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Protein-truncating variants can have profound effects on gene function and are critical for clinical genome interpretation and generating therapeutic hypotheses, but their relevance to medical phenotypes has not been systematically assessed. Here, we characterize the effect of 18,228 protein-truncating variants across 135 phenotypes from the UK Biobank and find 27 associations between medical phenotypes and protein-truncating variants in genes outside the major histocompatibility complex. We perform phenome-wide analyses and directly measure the effect in homozygous carriers, commonly referred to as "human knockouts," across medical phenotypes for genes implicated as being protective against disease or associated with at least one phenotype in our study. We find several genes with strong pleiotropic or non-additive effects. Our results illustrate the importance of protein-truncating variants in a variety of diseases.

Titel:	Medical relevance of protein-truncating variants across 337,205 individuals in the UK Biobank study.
Autor/in / Beteiligte Person:	DeBoever, C ; Tanigawa, Y ; Lindholm, ME ; McInnes, G ; Lavertu, A ; Ingelsson, E ; Chang, C ; Ashley, EA ; Bustamante, CD ; Daly, MJ ; Rivas, MA
Link:	Full Text Finder (Volltext)
Zeitschrift:	Nature communications, Jg. 9 (2018-04-24), Heft 1, S. 1612
Veröffentlichung:	[London] : Nature Pub. Group, 2018
Medientyp:	academicJournal
ISSN:	2041-1723 (electronic)
DOI:	10.1038/s41467-018-03910-9
Schlagwort:	Genome-Wide Association Study Humans Phenotype United Kingdom Databases, Nucleic Acid statistics & numerical data Proteins genetics Sequence Deletion
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Nat Commun] 2018 Apr 24; Vol. 9 (1), pp. 1612. <i>Date of Electronic Publication: </i>2018 Apr 24. MeSH Terms: Databases, Nucleic Acid* / statistics & numerical data ; Sequence Deletion* ; Proteins / *genetics ; Genome-Wide Association Study ; Humans ; Phenotype ; United Kingdom References: BMJ. 2017 Apr 24;357:j1648. (PMID: 28438747) ; PLoS Genet. 2017 Mar 8;13(3):e1006659. (PMID: 28273074) ; Gigascience. 2017 May 1;6(5):1-10. (PMID: 28327993) ; Nat Genet. 2008 Oct;40(10):1160-2. (PMID: 18776911) ; Bioinformatics. 2010 May 1;26(9):1205-10. (PMID: 20335276) ; Nat Rev Endocrinol. 2017 Sep;13(9):503-504. (PMID: 28707678) ; Gut. 2014 Jan;63(1):143-51. (PMID: 23300138) ; Invest Ophthalmol Vis Sci. 2015 Aug;56(9):5087-93. (PMID: 26237198) ; Nat Genet. 2018 Apr;50(4):559-571. (PMID: 29632382) ; Science. 2012 Feb 17;335(6070):823-8. 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(PMID: 15284851) Grant Information: P30 DK043351 United States DK NIDDK NIH HHS; MC_QA137853 United Kingdom MRC_ Medical Research Council; U01 HG007708 United States HG NHGRI NIH HHS; U24 EB023674 United States EB NIBIB NIH HHS; U01 HG009080 United States HG NHGRI NIH HHS; MC_PC_17228 United Kingdom MRC_ Medical Research Council; U24 HG008956 United States HG NHGRI NIH HHS; R01 HL135313 United States HL NHLBI NIH HHS; T32 LM012409 United States LM NLM NIH HHS Substance Nomenclature: 0 (Proteins) Entry Date(s): Date Created: 20180426 Date Completed: 20190204 Latest Revision: 20210109 Update Code: 20231215 PubMed Central ID: PMC5915386

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Medical relevance of protein-truncating variants across 337,205 individuals in the UK Biobank study.