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High-throughput sequencing of the synaptome in major depressive disorder

Molecular Psychiatry volume 21, pages 650–655 (2016)Cite this article

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Abstract

Major depressive disorder (MDD) is among the leading causes of worldwide disability. Despite its significant heritability, large-scale genome-wide association studies (GWASs) of MDD have yet to identify robustly associated common variants. Although increased sample sizes are being amassed for the next wave of GWAS, few studies have as yet focused on rare genetic variants in the study of MDD. We sequenced the exons of 1742 synaptic genes previously identified by proteomic experiments. PLINK/SEQ was used to perform single variant, gene burden and gene set analyses. The GeneMANIA interaction database was used to identify protein–protein interaction-based networks. Cases were selected from a familial collection of early-onset, recurrent depression and were compared with screened controls. After extensive quality control, we analyzed 259 cases with familial, early-onset MDD and 334 controls. The distribution of association test statistics for the single variant and gene burden analyses were consistent with the null hypothesis. However, analysis of prioritized gene sets showed a significant association with damaging singleton variants in a Cav2-adaptor gene set (odds ratio=2.6; P=0.0008) that survived correction for all gene sets and annotation categories tested (empirical P=0.049). In addition, we also found statistically significant evidence for an enrichment of rare variants in a protein-based network of 14 genes involved in actin polymerization and dendritic spine formation (nominal P=0.0031). In conclusion, we have identified a statistically significant gene set and gene network of rare variants that are over-represented in MDD, providing initial evidence that calcium signaling and dendrite regulation may be involved in the etiology of depression.

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Acknowledgements

This work was funded by the Johns Hopkins University Brain Science Institute (TW, JBP, FSG). Data and biomaterials were collected in six projects that participated in the NIMH Genetics of Recurrent Early-Onset Depression (GenRED) project. From 1999 to 2003, the principal investigators and co-investigators were New York State Psychiatric Institute, New York, R01-MH060912 (Myrna Weissman, PhD and James K Knowles, MD, PhD); University of Pittsburgh, R01-MH060866 (George S Zubenko, MD, PhD, and Wendy N Zubenko, EdD, RN, CS); Johns Hopkins University, Baltimore, R01-MH059552 (J Raymond DePaulo, MD, Melvin McInnis, MD and Dean MacKinnon, MD); University of Pennsylvania, Philadelphia, R01-MH61686 (Doug Levinson, MD [GenRED coordinator], Madeleine M Gladis, PhD, Kathleen Murphy-Eberenz, PhD and Peter Holmans, PhD [University of Wales College of Medicine]); University of Iowa, Iowa City, R01-MH059542 (Raymond Crowe, MD and William H Coryell, MD); Rush University Medical Center, Chicago, R01-MH059541-05 (William Scheftner, MD, Rush-Presbyterian).

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Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA

    M Pirooznia, D Avramopoulos, P P Zandi & F S Goes

  2. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA

    T Wang & D Avramopoulos

  3. Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA, USA

    J B Potash

  4. Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    P P Zandi

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Correspondence to F S Goes.

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Pirooznia, M., Wang, T., Avramopoulos, D. et al. High-throughput sequencing of the synaptome in major depressive disorder. Mol Psychiatry 21, 650–655 (2016). https://doi.org/10.1038/mp.2015.98

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