%0 Journal Article
%T Misexpression of inactive genes in whole blood is associated with nearby rare structural variants.
%A Vanderstichele T
%A Burnham KL
%A de Klein N
%A Tardaguila M
%A Howell B
%A Walter K
%A Kundu K
%A Koeppel J
%A Lee W
%A Tokolyi A
%A Persyn E
%A Nath AP
%A Marten J
%A Petrovski S
%A Roberts DJ
%A Di Angelantonio E
%A Danesh J
%A Berton A
%A Platt A
%A Butterworth AS
%A Soranzo N
%A Parts L
%A Inouye M
%A Paul DS
%A Davenport EE
%J Am J Hum Genet
%V 111
%N 8
%D 2024 Aug 8
%M 39053458
%F 11.043
%R 10.1016/j.ajhg.2024.06.017
%X 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 a third of inactive protein-coding 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 type of transcriptomic outlier analysis and extend our understanding of the variety of mechanisms by which genetic variants can influence gene expression.