Misexpression of inactive genes in whole blood is associated with nearby rare structural variants

Gene misexpression is the aberrant transcription of a gene in a context where it is usually inactive. Despite its known pathological consequences in specific rare diseases, we have a limited understanding of its wider prevalence and mechanisms in humans. To address this, we analyzed gene misexpression in 4,568 whole blood bulk RNA sequencing samples from INTERVAL study blood donors. We found that while individual misexpression events occur rarely, in aggregate they were found in almost all samples and over half of inactive genes. Using 2,821 paired whole genome and RNA sequencing samples, we identified that misexpression events are enriched in cis for rare structural variants. We established putative mechanisms through which a subset of SVs lead to gene misexpression, including transcriptional readthrough, transcript fusions and gene inversion. Overall, we develop misexpression as a novel type of transcriptomic outlier analysis and extend our understanding of the variety of mechanisms by which genetic variants can influence gene expression. ### Competing Interest Statement The authors declare the following interests: T.V. has received PhD studentship funding from AstraZeneca. J.M. completed this work while employed by the University of Cambridge, but is now an employee of Genomics plc. S.P. is a current employee and stockholder of AstraZeneca. D.J.R. is an employee of NHS Blood and Transplant. A.B. is currently an employee of Bayer AG, Research and Early Development Precision Medicine, Research & Development, Pharmaceutical Division, Wuppertal, DE. A.P. is a current employee and stockholder of AstraZeneca. D.S.P. is a current employee and stockholder of AstraZeneca. K. K. is a current employee and stockholder of AstraZeneca. J.D. serves on scientific advisory boards for AstraZeneca, Novartis, and UK Biobank, and has received multiple grants from academic, charitable and industry sources outside of the submitted work. M.I. is a trustee of the Public Health Genomics (PHG) Foundation, a member of the Scientific Advisory Board of Open Targets, and has a research collaboration with AstraZeneca which is unrelated to this study.