Rare Risk Variants Identification by Identity-by-Descent Mapping and Whole-Exome Sequencing Implicates Neuronal Development Pathways in Schizophrenia and Bipolar Disorder
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.
Keywordsschizophrenia 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.
- 8.Genovese G, Fromer M, Stahl EA, Ruderfer DM, Chambert K, Landén M, Moran JL, Purcell SM et al (2016) Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia. Nat Neurosci 19(11):1433–1441. https://doi.org/10.1038/nn.4402 CrossRefPubMedPubMedCentralGoogle Scholar
- 10.Ament SA, Szelinger S, Glusman G, Ashworth J, Hou L, Akula N, Shekhtman T, Badner JA et al (2015) Rare variants in neuronal excitability genes influence risk for bipolar disorder. Proc Natl Acad Sci U S A 112(11):3576–3581. https://doi.org/10.1073/pnas.1424958112
- 11.Lescai F, Als TD, Li Q, Nyegaard M, Andorsdottir G, Biskopstø M, Hedemand A, Fiorentino A et al (2017) Whole-exome sequencing of individuals from an isolated population implicates rare risk variants in bipolar disorder. Transl Psychiatry 7(2):e1034. https://doi.org/10.1038/tp.2017.3 CrossRefPubMedPubMedCentralGoogle Scholar
- 15.Cavalli-Sforza LL, Moroni A, Zei G (2004) Consanguinity, inbreeding, and genetic drift. Princeton University Press, PrincetonGoogle Scholar
- 16.Lorenzon A, Pilichou K, Rigato I, Vazza G, de Bortoli M, Calore M, Occhi G, Carturan E, Lazzarini E, Cason M, Mazzotti E, Poloni G, Mostacciuolo ML, Daliento L, Thiene G, Corrado D, Basso C, Bauce B, Rampazzo A (2015) Homozygous Desmocollin-2 mutations and Arrhythmogenic cardiomyopathy. Am J Cardiol 116:1245–1251. doi: https://doi.org/10.1016/j.amjcard.2015.07.037, 8
- 17.Vazza G, Bertolin C, Scudellaro E, Vettori A, Boaretto F, Rampinelli S, de Sanctis G, Perini G, Peruzzi P, Mostacciuolo ML (2007) Genome-wide scan supports the existence of a susceptibility locus for schizophrenia and bipolar disorder on chromosome 15q26. Mol Psychiatry 12:87–93. doi: https://doi.org/10.1038/sj.mp.4001895, 1
- 18.Albrechtsen A, Sand Korneliussen T, Moltke I, van Overseem Hansen T, Nielsen FC, Nielsen R (2009) Relatedness mapping and tracts of relatedness for genome-wide data in the presence of linkage disequilibrium. Genet Epidemiol 33(3):266–274. https://doi.org/10.1002/gepi.20378 CrossRefPubMedGoogle Scholar
- 24.Gulsuner S, Walsh T, Watts AC, Lee MK, Thornton AM, Casadei S, Rippey C, Shahin H et al (2013) Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell 154(3):518–529. https://doi.org/10.1016/j.cell.2013.06.049
- 25.Kirov G, Pocklington AJ, Holmans P, Ivanov D, Ikeda M, Ruderfer D, Moran J, Chambert K et al (2012) De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Mol Psychiatry 17(2):142–153. https://doi.org/10.1038/mp.2011.154 CrossRefPubMedGoogle Scholar
- 28.Coppe A, Andersson EI, Binatti A, Gasparini VR, Bortoluzzi S, Clemente M, Herling M, Maciejewski J et al (2017) Genomic landscape characterization of large granular lymphocyte leukemia with a systems genetics approach. Leukemia 31(5):1243–1246. https://doi.org/10.1038/leu.2017.49 CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Cruceanu C, Ambalavanan A, Spiegelman D, Gauthier J, Lafrenière RG, Dion PA, Alda M, Turecki G et al (2013) Family-based exome-sequencing approach identifies rare susceptibility variants for lithium-responsive bipolar disorder. Genome 56(10):634–640. https://doi.org/10.1139/gen-2013-0081 CrossRefPubMedGoogle Scholar
- 33.Cichon S, Mühleisen TW, Degenhardt FA, Mattheisen M, Miró X, Strohmaier J, Steffens M, Meesters C et al (2011) Genome-wide association study identifies genetic variation in neurocan as a susceptibility factor for bipolar disorder. Am J Hum Genet 88(3):372–381. https://doi.org/10.1016/j.ajhg.2011.01.017 CrossRefPubMedPubMedCentralGoogle Scholar
- 35.Kerrisk ME, Cingolani LA, Koleske AJ (2014) ECM receptors in neuronal structure, synaptic plasticity, and behavior. p 101–131Google Scholar
- 37.Lubbers BR, Smit AB, Spijker S, van den Oever MC (2014) Neural ECM in addiction, schizophrenia, and mood disorder. Prog Brain Res 214:263–284. https://doi.org/10.1016/B978-0-444-63486-3.00012-8 CrossRefPubMedGoogle Scholar
- 38.Pantazopoulos H, Wiseman JT, Markota M, Ehrenfeld L, Berretta S (2017) Decreased numbers of Somatostatin-expressing neurons in the amygdala of subjects with bipolar disorder or schizophrenia: Relationship to circadian rhythms. Biol Psychiatry 81(6):536–547. https://doi.org/10.1016/j.biopsych.2016.04.006 CrossRefPubMedGoogle Scholar