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Truncating mutations in RBM12 are associated with psychosis

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

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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.

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

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NCBI Reference Sequence

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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.

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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

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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.

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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.

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

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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

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