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.

  • Subscribe to Nature Human Behaviour for full access:

    $99

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

References

  1. 1.

    . in Memory and Emotion (Weidenfeld and Nicolson, 2003).

  2. 2.

    Post-traumatic stress disorder, hormones, and memory. Biol. Psychiatry 26, 221–223 (1989).

  3. 3.

    & Contributions of the amygdala to emotion processing: from animal models to human behavior. Neuron 48, 175–187 (2005).

  4. 4.

    , & A dual representation theory of posttraumatic stress disorder. Psychol. Rev. 103, 670–686 (1996).

  5. 5.

    , , & Intrusive images in psychological disorders: characteristics, neural mechanisms, and treatment implications. Psychol. Rev. 117, 210–232 (2010).

  6. 6.

    et al. A deletion variant of the α2b-adrenoceptor is related to emotional memory in Europeans and Africans. Nat. Neurosci. 10, 1137–1139 (2007).

  7. 7.

    et al. PKCα is genetically linked to memory capacity in healthy subjects and to risk for posttraumatic stress disorder in genocide survivors. Proc. Natl Acad. Sci. USA 109, 8746–8751 (2012).

  8. 8.

    et al. Deletion variant in the ADRA2B gene increases coupling between emotional responses at encoding and later retrieval of emotional memories. Neurobiol. Learn Mem. 112, 222–229 (2014).

  9. 9.

    , , & Genetic differences in emotionally enhanced memory. Neuropsychologia 49, 734–744 (2011).

  10. 10.

    et al. Human genome-guided identification of memory-modulating drugs. Proc. Natl Acad. Sci. USA 110, E4369–E4374 (2013).

  11. 11.

    , , , & The BclI polymorphism of the glucocorticoid receptor gene is associated with emotional memory performance in healthy individuals. Psychoneuroendocrinology 38, 1203–1207 (2013).

  12. 12.

    , , , & Alpha 2B adrenoceptor genotype moderates effect of reboxetine on negative emotional memory bias in healthy volunteers. J. Neurosci. 33, 17023–17028 (2013).

  13. 13.

    & FKBP5 risk alleles and the development of intrusive memories. Neurobiol. Learn. Mem. 125, 258–264 (2015).

  14. 14.

    , & The downside of strong emotional memories: how human memory-related genes influence the risk for posttraumatic stress disorder—a selective review. Neurobiol. Learn. Mem. 112, 75–86 (2014).

  15. 15.

    et al. Exome sequencing and the genetic basis of complex traits. Nat. Genet. 44, 623–630 (2012).

  16. 16.

    , , & The role and challenges of exome sequencing in studies of human diseases. Front. Genet. 4, 160 (2013).

  17. 17.

    et al. Phenotypic extremes in rare variant study designs. Eur. J. Hum. Genet. 24, 924–930 (2016).

  18. 18.

    , , , & Using extreme phenotype sampling to identify the rare causal variants of quantitative traits in association studies. Genet. Epidemiol. 35, 790–799 (2011).

  19. 19.

    & Rare variant association studies: considerations, challenges and opportunities. Genome Med. 7, 16 (2015).

  20. 20.

    et al. Power in the phenotypic extremes: a simulation study of power in discovery and replication of rare variants. Genet. Epidemiol. 35, 236–246 (2011).

  21. 21.

    et al. Exome sequencing of extreme phenotypes identifies DCTN4 as a modifier of chronic Pseudomonas aeruginosa infection in cystic fibrosis. Nat. Genet. 44, 886–889 (2012).

  22. 22.

    et al. Optimal unified approach for rare-variant association testing with application to small-sample case-control whole-exome sequencing studies. Am. J. Hum. Genet. 91, 224–237 (2012).

  23. 23.

    et al. Genetic variability in the regulation of gene expression in ten regions of the human brain. Nat. Neurosci. 17, 1418–1428 (2014).

  24. 24.

    et al. Quality control parameters on a large dataset of regionally dissected human control brains for whole genome expression studies. J. Neurochem. 119, 275–282 (2011).

  25. 25.

    & Cognitive neuroscience of emotional memory. Nat. Rev. Neurosci. 7, 54–64 (2006).

  26. 26.

    Retrieval of emotional memories. Psychol. Bull. 133, 761–779 (2007).

  27. 27.

    , , , & Genetic and environmental influences on trauma exposure and posttraumatic stress disorder symptoms: a twin study. Am. J. Psychiatry 159, 1675–1681 (2002).

  28. 28.

    , , & The validation of a self-report measure of posttraumatic stress disorder: The posttraumatic diagnostic scale. Psychol. Assess. 9, 445–451 (1997).

  29. 29.

    et al. An anatomically comprehensive atlas of the adult human brain transcriptome. Nature 489, 391–399 (2012).

  30. 30.

    et al. The UCSC genome browser database: 2016 update. Nucleic Acids Res. 44, D717–D725 (2016).

  31. 31.

    UniProt: a hub for protein information. Nucleic Acids Res. 43, D204–D212 (2015).

  32. 32.

    , & Emotional processing in anterior cingulate and medial prefrontal cortex. Trends Cogn. Sci. 15, 85–93 (2011).

  33. 33.

    , , & fMRI studies of successful emotional memory encoding: a quantitative meta-analysis. Neuropsychologia 48, 3459–3469 (2010).

  34. 34.

    et al. Increased anterior cingulate cortex and hippocampus activation in complex PTSD during encoding of negative words. Soc. Cogn. Affect. Neurosci. 8, 190–200 (2013).

  35. 35.

    et al. Emotion modulation in PTSD: clinical and neurobiological evidence for a dissociative subtype. Am. J. Psychiatry 167, 640–647 (2010).

  36. 36.

    , & Latest update on the Ro/SS-A autoantibody system. Autoimmun. Rev. 8, 632–637 (2009).

  37. 37.

    & Resolution of the identity of certain antigen–antibody systems in systemic lupus erythematosus and Sjogren’s syndrome: an interlaboratory collaboration. Arthritis Rheum. 22, 796–798 (1979).

  38. 38.

    , & Characterization of a soluble cytoplasmic antigen reactive with sera from patients with systemic lupus erythmatosus. J. Immunol. 102, 117–122 (1969).

  39. 39.

    et al. The Ro60 autoantigen binds endogenous retroelements and regulates inflammatory gene expression. Science 350, 455–459 (2015).

  40. 40.

    et al. Elevated risk for autoimmune disorders in Iraq and Afghanistan veterans with posttraumatic stress disorder. Biol. Psychiatry 77, 365–374 (2015).

  41. 41.

    et al. Genome-wide association studies of posttraumatic stress disorder in 2 cohorts of US army soldiers. JAMA Psychiatry 73, 695–704 (2016).

  42. 42.

    et al. Assessment of plasma C-reactive protein as a biomarker of posttraumatic stress disorder risk. JAMA Psychiatry 71, 423–431 (2014).

  43. 43.

    et al. Association of CRP genetic variation and CRP level with elevated PTSD symptoms and physiological responses in a civilian population with high levels of trauma. Am. J. Psychiatry 172, 353–362 (2015).

  44. 44.

    et al. Differential immune system DNA methylation and cytokine regulation in post-traumatic stress disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 156B, 700–708 (2011).

  45. 45.

    et al. Proinflammatory milieu in combat-related PTSD is independent of depression and early life stress. Brain Behav. Immun. 42, 81–88 (2014).

  46. 46.

    et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341 (2015).

  47. 47.

    et al. Regulation of learning and memory by meningeal immunity: a key role for IL-4. J. Exp. Med. 207, 1067–1080 (2010).

  48. 48.

    et al. Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour. Nature 535, 425–429 (2016).

  49. 49.

    et al. Genome-wide gene-based analysis suggests an association between Neuroligin 1 (NLGN1) and post-traumatic stress disorder. Transl. Psychiatry 6, e820 (2016).

  50. 50.

    et al. Genome-wide association study of posttraumatic stress disorder in a cohort of Iraq–Afghanistan era veterans. J. Affect. Disord. 184, 225–234 (2015).

  51. 51.

    et al. Genomic predictors of combat stress vulnerability and resilience in U.S. marines: a genome-wide association study across multiple ancestries implicates PRTFDC1 as a potential PTSD gene. Psychoneuroendocrinology 51, 459–471 (2015).

  52. 52.

    et al. A genome-wide identified risk variant for PTSD is a methylation quantitative trait locus and confers decreased cortical activation to fearful faces. Am. J. Med. Genet. B Neuropsychiatr. Genet. 168B, 327–336 (2015).

  53. 53.

    et al. A genome-wide association study of post-traumatic stress disorder identifies the retinoid-related orphan receptor alpha (RORA) gene as a significant risk locus. Mol. Psychiatry 18, 937–942 (2013).

  54. 54.

    et al. Genome-wide association study identifies new susceptibility loci for posttraumatic stress disorder. Biol. Psychiatry 74, 656–663 (2013).

  55. 55.

    et al. Genome-wide association study implicates a novel RNA gene, the lincRNA AC068718.1, as a risk factor for post-traumatic stress disorder in women. Psychoneuroendocrinology 38, 3029–3038 (2013).

  56. 56.

    et al. The psychiatric genomics consortium posttraumatic stress disorder workgroup: posttraumatic stress disorder enters the age of large-scale genomic collaboration. Neuropsychopharmacology 40, 2287–2297 (2015).

  57. 57.

    et al. Mood, stress and longevity: convergence on ANK3. Mol. Psychiatry 21, 1037–1049 (2016).

  58. 58.

    & Failed drug discovery in psychiatry: time for human genome-guided solutions. Trends Cogn. Sci. 19, 183–187 (2015).

  59. 59.

    , & International Affective Pictures System (IAPS): Affective Ratings of Pictures and Instruction Manual (Univ. Florida, 2008).

  60. 60.

    et al. Defining the role of common variation in the genomic and biological architecture of adult human height. Nat. Genet. 46, 1173–1186 (2014).

  61. 61.

    et al. Genetic studies of body mass index yield new insights for obesity biology. Nature 518, 197–206 (2015).

  62. 62.

    et al. Genetic analysis of association between calcium signaling and hippocampal activation, memory performance in the young and old, and risk for sporadic Alzheimer disease. JAMA Psychiatry 72, 1029–1036 (2015).

  63. 63.

    et al. Converging genetic and functional brain imaging evidence links neuronal excitability to working memory, psychiatric disease, and brain activity. Neuron 81, 1203–1213 (2014).

  64. 64.

    et al. Relationship of a common polymorphism of the glucocorticoid receptor gene to traumatic memories and posttraumatic stress disorder in patients after intensive care therapy. Crit. Care Med. 39, 643–650 (2011).

  65. 65.

    et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

  66. 66.

    et al. Long-range LD can confound genome scans in admixed populations. Am. J. Hum. Genet. 83, 132–135 (2008); author reply 83, 135–139 (2008).

  67. 67.

    Multivariate and propensity score matching software with automated balance optimization: the matching package for R. J. Stat. Softw. 42, 1–52 (2011).

  68. 68.

    & in Memory and Emotion (eds Reisberg, D. & Hertel, P.) 3–40 (Oxford Univ. Press, 2004).

  69. 69.

    & Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics 25, 1754–1760 (2009).

  70. 70.

    & BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841–842 (2010).

  71. 71.

    et al. The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297–1303 (2010).

  72. 72.

    et al. From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr. Protoc. Bioinformatics 43, 11.10.1–11.10.33 (2013).

  73. 73.

    et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat. Genet. 43, 491–498 (2011).

  74. 74.

    , , , & Three-stage quality control strategies for DNA re-sequencing data. Brief. Bioinform. 15, 879–889 (2014).

  75. 75.

    et al. Sequence and structural variation in a human genome uncovered by short-read, massively parallel ligation sequencing using two-base encoding. Genome Res. 19, 1527–1541 (2009).

  76. 76.

    et al. Complete Khoisan and Bantu genomes from southern Africa. Nature 463, 943–947 (2010).

  77. 77.

    et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly 6, 80–92 (2012).

  78. 78.

    & A groupwise association test for rare mutations using a weighted sum statistic. PLoS Genet. 5, e1000384 (2009).

  79. 79.

    et al. Pooled association tests for rare variants in exon-resequencing studies. Am. J. Hum. Genet. 86, 832–838 (2010).

  80. 80.

    , , & Rare-variant association analysis: study designs and statistical tests. Am. J. Hum. Genet. 95, 5–23 (2014).

  81. 81.

    et al. An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage 31, 968–980 (2006).

  82. 82.

    & Lesion Analysis in Neuropsychology, (Oxford Univ. Press, 1989).

  83. 83.

    et al. Validation of a mental health assessment in an African conflict population. Psychol. Assess. 22, 318–324 (2010).

  84. 84.

    et al. How to quantify exposure to traumatic stress? Reliability and predictive validity of measures for cumulative trauma exposure in a post-conflict population. Eur. J. Psychotraumatol. 6, 28306 (2015).

  85. 85.

    et al. Trauma, poverty and mental health among Somali and Rwandese refugees living in an African refugee settlement — an epidemiological study. Confl. Health 3, 6 (2009).

  86. 86.

    , , , & The risk of posttraumatic stress disorder after trauma depends on traumatic load and the catechol-o-methyltransferase Val(158)Met polymorphism. Biol. Psychiatry 67, 304–308 (2010).

  87. 87.

    et al. Psychological trauma and evidence for enhanced vulnerability for posttraumatic stress disorder through previous trauma among West Nile refugees. BMC Psychiatry 4, 34 (2004).

Download references

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.

Author information

Author notes

    • Dominique J.-F. de Quervain
    •  & Andreas Papassotiropoulos

    These authors jointly supervised this work.

Affiliations

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

    • Angela Heck
    • , Annette Milnik
    • , Christian Vogler
    • , Dominique J.-F. de Quervain
    •  & Andreas Papassotiropoulos
  4. Department Biozentrum, Life Sciences Training Facility, University of Basel, CH-4056 Basel, Switzerland.

    • Vanja Vukojevic
    • , Philippe Demougin
    • , Bernardo Delarue Bizzini
    •  & Andreas Papassotiropoulos
  5. Department of Biosystems Science and Engineering, ETH Zurich, CH-4058 Basel, Switzerland.

    • Jochen Singer
    • , Christian Beisel
    •  & Niko Beerenwinkel
  6. SIB Swiss Institute of Bioinformatics, CH-4056 Basel, Switzerland.

    • Jochen Singer
    • , Pablo Escobar
    • , Thierry Sengstag
    • , Torsten Schwede
    •  & Niko Beerenwinkel
  7. Department Biozentrum, University of Basel, CH-4056 Basel, Switzerland.

    • Pablo Escobar
    • , Thierry Sengstag
    •  & Torsten Schwede
  8. sciCORE Center for Scientific Computing, University of Basel, CH-4056 Basel, Switzerland.

    • Pablo Escobar
    • , Thierry Sengstag
    •  & Torsten Schwede
  9. Division of Cognitive Neuroscience, Department of Psychology, University of Basel, CH-4055 Basel, Switzerland.

    • David Coynel
    • , Matthias Fastenrath
    • , Eva Loos
    • , Nathalie Schicktanz
    •  & Dominique J.-F. de Quervain
  10. Clinical & Biological Psychology, Institute of Psychology & Education, Ulm University, D-89069 Ulm, Germany.

    • Iris-Tatjana Kolassa
    •  & Sarah Wilker
  11. Department of Psychology, University of Konstanz, D-78457 Konstanz, Germany.

    • Thomas Elbert

Authors

  1. Search for Angela Heck in:

  2. Search for Annette Milnik in:

  3. Search for Vanja Vukojevic in:

  4. Search for Jana Petrovska in:

  5. Search for Tobias Egli in:

  6. Search for Jochen Singer in:

  7. Search for Pablo Escobar in:

  8. Search for Thierry Sengstag in:

  9. Search for David Coynel in:

  10. Search for Virginie Freytag in:

  11. Search for Matthias Fastenrath in:

  12. Search for Philippe Demougin in:

  13. Search for Eva Loos in:

  14. Search for Francina Hartmann in:

  15. Search for Nathalie Schicktanz in:

  16. Search for Bernardo Delarue Bizzini in:

  17. Search for Christian Vogler in:

  18. Search for Iris-Tatjana Kolassa in:

  19. Search for Sarah Wilker in:

  20. Search for Thomas Elbert in:

  21. Search for Torsten Schwede in:

  22. Search for Christian Beisel in:

  23. Search for Niko Beerenwinkel in:

  24. Search for Dominique J.-F. de Quervain in:

  25. Search for Andreas Papassotiropoulos in:

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.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Angela Heck or Andreas Papassotiropoulos.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    Supplementary Tables 1–6, Supplementary Figures 1–6.