Molecular Neurobiology

, Volume 55, Issue 9, pp 7366–7376 | Cite as

Rare Risk Variants Identification by Identity-by-Descent Mapping and Whole-Exome Sequencing Implicates Neuronal Development Pathways in Schizophrenia and Bipolar Disorder

  • C. Salvoro
  • S. Bortoluzzi
  • A. Coppe
  • G. Valle
  • E. Feltrin
  • M. L. Mostacciuolo
  • G. VazzaEmail author


Schizophrenia (SCZ) and bipolar disorder (BPD) are highly heritable disorders with an estimated co-heritability of 68%. Hundreds of common alleles have been implicated, but recently a role for rare, high-penetrant variants has been also suggested in both disorders. This study investigated a familial cohort of SCZ and BPD patients from a closed population sample, where the high recurrence of the disorders and the homogenous genetic background indicate a possible enrichment in rare risk alleles. A total of 230 subjects (161 cases, 22 unaffected relatives, and 47 controls) were genetically investigated through an innovative strategy that integrates identity-by-descent (IBD) mapping and whole-exome sequencing (WES). IBD analysis allowed to track high-risk haplotypes (IBDrisk) shared exclusively by multiple patients from different families and possibly carrying the most penetrant alleles. A total of 444 non-synonymous sequence variants, of which 137 disruptive, were identified in IBDrisk haplotypes by WES. Interestingly, gene sets previously implicated in SCZ (i.e., post-synaptic density (PSD) proteins, voltage-gated calcium channels (VGCCs), and fragile X mental retardation protein (FMRP) targets) were found significantly enriched in genes carrying IBDrisk variants. Further, IBDrisk variants were preferentially affecting genes involved in the extracellular matrix (ECM) biology and axon guidance processes which appeared to be functionally connected in the pathway-derived meta-network analysis. Results thus confirm rare risk variants as key factors in SCZ and BPD pathogenesis and highlight a role for the development of neuronal connectivity in the etiology of both disorders.


schizophrenia bipolar disorder rare variants whole-exome sequencing identity-by-descent development of neuronal connectivity 



We thank all patients participating in the study, Dr. A. Pocklington for providing details on gene sets and A. Binatti for his help in network analysis. This study was partially supported by Telethon-Italy Foundation (Grant GGP07219).

Compliance with Ethical Standards

All participants provided signed consent and the study has been approved by the local Medical Ethic Committee of Chioggia.

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2018_922_MOESM1_ESM.docx (816 kb)
ESM 1 (DOCX 815 kb)


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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of BiologyUniversity of PadovaPadovaItaly
  2. 2.Department of Molecular MedicineUniversity of PadovaPadovaItaly

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