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Polygenic associations of neurodevelopmental genes in suicide attempt

Molecular Psychiatry volume 21, pages 1381–1390 (2016)Cite this article

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Abstract

The risk for suicidal behavior (SB) is elevated in schizophrenia (SCZ), bipolar disorder (BPD) and major depressive disorder (MDD), but also occurs in subjects without psychiatric diagnoses. Genome-wide association studies (GWAS) on SB may help to understand this risk, but have been hampered by low power due to limited sample sizes, weakly ascertained SB or a reliance on single-nucleotide protein (SNP)-by-SNP analyses. Here, we tried to mitigate such issues with polygenic risk score (PRS) association tests combined with hypothesis-driven strategies using a family-based sample of 660 trios with a well-ascertained suicide attempt (SA) outcome in the offspring (Genetic Investigation of Suicide and SA, GISS). Two complementary sources of PRS information were used. First, a PRS that was discovered and validated in the GISS SA revealed the polygenic association of SNPs in 750 neurodevelopmental genes, which was driven by the SA phenotype, rather than the major psychiatric diagnoses. Second, a PRS based on three different genome-wide association studies (on SCZ, BPD or MDD) from the Psychiatric Genomics Consortium (PGC) showed an association of the PGC-SCZ PRS in the SA subjects with and without major psychiatric diagnoses. We characterized the PGC-SCZ overlap in the SA subjects without diagnoses. The extended major histocompatibility complex region did not contribute to the overlap, but we delineated the genic overlap to neurodevelopmental genes that partially overlapped with those identified by the GISS PRS. Among the 590 SA polygenes implicated here, there were several developmentally important functions (cell adhesion/migration, small GTPase and receptor tyrosine kinase signaling), and 16 of the SA polygenes have previously been studied in SB (BDNF, CDH10, CDH12, CDH13, CDH9, CREB1, DLK1, DLK2, EFEMP1, FOXN3, IL2, LSAMP, NCAM1, nerve growth factor (NGF), NTRK2 and TBC1D1). These novel genome-wide insights, supported by two lines of evidence, suggested the importance of a polygenic neurodevelopmental etiology in SB, even in the absence of major psychiatric diagnoses.

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Acknowledgements

We wish to thank all interviewers at the Human Ecological Health organization/Odessa National Mechnikov University, Odessa, Ukraine; Vsevolod Rozanov for coordinating sample collection in Ukraine; Vladymyr Bogatov and laboratory technician Lars Holmberg for technical assistance; Tatyana Reytarova for logistical assistance; and all those who have given their consent to participate as research subjects in this study. We thank the SNP&SEQ Technology Platform at Uppsala University for their excellent quality of services and expertize in the genotyping conducted here. This GISS study was funded by the Knut and Alice Wallenberg Foundation.

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Authors and Affiliations

  1. National Centre for Suicide Research and Prevention of Mental Ill-Health, Karolinska Institute, Stockholm, Sweden

    M Sokolowski, J Wasserman & D Wasserman

  2. WHO collaborating Centre for research, methods, development and training in suicide prevention, Stockholm, Sweden,

    D Wasserman

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  1. M Sokolowski
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Correspondence to M Sokolowski.

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Sokolowski, M., Wasserman, J. & Wasserman, D. Polygenic associations of neurodevelopmental genes in suicide attempt. Mol Psychiatry 21, 1381–1390 (2016). https://doi.org/10.1038/mp.2015.187

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