Loss of function of OTUD7A in the schizophrenia- associated 15q13.3 deletion impairs synapse development and function in human neurons

Alena Kozlova, Siwei Zhang, Alex V. Kotlar, Brendan Jamison, Hanwen Zhang, Serena Shi, Marc P. Forrest, John McDaid, David J. Cutler, Michael P. Epstein, Michael E. Zwick, Zhiping P. Pang, Alan R. Sanders, Stephen T. Warren, Pablo V. Gejman, Jennifer G. Mulle, Jubao Duan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Identifying causative gene(s) within disease-associated large genomic regions of copy-number variants (CNVs) is challenging. Here, by targeted sequencing of genes within schizophrenia (SZ)-associated CNVs in 1,779 SZ cases and 1,418 controls, we identified three rare putative loss-of-function (LoF) mutations in OTU deubiquitinase 7A (OTUD7A) within the 15q13.3 deletion in cases but none in controls. To tie OTUD7A LoF with any SZ-relevant cellular phenotypes, we modeled the OTUD7A LoF mutation, rs757148409, in human induced pluripotent stem cell (hiPSC)-derived induced excitatory neurons (iNs) by CRISPR-Cas9 engineering. The mutant iNs showed a ∼50% decrease in OTUD7A expression without undergoing nonsense-mediated mRNA decay. The mutant iNs also exhibited marked reduction of dendritic complexity, density of synaptic proteins GluA1 and PSD-95, and neuronal network activity. Congruent with the neuronal phenotypes in mutant iNs, our transcriptomic analysis showed that the set of OTUD7A LoF-downregulated genes was enriched for those relating to synapse development and function and was associated with SZ and other neuropsychiatric disorders. These results suggest that OTUD7A LoF impairs synapse development and neuronal function in human neurons, providing mechanistic insight into the possible role of OTUD7A in driving neuropsychiatric phenotypes associated with the 15q13.3 deletion.

Original languageEnglish (US)
Pages (from-to)1500-1519
Number of pages20
JournalAmerican journal of human genetics
Volume109
Issue number8
DOIs
StatePublished - Aug 4 2022

Funding

MGS includes P.V. Gejman, A.R. Sanders, J. Duan (NorthShore University HealthSystem and University of Chicago, IL, USA), D.F. Levinson (Stanford University, CA, USA), J. Shi (National Cancer Institute, MD, USA), N.G. Buccola (Louisiana State University Health Sciences Center, LA, USA), B.J. Mowry (Queensland Centre for Mental Health Research, Brisbane, and Queensland Brain Institute, The University of Queensland, Australia), R. Freedman, A. Olincy (University of Colorado Denver, CO, USA), F. Amin (Atlanta Veterans Affairs Medical Center and Emory University, GA, USA), D.W. Black (University of Iowa Carver College of Medicine, IA, USA), J.M. Silverman (Mount Sinai School of Medicine, NY, USA), W.F. Byerley (University of California at San Francisco, San Francisco, CA, USA), C.R. Cloninger, D.M. Svrakic (Washington University, MO, USA). We thank the study participants of MGS. MGS was mainly supported by R01MH059571, R01MH081800, and U01MH079469 (to P.V.G.) and other NIH grants for other MGS sites (R01MH067257 to N.G.B. R01MH059588 to B.J.M. R01MH059565 to R.F. R01MH059587 to F.A. R01MH060870 to W.F.B. R01MH059566 to D.W.B. R01MH059586 to J.M.S. R01MH061675 to D.F.L. R01MH060879 to C.R.C. U01MH046276 to C.R.C. and U01MH079470 to D.F.L.). We thank the PGC-SZ group for providing early access of wave-3 SZ (PGC-SZ3) GWAS summary statistics. We also thank Rutgers University Cell and DNA repository (RUCDR; 2U24MH068457) for producing hiPSC lines from the MGS cohort. Funding was provided by NIH grants R01MH100915 (to P.V.G. and A.R.S.), R01MH100917 (to J.G.M. and S.T.W.), and R01MH106575 and R01MH116281 (to J.D.). A.K. designed and performed the main experiments and data analyses and wrote the manuscript. S.Z. performed transcriptomic data analyses and wrote the manuscript. B.J. and H.Z. helped with hiPSC editing and neuronal differentiation. S.S. performed the MAGMA analysis. J.M. performed the patch-clamp experiment. M.P.F. helped with neural dendritic and synaptic analyses. Z.P.P. helped with neuronal differentiation and neural phenotypic data interpretation. A.V.K. performed analysis of the targeted sequencing data. D.J.C. M.P.E. and M.E.Z. provided bioinformatic and statistical guidance and helped with interpretation of sequencing results. A.R.S. S.T.W. P.V.G. and J.G.M. conceived the study, provided the sequencing data, and wrote/edited the manuscript. J.D. conceived the study, designed and supervised the experiments and data analyses, and wrote the manuscript. The authors declare no competing interests. MGS includes P.V. Gejman, A.R. Sanders, J. Duan (NorthShore University HealthSystem and University of Chicago, IL, USA), D.F. Levinson (Stanford University, CA, USA), J. Shi (National Cancer Institute, MD, USA), N.G. Buccola (Louisiana State University Health Sciences Center, LA, USA), B.J. Mowry (Queensland Centre for Mental Health Research, Brisbane, and Queensland Brain Institute, The University of Queensland, Australia), R. Freedman, A. Olincy (University of Colorado Denver, CO, USA), F. Amin (Atlanta Veterans Affairs Medical Center and Emory University, GA, USA), D.W. Black (University of Iowa Carver College of Medicine, IA, USA), J.M. Silverman (Mount Sinai School of Medicine, NY, USA), W.F. Byerley (University of California at San Francisco, San Francisco, CA, USA), C.R. Cloninger, D.M. Svrakic (Washington University, MO, USA). We thank the study participants of MGS. MGS was mainly supported by R01MH059571 , R01MH081800 , and U01MH079469 (to P.V.G.) and other NIH grants for other MGS sites ( R01MH067257 to N.G.B., R01MH059588 to B.J.M., R01MH059565 to R.F., R01MH059587 to F.A., R01MH060870 to W.F.B., R01MH059566 to D.W.B., R01MH059586 to J.M.S., R01MH061675 to D.F.L., R01MH060879 to C.R.C., U01MH046276 to C.R.C., and U01MH079470 to D.F.L.). We thank the PGC-SZ group for providing early access of wave-3 SZ (PGC-SZ3) GWAS summary statistics. We also thank Rutgers University Cell and DNA repository (RUCDR; 2U24MH068457 ) for producing hiPSC lines from the MGS cohort. Funding was provided by NIH grants R01MH100915 (to P.V.G. and A.R.S.), R01MH100917 (to J.G.M. and S.T.W.), and R01MH106575 and R01MH116281 (to J.D.).

Keywords

  • 15q13.3 deletion
  • OTUD7A
  • copy number
  • human iPSC
  • neurodevelopment
  • neuron
  • schizophrenia
  • synapse
  • transcriptome
  • variant

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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