Increased burden of ultra-rare structural variants localizing to boundaries of topologically associated domains in schizophrenia

Nat Commun. 2020 Apr 15;11(1):1842. doi: 10.1038/s41467-020-15707-w.


Despite considerable progress in schizophrenia genetics, most findings have been for large rare structural variants and common variants in well-imputed regions with few genes implicated from exome sequencing. Whole genome sequencing (WGS) can potentially provide a more complete enumeration of etiological genetic variation apart from the exome and regions of high linkage disequilibrium. We analyze high-coverage WGS data from 1162 Swedish schizophrenia cases and 936 ancestry-matched population controls. Our main objective is to evaluate the contribution to schizophrenia etiology from a variety of genetic variants accessible to WGS but not by previous technologies. Our results suggest that ultra-rare structural variants that affect the boundaries of topologically associated domains (TADs) increase risk for schizophrenia. Alterations in TAD boundaries may lead to dysregulation of gene expression. Future mechanistic studies will be needed to determine the precise functional effects of these variants on biology.

Publication types

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

MeSH terms

  • Brain / metabolism
  • Exome / genetics
  • Genome, Human / genetics
  • Genome-Wide Association Study / methods*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Nervous System / metabolism
  • Quality Control
  • Schizophrenia / genetics*
  • Sequence Analysis, DNA