,A
AU  - Park,KS
AU  - Pato,C
AU  - Pulver,AE
AU  - Rahman,N
AU  - Remes,AM
AU  - Rioux,JD
AU  - Ripatti,S
AU  - Roden,DM
AU  - Saleheen,D
AU  - Salomaa,V
AU  - Samani,NJ
AU  - Scharf,J
AU  - Schunkert,H
AU  - Shoemaker,MB
AU  - Sklar,P
AU  - Soininen,H
AU  - Soko,H
AU  - Spector,T
AU  - Sullivan,PF
AU  - Suvisaari,J
AU  - Tai,ES
AU  - Teo,YY
AU  - Tiinamaija,T
AU  - Tsuang,M
AU  - Turner,D
AU  - Tusie-Luna,T
AU  - Vartiainen,E
AU  - Ware,JS
AU  - Watkins,H
AU  - Weersma,RK
AU  - Wessman,M
AU  - Wilson,JG
AU  - Xavier,RJ
AU  - Cook,SA
AU  - Barton,PJR
AU  - MacArthur,DG
AU  - Ware,JS
DO  - 10.1101/543504
PY  - 2019///
TI  - Characterising the loss-of-function impact of 5’ untranslated region variants in whole genome sequence data from 15,708 individuals
T2  - Nature Communications
UR  - http://dx.doi.org/10.1101/543504
UR  - http://hdl.handle.net/10044/1/70688
VL  - 11
ER  -

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