RT Journal Article
SR Electronic
T1 Schizophrenia risk from locus-specific human endogenous retroviruses
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 798017
DO 10.1101/798017
A1 Rodrigo R.R. Duarte
A1 Matthew L. Bendall
A1 Miguel de Mulder
A1 Christopher E. Ormsby
A1 Greta A. Beckerle
A1 Sashika Selvackadunco
A1 Claire Troakes
A1 Gustavo Reyes-Terán
A1 Keith A. Crandall
A1 Deepak P. Srivastava
A1 Douglas F. Nixon
A1 Timothy R. Powell
YR 2019
UL http://biorxiv.org/content/early/2019/10/08/798017.abstract
AB Schizophrenia genome-wide association studies highlight the substantial contribution of risk attributed to the non-coding genome where human endogenous retroviruses (HERVs) are encoded. These ancient viral elements have previously been overlooked in genetic and transcriptomic studies due to their poor annotation and repetitive nature. Using a new, comprehensive HERV annotation, we found that the fraction of the genome where HERVs are located (the ‘retrogenome’) is enriched for schizophrenia risk variants, and that there are 148 disparate HERVs involved in susceptibility. Analysis of RNA-sequencing data from the dorsolateral prefrontal cortex of 259 schizophrenia cases and 279 controls from the CommonMind Consortium showed that HERVs are actively expressed in the brain (n = 3,979), regulated in cis by common genetic variants (n = 1,759), and differentially expressed in patients (n = 81). Convergent analyses implicate LTR25_6q21 and ERVLE_8q24.3h as HERVs of etiological relevance to schizophrenia, which are co-regulated with genes involved in neuronal and mitochondrial function, respectively. Our findings provide a strong rationale for exploring the retrogenome and the expression of these locus-specific HERVs as novel risk factors for schizophrenia and potential diagnostic biomarkers and treatment targets.