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Exome sequencing of healthy phenotypic extremes links TROVE2 to emotional memory and PTSD

Nature Human Behaviour volume 1, Article number: 0081 (2017) Cite this article

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Abstract

Many mental disorders represent the extremes of the normal distribution of traits, which are related to multiple cognitive and emotional dimensions. By performing whole-exome sequencing of healthy, young subjects with extremely high versus extremely low aversive memory performance, we identified TROVE2 as a gene implicated in emotional memory in health and disease. TROVE2 encodes Ro60, a broadly expressed RNA-binding protein implicated in the regulation of inflammatory gene expression and autoimmunity. A regulatory TROVE2 variant was linked to higher emotional memory capacity and higher emotional memory-related brain activation in healthy subjects. In addition, TROVE2 was associated with traumatic memory and the frequency of post-traumatic stress disorder in genocide survivors.

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Figure 1: Frequency histogram of aversive memory performance in 3,418 healthy, young adults.
Figure 2: Sequencing results of TROVE2 (positions according to the GRCh37/hg19 coordinates).
Figure 3: TROVE2 rs72740218 genotype-dependent differences in brain activity related to successful memory encoding of aversive stimuli compared with neutral stimuli in 1,258 healthy young subjects.
Figure 4: Association of TROVE2 SNPs rs72740218 and rs6692342 in the human frontal cortex.
Figure 5: Schematic representation of selected TROVE2 RefSeq transcript variants (positions according to GRCh37/hg19 coordinates).

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Acknowledgements

This work was funded by the University of Basel, the Swiss National Science Foundation (grants 163434, 147570 and 159740 to D.J.-F.d.Q. and A.P.), the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement 602450 (IMAGEMEND; grant to A.P. and D.J.-F.d.Q.), the Novartis Foundation for medical-biological Research (grant 15C219 to A.P.), and by the German Research Foundation (Deutsche Forschungsgemeinschaft; grants to I.-T.K. and T.El.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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Author notes

  1. Dominique J.-F. de Quervain and Andreas Papassotiropoulos: These authors jointly supervised this work.

Authors and Affiliations

  1. Division of Molecular Neuroscience, Department of Psychology, University of Basel, Basel, CH-4055, Switzerland.

    Angela Heck, Annette Milnik, Vanja Vukojevic, Jana Petrovska, Tobias Egli, Virginie Freytag, Philippe Demougin, Francina Hartmann, Bernardo Delarue Bizzini, Christian Vogler & Andreas Papassotiropoulos

  2. Transfaculty Research Platform Molecular and Cognitive Neurosciences, University of Basel, Basel, CH-4055, Switzerland.

    Angela Heck, Annette Milnik, Vanja Vukojevic, Jana Petrovska, Tobias Egli, David Coynel, Virginie Freytag, Matthias Fastenrath, Philippe Demougin, Eva Loos, Francina Hartmann, Nathalie Schicktanz, Bernardo Delarue Bizzini, Christian Vogler, Dominique J.-F. de Quervain & Andreas Papassotiropoulos

  3. Psychiatric University Clinics, University of Basel, Basel, CH-4055, Switzerland.

    Angela Heck, Annette Milnik, Christian Vogler, Dominique J.-F. de Quervain & Andreas Papassotiropoulos

  4. Department Biozentrum, Life Sciences Training Facility, University of Basel, Basel, CH-4056, Switzerland.

    Vanja Vukojevic, Philippe Demougin, Bernardo Delarue Bizzini & Andreas Papassotiropoulos

  5. Department of Biosystems Science and Engineering, ETH Zurich, Basel, CH-4058, Switzerland.

    Jochen Singer, Christian Beisel & Niko Beerenwinkel

  6. SIB Swiss Institute of Bioinformatics, Basel, CH-4056, Switzerland.

    Jochen Singer, Pablo Escobar, Thierry Sengstag, Torsten Schwede & Niko Beerenwinkel

  7. Department Biozentrum, University of Basel, Basel, CH-4056, Switzerland.

    Pablo Escobar, Thierry Sengstag & Torsten Schwede

  8. sciCORE Center for Scientific Computing, University of Basel, Basel, CH-4056, Switzerland.

    Pablo Escobar, Thierry Sengstag & Torsten Schwede

  9. Division of Cognitive Neuroscience, Department of Psychology, University of Basel, Basel, CH-4055, Switzerland.

    David Coynel, Matthias Fastenrath, Eva Loos, Nathalie Schicktanz & Dominique J.-F. de Quervain

  10. Clinical & Biological Psychology, Institute of Psychology & Education, Ulm University, Ulm, D-89069, Germany.

    Iris-Tatjana Kolassa & Sarah Wilker

  11. Department of Psychology, University of Konstanz, Konstanz, D-78457, Germany.

    Thomas Elbert

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Contributions

A.P., D.J.-F.d.Q., A.H., A.M. and M.F. conceived and designed the study. A.H., A.M., V.V., J.P., T.Eg., J.S., D.C., V.F., M.F., P.D., E.L., F.H., N.S., B.D.B., C.V., I.-T.K., S.W., T.El., D.J.-F.d.Q. and A.P. analysed the data. P.E., T.Se., T.Sc., C.B. and N.B. provided bioinformatic support. A.P., A.H. and D.J.-F.d.Q. wrote the manuscript. All authors reviewed and approved the final manuscript.

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Correspondence to Angela Heck or Andreas Papassotiropoulos.

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Heck, A., Milnik, A., Vukojevic, V. et al. Exome sequencing of healthy phenotypic extremes links TROVE2 to emotional memory and PTSD. Nat Hum Behav 1, 0081 (2017). https://doi.org/10.1038/s41562-017-0081

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