Emdin, Connor A.Elosua Llanos, RobertoKathiresan, Sekar2019-06-132019-06-132018Emdin CA, Khera AV, Chaffin M, Klarin D, Natarajan P, Aragam K. et al. Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease. Nat Commun. 2018 Apr 24;9(1):1613. DOI: 10.1038/s41467-018-03911-82041-1723http://hdl.handle.net/10230/41746Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease.application/pdfengThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.DiabetisFenotipMetabolismeinfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41467-018-03911-8info:eu-repo/semantics/openAccess