Transcriptional signatures of schizophrenia in hiPSC-derived NPCs and neurons are concordant with post-mortem adult brains

Nat Commun. 2017 Dec 20;8(1):2225. doi: 10.1038/s41467-017-02330-5.

Abstract

The power of human induced pluripotent stem cell (hiPSC)-based studies to resolve the smaller effects of common variants within the size of cohorts that can be realistically assembled remains uncertain. We identified and accounted for a variety of technical and biological sources of variation in a large case/control schizophrenia (SZ) hiPSC-derived cohort of neural progenitor cells and neurons. Reducing the stochastic effects of the differentiation process by correcting for cell type composition boosted the SZ signal and increased the concordance with post-mortem data sets. We predict a growing convergence between hiPSC and post-mortem studies as both approaches expand to larger cohort sizes. For studies of complex genetic disorders, to maximize the power of hiPSC cohorts currently feasible, in most cases and whenever possible, we recommend expanding the number of individuals even at the expense of the number of replicate hiPSC clones.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antigens, Surface / genetics
  • Autopsy
  • Brain / metabolism*
  • Case-Control Studies
  • Child
  • DNA Copy Number Variations
  • Female
  • Humans
  • Induced Pluripotent Stem Cells / metabolism*
  • Linear Models
  • Male
  • Nanog Homeobox Protein / genetics
  • Nestin / genetics
  • Neural Stem Cells / metabolism*
  • Neurons / metabolism*
  • Octamer Transcription Factor-3 / genetics
  • Proteoglycans / genetics
  • RNA, Messenger / metabolism*
  • SOXB1 Transcription Factors / genetics
  • Schizophrenia / genetics*
  • Sequence Analysis, RNA
  • Stage-Specific Embryonic Antigens / genetics
  • Synapsins / genetics
  • Transcriptome
  • Young Adult

Substances

  • Antigens, Surface
  • NANOG protein, human
  • NES protein, human
  • Nanog Homeobox Protein
  • Nestin
  • Octamer Transcription Factor-3
  • POU5F1 protein, human
  • Proteoglycans
  • RNA, Messenger
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • Stage-Specific Embryonic Antigens
  • Synapsins
  • TRA-1-60 antigen, human
  • stage-specific embryonic antigen-4