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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

NCBI Reference Sequence

References

  1. 1.

    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).

  2. 2.

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

  3. 3.

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

  4. 4.

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

  5. 5.

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

  6. 6.

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

  7. 7.

    , & The rules and impact of nonsense-mediated mRNA decay in human cancers. Nat. Genet. 48, 1112–1118 (2016).

  8. 8.

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

  9. 9.

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

  10. 10.

    , & High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch. Gen. Psychiatry 56, 940–945 (1999).

  11. 11.

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

  12. 12.

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

  13. 13.

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

  14. 14.

    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).

  15. 15.

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

  16. 16.

    , & RNA-binding proteins: modular design for efficient function. Nat. Rev. Mol. Cell Biol. 8, 479–490 (2007).

  17. 17.

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

  18. 18.

    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).

  19. 19.

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

  20. 20.

    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).

  21. 21.

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

  22. 22.

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

  23. 23.

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

  24. 24.

    , , , & Zic2 controls the migration of specific neuronal populations in the developing forebrain. J. Neurosci. 35, 11266–11280 (2015).

  25. 25.

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

  26. 26.

    , & Insulin-like growth factor-1 rescues synaptic and motor deficits in a mouse model of autism and developmental delay. Mol. Autism 4, 9 (2013).

  27. 27.

    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).

  28. 28.

    , & Research diagnostic criteria: rationale and reliability. Arch. Gen. Psychiatry 35, 773–782 (1978).

  29. 29.

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

  30. 30.

    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).

  31. 31.

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

  32. 32.

    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).

  33. 33.

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

  34. 34.

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

  35. 35.

    , , & California Verbal Learning Test. Manual. Research Edition (The Psychological Corporation, Harcourt Brace & Company, 1987).

  36. 36.

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

  37. 37.

    & The Halstead Reitan Neuropsychological Test Battery (Neuropsychology Press, 1985).

  38. 38.

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

  39. 39.

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

  40. 40.

    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).

  41. 41.

    & Construction of multilocus genetic linkage maps in humans. Proc. Natl. Acad. Sci. USA 84, 2363–2367 (1987).

  42. 42.

    & general model for the genetic analysis of pedigree data. Hum. Hered. 21, 523–542 (1971).

  43. 43.

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

  44. 44.

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

  45. 45.

    Multilingual Aphasia Examination (1989).

  46. 46.

    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).

  47. 47.

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

  48. 48.

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

  49. 49.

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

  50. 50.

    , , & T.W. Planning and spatial working memory following frontal lobe lesions in man. Neuropsychologia 28, 1021–1034 (1990).

  51. 51.

    , , , & 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).

  52. 52.

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

  53. 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

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. Search for Stacy Steinberg in:

  2. Search for Steinunn Gudmundsdottir in:

  3. Search for Gardar Sveinbjornsson in:

  4. Search for Jaana Suvisaari in:

  5. Search for Tiina Paunio in:

  6. Search for Minna Torniainen-Holm in:

  7. Search for Michael L Frigge in:

  8. Search for Gudrun A Jonsdottir in:

  9. Search for Johanna Huttenlocher in:

  10. Search for Sunna Arnarsdottir in:

  11. Search for Oddur Ingimarsson in:

  12. Search for Magnus Haraldsson in:

  13. Search for Thorarinn Tyrfingsson in:

  14. Search for Thorgeir E Thorgeirsson in:

  15. Search for Augustine Kong in:

  16. Search for Gudmundur L Norddahl in:

  17. Search for Daniel F Gudbjartsson in:

  18. Search for Engilbert Sigurdsson in:

  19. Search for Hreinn Stefansson in:

  20. Search for Kari Stefansson in:

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.

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.

Corresponding author

Correspondence to Kari Stefansson.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–9 and Supplementary Tables 1–5

About this article

Publication history

Received

Accepted

Published

DOI

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

Further reading