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

Author

Listed:
  • Rodrigo R. R. Duarte

    (King’s College London
    Cornell University)

  • Oliver Pain

    (King’s College London)

  • Matthew L. Bendall

    (Cornell University)

  • Miguel Mulder Rougvie

    (Cornell University)

  • Jez L. Marston

    (Cornell University)

  • Sashika Selvackadunco

    (King’s College London
    King’s College London)

  • Claire Troakes

    (King’s College London
    King’s College London)

  • Szi Kay Leung

    (University of Exeter)

  • Rosemary A. Bamford

    (University of Exeter)

  • Jonathan Mill

    (University of Exeter)

  • Paul F. O’Reilly

    (Mount Sinai)

  • Deepak P. Srivastava

    (King’s College London
    King’s College London)

  • Douglas F. Nixon

    (Cornell University
    Northwell Health)

  • Timothy R. Powell

    (King’s College London
    Cornell University)

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.

Suggested Citation

  • Rodrigo R. R. Duarte & Oliver Pain & Matthew L. Bendall & Miguel Mulder Rougvie & Jez L. Marston & Sashika Selvackadunco & Claire Troakes & Szi Kay Leung & Rosemary A. Bamford & Jonathan Mill & Paul F, 2024. "Integrating human endogenous retroviruses into transcriptome-wide association studies highlights novel risk factors for major psychiatric conditions," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48153-z
    DOI: 10.1038/s41467-024-48153-z
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    References listed on IDEAS

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    1. Denis A Baird & Jimmy Z Liu & Jie Zheng & Solveig K Sieberts & Thanneer Perumal & Benjamin Elsworth & Tom G Richardson & Chia-Yen Chen & Minerva M Carrasquillo & Mariet Allen & Joseph S Reddy & Philip, 2021. "Identifying drug targets for neurological and psychiatric disease via genetics and the brain transcriptome," PLOS Genetics, Public Library of Science, vol. 17(1), pages 1-26, January.
    2. Oliver Pain & Kylie P Glanville & Saskia P Hagenaars & Saskia Selzam & Anna E Fürtjes & Héléna A Gaspar & Jonathan R I Coleman & Kaili Rimfeld & Gerome Breen & Robert Plomin & Lasse Folkersen & Cathry, 2021. "Evaluation of polygenic prediction methodology within a reference-standardized framework," PLOS Genetics, Public Library of Science, vol. 17(5), pages 1-22, May.
    3. Vassily Trubetskoy & Antonio F. Pardiñas & Ting Qi & Georgia Panagiotaropoulou & Swapnil Awasthi & Tim B. Bigdeli & Julien Bryois & Chia-Yen Chen & Charlotte A. Dennison & Lynsey S. Hall & Max Lam & K, 2022. "Mapping genomic loci implicates genes and synaptic biology in schizophrenia," Nature, Nature, vol. 604(7906), pages 502-508, April.
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