Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Truncating mutations in RBM12 are associated with psychosis

Nature Genetics volume 49, pages 1251–1254 (2017)Cite this article

Subjects

Abstract

Thus far, a handful of highly penetrant mutations conferring risk of psychosis have been discovered. Here we used whole-genome sequencing and long-range phasing to investigate an Icelandic kindred containing ten individuals with psychosis (schizophrenia, schizoaffective disorder or psychotic bipolar disorder). We found that all affected individuals carry RBM12 (RNA-binding-motif protein 12) c.2377G>T (P = 2.2 × 10−4), a nonsense mutation that results in the production of a truncated protein lacking a predicted RNA-recognition motif. We replicated the association in a Finnish family in which a second RBM12 truncating mutation (c.2532delT) segregates with psychosis (P = 0.020). c.2377G>T is not fully penetrant for psychosis; however, we found that carriers unaffected by psychosis resemble patients with schizophrenia in their non-psychotic psychiatric disorder and neuropsychological test profile (P = 0.0043) as well as in their life outcomes (including an increased chance of receiving disability benefits, P = 0.011). As RBM12 has not previously been linked to psychosis, this work provides new insight into psychiatric disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Icelandic family with psychosis.
Figure 2: Psychosis-associated truncating mutations in RBM12.
Figure 3: Finnish family with psychosis.
Figure 4

Similar content being viewed by others

Accession codes

Accessions

NCBI Reference Sequence

References

  1. Power, R.A. et al. Fecundity of patients with schizophrenia, autism, bipolar disorder, depression, anorexia nervosa, or substance abuse vs their unaffected siblings. JAMA Psychiatry 70, 22–30 (2013).

    Article  Google Scholar 

  2. Genovese, G. et al. Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia. Nat. Neurosci. 19, 1433–1441 (2016).

    Article  CAS  Google Scholar 

  3. Singh, T. et al. Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders. Nat. Neurosci. 19, 571–577 (2016).

    Article  CAS  Google Scholar 

  4. Purcell, S.M. et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature 506, 185–190 (2014).

    Article  CAS  Google Scholar 

  5. Fromer, M. et al. De novo mutations in schizophrenia implicate synaptic networks. Nature 506, 179–184 (2014).

    Article  CAS  Google Scholar 

  6. Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016).

    Article  CAS  Google Scholar 

  7. Lindeboom, R.G., Supek, F. & Lehner, B. The rules and impact of nonsense-mediated mRNA decay in human cancers. Nat. Genet. 48, 1112–1118 (2016).

    Article  CAS  Google Scholar 

  8. Finn, R.D. et al. The Pfam protein families database: towards a more sustainable future. Nucleic Acids Res. 44, D279–D285 (2016).

    Article  CAS  Google Scholar 

  9. Walter, K. et al. The UK10K project identifies rare variants in health and disease. Nature 526, 82–90 (2015).

    Article  CAS  Google Scholar 

  10. Murphy, K.C., Jones, L.A. & Owen, M.J. High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch. Gen. Psychiatry 56, 940–945 (1999).

    Article  CAS  Google Scholar 

  11. Stefansson, H. et al. CNVs conferring risk of autism or schizophrenia affect cognition in controls. Nature 505, 361–366 (2014).

    Article  CAS  Google Scholar 

  12. Bulik-Sullivan, B. et al. An atlas of genetic correlations across human diseases and traits. Nat. Genet. 47, 1236–1241 (2015).

    Article  CAS  Google Scholar 

  13. St Clair, D. et al. Association within a family of a balanced autosomal translocation with major mental illness. Lancet 336, 13–16 (1990).

    Article  CAS  Google Scholar 

  14. Sheehan, D.V. et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J. Clin. Psychiatry 59 (Suppl. 20), 22–33, quiz 34–57 (1998).

    PubMed  Google Scholar 

  15. Tansey, K.E. et al. Common alleles contribute to schizophrenia in CNV carriers. Mol. Psychiatry 21, 1085–1089 (2016).

    Article  CAS  Google Scholar 

  16. Lunde, B.M., Moore, C. & Varani, G. RNA-binding proteins: modular design for efficient function. Nat. Rev. Mol. Cell Biol. 8, 479–490 (2007).

    Article  CAS  Google Scholar 

  17. GTEx Consortium. The Genotype-Tissue Expression (GTEx) project. Nat Genet. 45, 580–585 (2013).

  18. Fagerberg, L. et al. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol. Cell. Proteomics 13, 397–406 (2014).

    Article  CAS  Google Scholar 

  19. Miller, J.A. et al. Transcriptional landscape of the prenatal human brain. Nature 508, 199–206 (2014).

    Article  CAS  Google Scholar 

  20. Zhang, Y. et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J. Neurosci. 34, 11929–11947 (2014).

    Article  CAS  Google Scholar 

  21. Sun, M. et al. Multiplex chromosomal exome sequencing accelerates identification of ENU-induced mutations in the mouse. G3 (Bethesda) 2, 143–150 (2012).

    Article  CAS  Google Scholar 

  22. Matys, V. et al. TRANSFAC and its module TRANSCompel: transcriptional gene regulation in eukaryotes. Nucleic Acids Res. 34, D108–D110 (2006).

    Article  CAS  Google Scholar 

  23. Merzdorf, C.S. Emerging roles for zic genes in early development. Dev. Dyn. 236, 922–940 (2007).

    Article  CAS  Google Scholar 

  24. Murillo, B., Ruiz-Reig, N., Herrera, M., Fairén, A. & Herrera, E. Zic2 controls the migration of specific neuronal populations in the developing forebrain. J. Neurosci. 35, 11266–11280 (2015).

    Article  CAS  Google Scholar 

  25. Krumm, N. et al. Excess of rare, inherited truncating mutations in autism. Nat. Genet. 47, 582–588 (2015).

    Article  CAS  Google Scholar 

  26. Bozdagi, O., Tavassoli, T. & Buxbaum, J.D. Insulin-like growth factor-1 rescues synaptic and motor deficits in a mouse model of autism and developmental delay. Mol. Autism 4, 9 (2013).

    Article  CAS  Google Scholar 

  27. Homann, O.R. et al. Whole-genome sequencing in multiplex families with psychoses reveals mutations in the SHANK2 and SMARCA1 genes segregating with illness. Mol. Psychiatry 21, 1690–1695 (2016).

    Article  CAS  Google Scholar 

  28. Spitzer, R.L., Endicott, J. & Robins, E. Research diagnostic criteria: rationale and reliability. Arch. Gen. Psychiatry 35, 773–782 (1978).

    Article  CAS  Google Scholar 

  29. Spitzer, R. The Schedule for Affective Disorders and Schizophrenia, Lifetime Version (New York State Psychiatric Institute, 1977).

  30. Paunio, T. et al. Genome-wide scan in a nationwide study sample of schizophrenia families in Finland reveals susceptibility loci on chromosomes 2q and 5q. Hum. Mol. Genet. 10, 3037–3048 (2001).

    Article  CAS  Google Scholar 

  31. Hovatta, I. et al. Schizophrenia in the genetic isolate of Finland. Am. J. Med. Genet. 74, 353–360 (1997).

    Article  CAS  Google Scholar 

  32. McGuffin, P. Farmer, A.&Harvey, I.A polydiagnostic application of operational criteria in studies of psychotic illness. Development and reliability of the OPCRIT system. Arch. Gen. Psychiatry 48, 764–770 (1991).

    Article  CAS  Google Scholar 

  33. Wechsler, D. Wechsler Adult Intelligence Scale—Revised (WAIS-R), Manual (Psychological Corporation, 1981).

  34. Wechsler, D. Wechsler Memory Scale—Revised (WMS-R), Manual (Harcourt Brace Jovanovich, 1987).

  35. Delis, D.C., Kramer, J.H., Kaplan, E. & Ober, B.A. California Verbal Learning Test. Manual. Research Edition (The Psychological Corporation, Harcourt Brace & Company, 1987).

  36. Golden, C. Stroop Color and Word Test: Manual for Clinical and Experimental Uses (Stoelting, 1978).

  37. Reitan, R.M. & Wolfson, D. The Halstead Reitan Neuropsychological Test Battery (Neuropsychology Press, 1985).

  38. Gudbjartsson, D.F. et al. Large-scale whole-genome sequencing of the Icelandic population. Nat. Genet. 47, 435–444 (2015).

    Article  CAS  Google Scholar 

  39. Styrkarsdottir, U. et al. Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits. Nature 497, 517–520 (2013).

    Article  CAS  Google Scholar 

  40. Steinthorsdottir, V. et al. Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes. Nat. Genet. 46, 294–298 (2014).

    Article  CAS  Google Scholar 

  41. Lander, E.S. & Green, P. Construction of multilocus genetic linkage maps in humans. Proc. Natl. Acad. Sci. USA 84, 2363–2367 (1987).

    Article  CAS  Google Scholar 

  42. Elston, R.C. & Stewart, J.A general model for the genetic analysis of pedigree data. Hum. Hered. 21, 523–542 (1971).

    Article  CAS  Google Scholar 

  43. Wechsler, D. Wechsler Abbreviated Scale of Intelligence (Psychological Corporation Harcourt Brace, 1999).

  44. Wechsler, D. Wechsler Memory Scale 3rd edn. (AJA Associates, 1997).

  45. Benton, A.H.K. Multilingual Aphasia Examination (1989).

  46. Morris, J.C. et al. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part I. Clinical and neuropsychological assessment of Alzheimer's disease. Neurology 39, 1159–1165 (1989).

    Article  CAS  Google Scholar 

  47. Stroop, J.R. Studies of interference in serial verbal reactions. J. Exp. Psychol. 18, 643–662 (1935).

    Article  Google Scholar 

  48. Reitan, R.M. Validity of the Trail Making Test as an indicator of organic brain damage. Percept. Mot. Skills 8, 271–276 (1958).

    Article  Google Scholar 

  49. Berg, E.A. A simple objective technique for measuring flexibility in thinking. J. Gen. Psychol. 39, 15–22 (1948).

    Article  CAS  Google Scholar 

  50. Owen, A.M., Downes, J.J., Sahakian, B.J. & Polkey, C.E.&Robbins T.W. Planning and spatial working memory following frontal lobe lesions in man. Neuropsychologia 28, 1021–1034 (1990).

    Article  CAS  Google Scholar 

  51. Sahakian, B., Jones, G., Levy, R., Gray, J. & Warburton, D. The effects of nicotine on attention, information processing, and short-term memory in patients with dementia of the Alzheimer type. Br. J. Psychiatry 154, 797–800 (1989).

    Article  CAS  Google Scholar 

  52. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014).

  53. Psychiatric GWAS Consortium Bipolar Disorder Working Group. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat. Genet. 43, 977–983 (2011).

Download references

Acknowledgements

We thank the participants and the core research staff who made this study possible. The study was funded in part by the National Institute on Drug Abuse (NIDA) (R01-DA034076) and EU FP7-People-2011-IAPP grant agreement 286213 (PsychDPC). The manuscript uses data sets obtained from the database of Genotypes and Phenotypes (dbGaP) through accession phs000473.v2.p2 based on samples provided by the Swedish Cohort Collection supported by NIMH grant R01MH077139, the Sylvan C. Herman Foundation, the Stanley Medical Research Institute and the Swedish Research Council (grants 2009-4959 and 2011-4659) and exome sequenced with support from NIMH Grand Opportunity grant RCMH089905, the Sylvan C. Herman Foundation, a grant from the Stanley Medical Research Institute and multiple gifts to the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard. The study also makes use of data generated by the UK10K Consortium. A full list of the investigators who contributed to the generation of the data is available from http://www.UK10K.org/. Funding for UK10K was provided by the Wellcome Trust under award WT091310.

Author information

Authors and Affiliations

  1. deCODE Genetics/Amgen, Reykjavik, Iceland

    Stacy Steinberg, Steinunn Gudmundsdottir, Gardar Sveinbjornsson, Michael L Frigge, Gudrun A Jonsdottir, Johanna Huttenlocher, Sunna Arnarsdottir, Thorgeir E Thorgeirsson, Augustine Kong, Gudmundur L Norddahl, Daniel F Gudbjartsson, Hreinn Stefansson & Kari Stefansson

  2. National Institute for Health and Welfare (THL), Helsinki, Finland

    Jaana Suvisaari, Tiina Paunio & Minna Torniainen-Holm

  3. Department of Psychiatry, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

    Tiina Paunio

  4. Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland

    Minna Torniainen-Holm

  5. Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany

    Johanna Huttenlocher

  6. Department of Psychiatry, Landspitali, National University Hospital, Reykjavik, Iceland

    Sunna Arnarsdottir, Oddur Ingimarsson, Magnus Haraldsson & Engilbert Sigurdsson

  7. Faculty of Medicine, University of Iceland, Reykjavik, Iceland

    Oddur Ingimarsson, Magnus Haraldsson, Engilbert Sigurdsson & Kari Stefansson

  8. National Center of Addiction Medicine, Vogur Hospital, Reykjavik, Iceland

    Thorarinn Tyrfingsson

Authors
  1. Stacy Steinberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Steinunn Gudmundsdottir
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gardar Sveinbjornsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jaana Suvisaari
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tiina Paunio
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Minna Torniainen-Holm
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michael L Frigge
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gudrun A Jonsdottir
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Johanna Huttenlocher
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sunna Arnarsdottir
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Oddur Ingimarsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Magnus Haraldsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Thorarinn Tyrfingsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Thorgeir E Thorgeirsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Augustine Kong
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Gudmundur L Norddahl
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Daniel F Gudbjartsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Engilbert Sigurdsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Hreinn Stefansson
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Kari Stefansson
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.S., S.G., M.T.-H., G.S., M.L.F., G.A.J., T.E.T. and A.K. analyzed data. G.S. and D.F.G. contributed statistical methods. S.G. and G.L.N. performed laboratory experiments. J.S., T.P., S.A., O.I., M.H., T.T. and E.S. performed recruitment and phenotyping. J.H. carried out genotyping. S.S., H.S. and K.S. drafted the manuscript. All authors contributed to the final version of the manuscript.

Corresponding author

Correspondence to Kari Stefansson.

Ethics declarations

Competing interests

S.S., S.G., G.S., M.L.F., G.A.J., S.A., T.E.T., A.K., G.L.N., D.F.G., H.S. and K.S. are employees of deCODE Genetics/Amgen.

Integrated supplementary information

Supplementary Figure 1 Relationship of the Icelandic psychosis family to five individuals (X1–X5) who carry the haplotype harboring RBM12 c.2377G>T but not RBM12 c.2377G>T.

An asterisk marks whole-genome-sequenced individuals. For individuals with samples, RBM12 c.2377 genotypes are shown.

Supplementary Figure 2 Sharing between C1 (the haplotype inherited from B2) and individuals depicted in Supplementary Figure 1.

The location of RBM12 c.2377G>T is indicated by a dotted line. Individuals who do not carry c.2377G>T are shown in gray. P, paternal; U, unspecified; M, maternal.

Supplementary Figure 3 Western blots.

(a) Western blot stained with an antibody that recognizes amino acids 422–530 of RBM12. (b) Western blot stained with anti-β-actin antibody.

Supplementary Figure 4 Score on neuropsychological test principal component 1 for c.2377G>T carriers (C1–C5) and non-carriers (NC1–NC6).

Supplementary Figure 5 Individual neuropsychological test results for Icelandic controls (n = 763), patients with schizophrenia (n = 198), RBM12 c.2377G>T family non-carriers and c.2377G>T carriers.

When the c.2377G>T family non-carriers (NC) are within 0.5 s.d. of the controls, color bars indicate that the carriers are >1.5 s.d. from controls (purple), between 1.5 and 1 s.d. from controls (light blue), between 0.5 and 0 s.d. from controls (green), or between 0 and –0.5 s.d. from controls (yellow). Ctrl, controls; SZ, patients with schizophrenia; NC, non-carriers; C, carriers. The line in the NC and C columns indicates the median.

Supplementary Figure 6 Individual neuropsychological test results for the Finnish psychosis family and patients with schizophrenia (n = 142) from the same region.

FI-B1, who had a subarachnoid hemorrhage before assessment was carried out, is designated with an x. The line in the “fam” and “car” columns indicates the median. SZ, patients with schizophrenia; fam, healthy non-carriers from the Finnish psychosis family; car, c.2532delT carriers with psychosis. Note that the TMT B was not administered for the c.2532delT carriers as it was deemed too difficult for them.

Supplementary Figure 7 Odds ratios and standard errors from the regression of psychosis on bipolar and schizophrenia polygenic scores.

Left, the Icelandic psychosis family. Comparison of ten patients with psychosis and 18 non-psychotic individuals, all c.2377G>T carriers. Right, the Finnish psychosis family. Comparison of four patients with psychosis carrying c.2532delT and four non-psychotic full-siblings who do not carry c.2532delT. Note that scores were shifted and scaled to have a mean of zero and a standard deviation of 1 in the group unaffected by psychosis in each family.

Supplementary Figure 8 Relative intensity of the full-length RBM12 band detected by western blot using two antibodies.

Left, relative intensity from two experiments with antibody A, recognizing amino acids 834–932 at the C terminus of RBM12. Mean relative intensity was lower in carriers (C) than in non-carriers (NC) (P = 0.0057 (t test)). Right, relative intensity from two experiments with antibody B, recognizing amino acids 422–530 of RBM12. Mean relative intensity was lower in carriers (C) than in non-carriers (NC) (P = 0.14 based on the t test). Note that all values are normalized for β-actin and shifted so that the non-carriers have a mean of 1. Individuals are shown as open circles and the mean for each group is indicated by a blue, filled circle.

Supplementary Figure 9 Contribution of carriers to the score depending on affected status.

The red line indicates the weight of affecteds and the blue line the weight of unaffecteds.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–9 and Supplementary Tables 1–5 (PDF 1657 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Steinberg, S., Gudmundsdottir, S., Sveinbjornsson, G. et al. Truncating mutations in RBM12 are associated with psychosis. Nat Genet 49, 1251–1254 (2017). https://doi.org/10.1038/ng.3894

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.3894

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing