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

TitleMedical relevance of protein-truncating variants across 337,205 individuals in the UK Biobank study.
Publication TypeJournal Article
Year of Publication2018
AuthorsDeBoever, C, Tanigawa, Y, Lindholm, ME, McInnes, G, Lavertu, A, Ingelsson, E, Chang, C, Ashley, EA, Bustamante, CD, Daly, MJ, Rivas, MA
JournalNat Commun
Date Published2018 04 24
KeywordsDatabases, Nucleic Acid, Genome-Wide Association Study, Humans, Phenotype, Proteins, Sequence Deletion, United Kingdom

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.

Alternate JournalNat Commun
PubMed ID29691392
PubMed Central IDPMC5915386
Grant ListP30 DK043351 / DK / NIDDK NIH HHS / United States
MC_QA137853 / / Medical Research Council / United Kingdom
U01 HG007708 / HG / NHGRI NIH HHS / United States
U24 EB023674 / EB / NIBIB NIH HHS / United States
U01 HG009080 / HG / NHGRI NIH HHS / United States
U24 HG008956 / HG / NHGRI NIH HHS / United States
R01 HL135313 / HL / NHLBI NIH HHS / United States
T32 LM012409 / LM / NLM NIH HHS / United States