Integrating human endogenous retroviruses into transcriptome-wide association studies highlights novel risk factors for major psychiatric conditions

Rodrigo R Rafagnin Duarte; Ollie Pain; Matthew   Bendall; Miguel  de Mulder Rougvie; Jez  Marston; Sashika Selvackadunco; Claire Troakes; Szi Kay Leung; Rosemary Bamford; Jonathan Mill; Paul F. O’reilly; Deepak Srivastava; Douglas F Nixon; Timothy Powell

doi:10.1038/s41467-024-48153-z

Integrating human endogenous retroviruses into transcriptome-wide association studies highlights novel risk factors for major psychiatric conditions

Rodrigo R Rafagnin Duarte, Ollie Pain, Matthew Bendall, Miguel de Mulder Rougvie, Jez Marston, Sashika Selvackadunco, Claire Troakes, Szi Kay Leung, Rosemary Bamford, Jonathan Mill, Paul F. O’reilly, Deepak Srivastava, Douglas F Nixon, Timothy Powell

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

204 Downloads (Pure)

Abstract

Human endogenous retroviruses (HERVs) are repetitive elements previously implicated in major psychiatric conditions, but their role in aetiology remains unclear. Here, we perform specialised transcriptome-wide association studies that consider HERV expression quantified to precise genomic locations, using RNA sequencing and genetic data from 792 post-mortem brain samples. In Europeans, we identify 1238 HERVs with expression regulated in cis, of which 26 represent expression signals associated with psychiatric disorders, with ten being conditionally independent from neighbouring expression signals. Of these, five are additionally significant in fine-mapping analyses and thus are considered high confidence risk HERVs. These include two HERV expression signatures specific to schizophrenia risk, one shared between schizophrenia and bipolar disorder, and one specific to major depressive disorder. No robust signatures are identified for autism spectrum conditions or attention deficit hyperactivity disorder in Europeans, or for any psychiatric trait in other ancestries, although this is likely a result of relatively limited statistical power. Ultimately, our study highlights extensive HERV expression and regulation in the adult cortex, including in association with psychiatric disorder risk, therefore providing a rationale for exploring neurological HERV expression in complex neuropsychiatric traits.

Original language	English
Article number	3803
Journal	Nature Communications
Volume	15
DOIs	https://doi.org/10.1038/s41467-024-48153-z
Publication status	Published - 22 May 2024

Access to Document

10.1038/s41467-024-48153-z

Integrating human endogenous retroviruses_Duarte_publishedonline22May2024_GOLD_VOR (CC BY-NC-ND)Final published version, 2.86 MBLicence: CC BY-NC-ND
Duarte et al., 2024Licence: CC BY

Cite this

Rafagnin Duarte, R. R., Pain, O., Bendall, M., de Mulder Rougvie, M., Marston, J., Selvackadunco, S., Troakes, C., Leung, S. K., Bamford, R., Mill, J., O’reilly, P. F., Srivastava, D., Nixon, D. F., & Powell, T. (2024). Integrating human endogenous retroviruses into transcriptome-wide association studies highlights novel risk factors for major psychiatric conditions. Nature Communications, 15, Article 3803. https://doi.org/10.1038/s41467-024-48153-z

@article{b01c04e3a56749339379e95a591f4a88,

title = "Integrating human endogenous retroviruses into transcriptome-wide association studies highlights novel risk factors for major psychiatric conditions",

abstract = "Human endogenous retroviruses (HERVs) are repetitive elements previously implicated in major psychiatric conditions, but their role in aetiology remains unclear. Here, we perform specialised transcriptome-wide association studies that consider HERV expression quantified to precise genomic locations, using RNA sequencing and genetic data from 792 post-mortem brain samples. In Europeans, we identify 1238 HERVs with expression regulated in cis, of which 26 represent expression signals associated with psychiatric disorders, with ten being conditionally independent from neighbouring expression signals. Of these, five are additionally significant in fine-mapping analyses and thus are considered high confidence risk HERVs. These include two HERV expression signatures specific to schizophrenia risk, one shared between schizophrenia and bipolar disorder, and one specific to major depressive disorder. No robust signatures are identified for autism spectrum conditions or attention deficit hyperactivity disorder in Europeans, or for any psychiatric trait in other ancestries, although this is likely a result of relatively limited statistical power. Ultimately, our study highlights extensive HERV expression and regulation in the adult cortex, including in association with psychiatric disorder risk, therefore providing a rationale for exploring neurological HERV expression in complex neuropsychiatric traits.",

author = "{Rafagnin Duarte}, {Rodrigo R} and Ollie Pain and Matthew Bendall and {de Mulder Rougvie}, Miguel and Jez Marston and Sashika Selvackadunco and Claire Troakes and Leung, {Szi Kay} and Rosemary Bamford and Jonathan Mill and O{\textquoteright}reilly, {Paul F.} and Deepak Srivastava and Nixon, {Douglas F} and Timothy Powell",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = may,

day = "22",

doi = "10.1038/s41467-024-48153-z",

language = "English",

volume = "15",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Rafagnin Duarte, RR , Pain, O, Bendall, M, de Mulder Rougvie, M, Marston, J, Selvackadunco, S, Troakes, C, Leung, SK, Bamford, R, Mill, J, O’reilly, PF, Srivastava, D, Nixon, DF & Powell, T 2024, 'Integrating human endogenous retroviruses into transcriptome-wide association studies highlights novel risk factors for major psychiatric conditions', Nature Communications, vol. 15, 3803. https://doi.org/10.1038/s41467-024-48153-z

TY - JOUR

T1 - Integrating human endogenous retroviruses into transcriptome-wide association studies highlights novel risk factors for major psychiatric conditions

AU - Rafagnin Duarte, Rodrigo R

AU - Pain, Ollie

AU - Bendall, Matthew

AU - de Mulder Rougvie, Miguel

AU - Marston, Jez

AU - Selvackadunco, Sashika

AU - Troakes, Claire

AU - Leung, Szi Kay

AU - Bamford, Rosemary

AU - Mill, Jonathan

AU - O’reilly, Paul F.

AU - Srivastava, Deepak

AU - Nixon, Douglas F

AU - Powell, Timothy

PY - 2024/5/22

Y1 - 2024/5/22

N2 - Human endogenous retroviruses (HERVs) are repetitive elements previously implicated in major psychiatric conditions, but their role in aetiology remains unclear. Here, we perform specialised transcriptome-wide association studies that consider HERV expression quantified to precise genomic locations, using RNA sequencing and genetic data from 792 post-mortem brain samples. In Europeans, we identify 1238 HERVs with expression regulated in cis, of which 26 represent expression signals associated with psychiatric disorders, with ten being conditionally independent from neighbouring expression signals. Of these, five are additionally significant in fine-mapping analyses and thus are considered high confidence risk HERVs. These include two HERV expression signatures specific to schizophrenia risk, one shared between schizophrenia and bipolar disorder, and one specific to major depressive disorder. No robust signatures are identified for autism spectrum conditions or attention deficit hyperactivity disorder in Europeans, or for any psychiatric trait in other ancestries, although this is likely a result of relatively limited statistical power. Ultimately, our study highlights extensive HERV expression and regulation in the adult cortex, including in association with psychiatric disorder risk, therefore providing a rationale for exploring neurological HERV expression in complex neuropsychiatric traits.

AB - Human endogenous retroviruses (HERVs) are repetitive elements previously implicated in major psychiatric conditions, but their role in aetiology remains unclear. Here, we perform specialised transcriptome-wide association studies that consider HERV expression quantified to precise genomic locations, using RNA sequencing and genetic data from 792 post-mortem brain samples. In Europeans, we identify 1238 HERVs with expression regulated in cis, of which 26 represent expression signals associated with psychiatric disorders, with ten being conditionally independent from neighbouring expression signals. Of these, five are additionally significant in fine-mapping analyses and thus are considered high confidence risk HERVs. These include two HERV expression signatures specific to schizophrenia risk, one shared between schizophrenia and bipolar disorder, and one specific to major depressive disorder. No robust signatures are identified for autism spectrum conditions or attention deficit hyperactivity disorder in Europeans, or for any psychiatric trait in other ancestries, although this is likely a result of relatively limited statistical power. Ultimately, our study highlights extensive HERV expression and regulation in the adult cortex, including in association with psychiatric disorder risk, therefore providing a rationale for exploring neurological HERV expression in complex neuropsychiatric traits.

UR - http://www.scopus.com/inward/record.url?scp=85194015243&partnerID=8YFLogxK

U2 - 10.1038/s41467-024-48153-z

DO - 10.1038/s41467-024-48153-z

M3 - Article

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

M1 - 3803

ER -

Integrating human endogenous retroviruses into transcriptome-wide association studies highlights novel risk factors for major psychiatric conditions

Abstract

Access to Document

Other files and links

Fingerprint

Cite this