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De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia

Nature Genetics volume 44, pages 1365–1369 (2012)Cite this article

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Abstract

To evaluate evidence for de novo etiologies in schizophrenia, we sequenced at high coverage the exomes of families recruited from two populations with distinct demographic structures and history. We sequenced a total of 795 exomes from 231 parent-proband trios enriched for sporadic schizophrenia cases, as well as 34 unaffected trios. We observed in cases an excess of de novo nonsynonymous single-nucleotide variants as well as a higher prevalence of gene-disruptive de novo mutations relative to controls. We found four genes (LAMA2, DPYD, TRRAP and VPS39) affected by recurrent de novo events within or across the two populations, which is unlikely to have occurred by chance. We show that de novo mutations affect genes with diverse functions and developmental profiles, but we also find a substantial contribution of mutations in genes with higher expression in early fetal life. Our results help define the genomic and neural architecture of schizophrenia.

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Figure 1: Enrichment of nonsynonymous or functional de novo variants according to temporal expression profiles of genes mutated in schizophrenia.

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Acknowledgements

We are enormously grateful to all the families who participated in this research. We thank H. Pretorius and nursing sisters R. van Wyk, C. Botha and H. van den Berg for their assistance with subject recruitment, family history assessments and diagnostic evaluations. We thank S.L. Lundy for valuable assistance with clinical database maintenance and L. Rodriguez-Murillo for help with Supplementary Figure 9. We also thank B. Plummer and M. Robinson and the HudsonAlpha Genomics Services Laboratory for experimental support. Finally, we thank L.J. Mienie for the thymine loading test. This work was partially supported by National Institute of Mental Health (NIMH) grants MH061399 (to M.K.) and MH077235 (to J.A.G.) and the Lieber Center for Schizophrenia Research at Columbia University. B.X. was partially supported by a National Alliance for Research in Schizophrenia and Depression (NARSAD) Young Investigator Award.

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Authors and Affiliations

  1. Department of Psychiatry, Columbia University, New York, New York, USA

    Bin Xu, Scarlet Woodrick, Yan Sun & Maria Karayiorgou

  2. Department of Biostatistics, Columbia University, New York, New York, USA

    Iuliana Ionita-Laza

  3. Weskoppies Hospital, Pretoria, South Africa

    J Louw Roos

  4. Department of Psychiatry, University of Pretoria, Pretoria, South Africa

    J Louw Roos

  5. HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA

    Braden Boone & Shawn Levy

  6. Department of Physiology & Cellular Biophysics, Columbia University, New York, New York, USA

    Scarlet Woodrick & Joseph A Gogos

  7. Department of Neuroscience, Columbia University, New York, New York, USA

    Joseph A Gogos

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  1. Bin Xu
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Contributions

B.X., J.A.G. and M.K. designed the study, interpreted the data and prepared the manuscript. B.X. developed the analysis pipeline and had the primary role in the analysis and validation of sequence data. I.I.-L. performed statistical analysis of the sequence data. J.L.R. contributed to sample collection and clinical characterization. S.W. and Y.S. contributed to sample preparation and de novo mutation validation. B.B. performed exome library construction, capture and sequencing and initial analysis of SNV genotyping and indel variant calls. S.L. supervised the sequencing project at the HudsonAlpha Institute.

Corresponding authors

Correspondence to Joseph A Gogos or Maria Karayiorgou.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Figures 1–9 and Supplementary Tables 1, 3–5, 7–9 and 11 (PDF 1422 kb)

Supplementary Table 2

De novo mutations identified in all three cohorts examined (XLS 63 kb)

Supplementary Table 6

List of prenatally-biased genes (XLS 33 kb)

Supplementary Table 10

Functional enrichment analysis of hsa-mir-367 and hsa-mir-1244 targets (XLS 32 kb)

Supplementary Table 12

HSF prediction results for splice site mutations in three genes with recurrent de novo mutations (XLS 25 kb)

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Xu, B., Ionita-Laza, I., Roos, J. et al. De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia. Nat Genet 44, 1365–1369 (2012). https://doi.org/10.1038/ng.2446

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