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

Halvorsen, Matthew ; Huh, Ruth ; Oskolkov, Nikolay LU ; Wen, Jia ; Netotea, Sergiu ; Giusti-Rodriguez, Paola ; Karlsson, Robert ; Bryois, Julien ; Nystedt, Björn and Ameur, Adam , et al. (2020) In Nature Communications 11(1).
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
11
issue
1
article number
1842
publisher
Nature Publishing Group
external identifiers
  • pmid:32296054
  • scopus:85083479362
ISSN
2041-1723
DOI
10.1038/s41467-020-15707-w
language
English
LU publication?
yes
id
02159492-c2dc-495a-a7c2-6caa6a1a57a3
date added to LUP
2020-04-30 08:59:53
date last changed
2024-06-13 15:28:04
@article{02159492-c2dc-495a-a7c2-6caa6a1a57a3,
  abstract     = {{<p>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.</p>}},
  author       = {{Halvorsen, Matthew and Huh, Ruth and Oskolkov, Nikolay and Wen, Jia and Netotea, Sergiu and Giusti-Rodriguez, Paola and Karlsson, Robert and Bryois, Julien and Nystedt, Björn and Ameur, Adam and Kähler, Anna K. and Ancalade, Na Eshia and Farrell, Martilias and Crowley, James J. and Li, Yun and Magnusson, Patrik K.E. and Gyllensten, Ulf and Hultman, Christina M. and Sullivan, Patrick F. and Szatkiewicz, Jin P.}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Increased burden of ultra-rare structural variants localizing to boundaries of topologically associated domains in schizophrenia}},
  url          = {{http://dx.doi.org/10.1038/s41467-020-15707-w}},
  doi          = {{10.1038/s41467-020-15707-w}},
  volume       = {{11}},
  year         = {{2020}},
}