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Comment on: What genes are differentially expressed in individuals with schizophrenia? A systematic review

Molecular Psychiatry volume 28, pages 523–525 (2023)Cite this article

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Following the recent review by Merikangas et al. [1] summarizing differential gene expression in schizophrenia, we wanted to provide readers with our perspective on the state of the field in order to highlight current resources and ongoing challenges. We have led data collection and analysis of post mortem brains of control and schizophrenia samples across multiple large-scale cohorts, and we have provided data and results resources for each of these studies (Table 1) [2,3,4,5,6,7,8,9].

Table 1 Recent large-scale efforts generating RNA-seq data to identify differential gene expression associated with schizophrenia in post-mortem human brains.
Full size table

Based on empirical results and the principles of statistics [8], sample size is the most important factor in determining the statistical power to identify differential gene expression [2,3,4,5,6,7,8,9,10]. Moreover, the concordance across studies is expected to increase with sample size. Given these considerations, the work by Merikangas, et al. [1] evaluating the concordance in differential gene expression across smaller-scale studies using the overlap of genome-wide significant genes substantially understates the reproducibility of findings from differential expression analysis in schizophrenia.

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References

  1. Merikangas AK, Shelly M, Knighton A, Kotler N, Tanenbaum N, Almasy L What genes are differentially expressed in individuals with schizophrenia? A systematic review. Mol Psychiatry. 2022. https://doi.org/10.1038/s41380-021-01420-7.

  2. Collado-Torres L, Burke EE, Peterson A, Shin J, Straub RE, Rajpurohit A, et al. Regional heterogeneity in gene expression, regulation, and coherence in the frontal cortex and hippocampus across development and Schizophrenia. Neuron. 2019;103:203–216.e8.

    Article  CAS  Google Scholar 

  3. Jaffe AE, Straub RE, Shin JH, Tao R, Gao Y, Collado-Torres L, et al. Developmental and genetic regulation of the human cortex transcriptome illuminate schizophrenia pathogenesis. Nat Neurosci. 2018;21:1117–25.

    Article  CAS  Google Scholar 

  4. Gandal MJ, Zhang P, Hadjimichael E, Walker RL, Chen C, Liu S et al. Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder. Science. 2018; 362. https://doi.org/10.1126/science.aat8127.

  5. Gandal MJ, Haney JR, Parikshak NN, Leppa V, Ramaswami G, Hartl C, et al. Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science. 2018;359:693–7.

    Article  CAS  Google Scholar 

  6. Hoffman GE, Ma Y, Montgomery KS, Bendl J, Jaiswal MK, Kozlenkov A, et al. Sex differences in the human brain transcriptome of cases with schizophrenia. Biol Psychiatry. 2022;91:92–101.

    Article  CAS  Google Scholar 

  7. Hoffman GE, Bendl J, Voloudakis G, Montgomery KS, Sloofman L, Wang Y-C, et al. CommonMind consortium provides transcriptomic and epigenomic data for schizophrenia and bipolar disorder. Sci Data. 2019;6:180.

    Article  Google Scholar 

  8. Fromer M, Roussos P, Sieberts SK, Johnson JS, Kavanagh DH, Perumal TM, et al. Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nat Neurosci. 2016;19:1442–53.

    Article  CAS  Google Scholar 

  9. Jaffe AE, Hoeppner DJ, Saito T, Blanpain L, Ukaigwe J, Burke EE, et al. Profiling gene expression in the human dentate gyrus granule cell layer reveals insights into schizophrenia and its genetic risk. Nat Neurosci. 2020;23:510–9.

    Article  CAS  Google Scholar 

  10. Jaffe AE, Tao R, Norris AL, Kealhofer M, Nellore A, Shin JH, et al. qSVA framework for RNA quality correction in differential expression analysis. Proc Natl Acad Sci USA. 2017;114:7130–5.

    Article  CAS  Google Scholar 

  11. Storey JD, Tibshirani R. Statistical significance for genomewide studies. Proc Natl Acad Sci USA. 2003;100:9440–5.

    Article  CAS  Google Scholar 

  12. Semick SA, Collado-Torres L, Markunas CA, Shin JH, Deep-Soboslay A, Tao R, et al. Developmental effects of maternal smoking during pregnancy on the human frontal cortex transcriptome. Mol Psychiatry. 2020;25:3267–77.

    Article  Google Scholar 

  13. Hernandez LM, Kim M, Hoftman GD, Haney JR, de la Torre-Ubieta L, Pasaniuc B, et al. Transcriptomic insight into the polygenic mechanisms underlying psychiatric disorders. Biol Psychiatry. 2021;89:54–64.

    Article  CAS  Google Scholar 

  14. Perzel Mandell KA, Eagles NJ, Deep-Soboslay A, Tao R, Han S, Wilton R et al. Molecular phenotypes associated with antipsychotic drugs in the human caudate nucleus. Mol Psychiatry. 2022. https://doi.org/10.1038/s41380-022-01453-6.

  15. Gusev A, Ko A, Shi H, Bhatia G, Chung W, Penninx BWJH, et al. Integrative approaches for large-scale transcriptome-wide association studies. Nat Genet. 2016;48:245–52.

    Article  CAS  Google Scholar 

  16. Yao DW, O’Connor LJ, Price AL, Gusev A. Quantifying genetic effects on disease mediated by assayed gene expression levels. Nat Genet. 2020;52:626–33.

    Article  CAS  Google Scholar 

  17. de la Torre-Ubieta L, Stein JL, Won H, Opland CK, Liang D, Lu D, et al. The dynamic landscape of open chromatin during human cortical neurogenesis. Cell. 2018;172:289–304.e18.

    Article  Google Scholar 

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Author information

Author notes

  1. Andrew E. Jaffe

    Present address: Neumora Therapeutics, Watertown, MA, USA

Authors and Affiliations

  1. Center for Disease Neurogenomics, Department of Psychiatry, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Gabriel E. Hoffman & Panos Roussos

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

    Andrew E. Jaffe & Daniel R. Weinberger

  3. Department of Psychiatry and Behavioral Sciences, Department of Genetic Medicine, Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Andrew E. Jaffe & Daniel R. Weinberger

  4. Lieber Institute for Brain Development, Baltimore, MD, USA

    Andrew E. Jaffe, Leonardo Collado-Torres & Daniel R. Weinberger

  5. Intellectual and Developmental Disabilities Research Center, Department of Psychiatry, Department of Human Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA

    Michael J. Gandal & Daniel H. Geschwind

  6. Sage Bionetworks, Seattle, Washington, USA

    Solveig K. Sieberts

  7. Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Bernie Devlin

  8. Program in Neurogenetics, Department of Neurology, Center for Autism Research and Treatment, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA

    Daniel H. Geschwind

  9. Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Daniel R. Weinberger

  10. Mental Illness Research, Education and Clinical Centers, James J. Peters VA Medical Center, Bronx, NY, USA

    Panos Roussos

  11. Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA

    Panos Roussos

Authors
  1. Gabriel E. Hoffman
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  2. Andrew E. Jaffe
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  3. Michael J. Gandal
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Contributions

GEH, AEJ and MJG led the writing of the manuscript. LCT, SKS, BD, DHG, DRW and PR contributed to writing the manuscript.

Corresponding authors

Correspondence to Gabriel E. Hoffman, Andrew E. Jaffe or Michael J. Gandal.

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Hoffman, G.E., Jaffe, A.E., Gandal, M.J. et al. Comment on: What genes are differentially expressed in individuals with schizophrenia? A systematic review. Mol Psychiatry 28, 523–525 (2023). https://doi.org/10.1038/s41380-022-01781-7

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