Rare Risk Variants Identification by Identity-by-Descent Mapping and Whole-Exome Sequencing Implicates Neuronal Development Pathways in Schizophrenia and Bipolar Disorder
| Autor: | Giovanni Vazza, Cecilia Salvoro, Maria Luisa Mostacciuolo, Stefania Bortoluzzi, Alessandro Coppe, Giorgio Valle, E. Feltrin |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Neuroscience (miscellaneous) Biology Identity by descent 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Risk Factors Genetic variation Exome Sequencing medicine Humans Gene Regulatory Networks Genetic Predisposition to Disease Bipolar disorder whole-exome sequencing Allele Gene Exome sequencing Genetics Neurons bipolar disorder Haplotype Genetic Variation rare variants medicine.disease schizophrenia 030104 developmental biology Neurology Schizophrenia development of neuronal connectivity identity-by-descent 030217 neurology & neurosurgery |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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