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Joint reanalysis of 29 correlated SNPs supports the role of PCLO/Piccolo as a causal risk factor for major depressive disorder

Molecular Psychiatry volume 14, pages 650–652 (2009)Cite this article

The first genome-wide association study (GWAS) for major depressive disorder (MDD) has implicated the pre-synaptic protein, Piccolo, but results from multiple replication cohorts remained inconclusive. Here, we present a reanalysis of the Piccolo replication study and argue that the data favor a non-synonymous coding single nucleotide polymorphism (SNP) in a well-characterized protein domain to be a causal risk factor for major depression.

In the first GWAS for MDD, multiple SNPs within the PCLO gene that codes for the pre-synaptic protein, Piccolo, reached nominal P-values in the magnitude of 10−7.1 One of the most strongly associated SNPs was rs2522833, a non-synonymous coding SNP in a well-characterized protein domain, the C2-domain, of Piccolo. A panel of 30 SNPs was followed up in a finemapping/replication effort that involved five additional MDD cohorts. In the replication stage, a nominally significant P-value was observed for rs2522833 in one cohort. Although these results are highly suggestive, the original finding did not reach genome-wide significance, and after permutation-based correction for testing multiple correlated SNPs and cohorts, the replication study was not conclusive.1

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Acknowledgements

This study was carried out within the framework of the Top Institute Pharma project: number T5-203.

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Authors and Affiliations

  1. Department of Medical Genomics, VU University Medical Center, Amsterdam, The Netherlands

    Z Bochdanovits, D Posthuma & P Heutink

  2. Department of Functional Genomics, Vrije Universiteit and VU University Medical Center, Amsterdam, The Netherlands

    M Verhage

  3. Department of Molecular and Cellular Neurobiology, Vrije Universiteit and VU University Medical Center, Amsterdam, The Netherlands

    A B Smit

  4. Department of Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands

    E J C de Geus, D Posthuma & D I Boomsma

  5. Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands

    B W J H Penninx & W J Hoogendijk

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  1. Z Bochdanovits
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  2. M Verhage
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  3. A B Smit
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  6. D I Boomsma
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  7. B W J H Penninx
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  8. W J Hoogendijk
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  9. P Heutink
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Correspondence to Z Bochdanovits.

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Bochdanovits, Z., Verhage, M., Smit, A. et al. Joint reanalysis of 29 correlated SNPs supports the role of PCLO/Piccolo as a causal risk factor for major depressive disorder. Mol Psychiatry 14, 650–652 (2009). https://doi.org/10.1038/mp.2009.37

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