Synergistic effects of common schizophrenia risk variants

Nat Genet. 2019 Oct;51(10):1475-1485. doi: 10.1038/s41588-019-0497-5. Epub 2019 Sep 23.


The mechanisms by which common risk variants of small effect interact to contribute to complex genetic disorders are unclear. Here, we apply a genetic approach, using isogenic human induced pluripotent stem cells, to evaluate the effects of schizophrenia (SZ)-associated common variants predicted to function as SZ expression quantitative trait loci (eQTLs). By integrating CRISPR-mediated gene editing, activation and repression technologies to study one putative SZ eQTL (FURIN rs4702) and four top-ranked SZ eQTL genes (FURIN, SNAP91, TSNARE1 and CLCN3), our platform resolves pre- and postsynaptic neuronal deficits, recapitulates genotype-dependent gene expression differences and identifies convergence downstream of SZ eQTL gene perturbations. Our observations highlight the cell-type-specific effects of common variants and demonstrate a synergistic effect between SZ eQTL genes that converges on synaptic function. We propose that the links between rare and common variants implicated in psychiatric disease risk constitute a potentially generalizable phenomenon occurring more widely in complex genetic disorders.

Publication types

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

MeSH terms

  • CRISPR-Cas Systems
  • Chloride Channels / antagonists & inhibitors
  • Chloride Channels / genetics
  • Chloride Channels / metabolism
  • Female
  • Furin / antagonists & inhibitors
  • Furin / genetics
  • Furin / metabolism
  • Gene Editing
  • Gene Expression Regulation*
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / pathology*
  • Male
  • Monomeric Clathrin Assembly Proteins / antagonists & inhibitors
  • Monomeric Clathrin Assembly Proteins / genetics
  • Monomeric Clathrin Assembly Proteins / metabolism
  • Polymorphism, Single Nucleotide*
  • Quantitative Trait Loci*
  • SNARE Proteins / antagonists & inhibitors
  • SNARE Proteins / genetics
  • SNARE Proteins / metabolism
  • Schizophrenia / genetics*
  • Schizophrenia / pathology*


  • Chloride Channels
  • ClC-3 channel
  • Monomeric Clathrin Assembly Proteins
  • SNARE Proteins
  • TSNARE1 protein, human
  • clathrin assembly protein AP180
  • FURIN protein, human
  • Furin