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A burden of rare copy number variants in obsessive-compulsive disorder

Halvorsen, Matthew W. ; de Schipper, Elles ; Bäckman, Julia ; Strom, Nora I. ; Hagen, Kristen ; Zayats, Tetyana ; Eide, Thorstein Olsen ; Noh, Hyun Ji ; Morrill, Kathleen and Lichtenstein, Paul , et al. (2024) In Molecular Psychiatry
Abstract

Current genetic research on obsessive-compulsive disorder (OCD) supports contributions to risk specifically from common single nucleotide variants (SNVs), along with rare coding SNVs and small insertion-deletions (indels). The contribution to OCD risk from rare copy number variants (CNVs), however, has not been formally assessed at a similar scale. Here we describe an analysis of rare CNVs called from genotype array data in 2248 deeply phenotyped OCD cases and 3608 unaffected controls from Sweden and Norway. Cases carry an elevated burden of CNVs ≥30 kb in size (OR = 1.12, P = 1.77 × 10−3). The excess rate of these CNVs in cases versus controls was around 0.07 (95% CI 0.02–0.11, P = 2.58 × 10−3). This signal was... (More)

Current genetic research on obsessive-compulsive disorder (OCD) supports contributions to risk specifically from common single nucleotide variants (SNVs), along with rare coding SNVs and small insertion-deletions (indels). The contribution to OCD risk from rare copy number variants (CNVs), however, has not been formally assessed at a similar scale. Here we describe an analysis of rare CNVs called from genotype array data in 2248 deeply phenotyped OCD cases and 3608 unaffected controls from Sweden and Norway. Cases carry an elevated burden of CNVs ≥30 kb in size (OR = 1.12, P = 1.77 × 10−3). The excess rate of these CNVs in cases versus controls was around 0.07 (95% CI 0.02–0.11, P = 2.58 × 10−3). This signal was largely driven by CNVs overlapping protein-coding regions (OR = 1.19, P = 3.08 × 10−4), particularly deletions impacting loss-of-function intolerant genes (pLI >0.995, OR = 4.12, P = 2.54 × 10−5). We did not identify any specific locus where CNV burden was associated with OCD case status at genome-wide significance, but we noted non-random recurrence of CNV deletions in cases (permutation P = 2.60 × 10−3). In cases where sufficient clinical data were available (n = 1612) we found that carriers of neurodevelopmental duplications were more likely to have comorbid autism (P < 0.001), and that carriers of deletions overlapping neurodevelopmental genes had lower treatment response (P = 0.02). The results demonstrate a contribution of rare CNVs to OCD risk, and suggest that studies of rare coding variation in OCD would have increased power to identify risk genes if this class of variation were incorporated into formal tests.

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type
Contribution to journal
publication status
in press
subject
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Molecular Psychiatry
publisher
Springer Nature
external identifiers
  • pmid:39463448
  • scopus:85207354815
ISSN
1359-4184
DOI
10.1038/s41380-024-02763-7
language
English
LU publication?
yes
id
2cfe4034-ad59-4c04-a383-ca5dc2a165f8
date added to LUP
2025-01-13 15:23:26
date last changed
2025-07-01 16:57:49
@article{2cfe4034-ad59-4c04-a383-ca5dc2a165f8,
  abstract     = {{<p>Current genetic research on obsessive-compulsive disorder (OCD) supports contributions to risk specifically from common single nucleotide variants (SNVs), along with rare coding SNVs and small insertion-deletions (indels). The contribution to OCD risk from rare copy number variants (CNVs), however, has not been formally assessed at a similar scale. Here we describe an analysis of rare CNVs called from genotype array data in 2248 deeply phenotyped OCD cases and 3608 unaffected controls from Sweden and Norway. Cases carry an elevated burden of CNVs ≥30 kb in size (OR = 1.12, P = 1.77 × 10<sup>−3</sup>). The excess rate of these CNVs in cases versus controls was around 0.07 (95% CI 0.02–0.11, P = 2.58 × 10<sup>−3</sup>). This signal was largely driven by CNVs overlapping protein-coding regions (OR = 1.19, P = 3.08 × 10<sup>−4</sup>), particularly deletions impacting loss-of-function intolerant genes (pLI &gt;0.995, OR = 4.12, P = 2.54 × 10<sup>−5</sup>). We did not identify any specific locus where CNV burden was associated with OCD case status at genome-wide significance, but we noted non-random recurrence of CNV deletions in cases (permutation P = 2.60 × 10<sup>−3</sup>). In cases where sufficient clinical data were available (n = 1612) we found that carriers of neurodevelopmental duplications were more likely to have comorbid autism (P &lt; 0.001), and that carriers of deletions overlapping neurodevelopmental genes had lower treatment response (P = 0.02). The results demonstrate a contribution of rare CNVs to OCD risk, and suggest that studies of rare coding variation in OCD would have increased power to identify risk genes if this class of variation were incorporated into formal tests.</p>}},
  author       = {{Halvorsen, Matthew W. and de Schipper, Elles and Bäckman, Julia and Strom, Nora I. and Hagen, Kristen and Zayats, Tetyana and Eide, Thorstein Olsen and Noh, Hyun Ji and Morrill, Kathleen and Lichtenstein, Paul and Kähler, Anna K. and Höffler, Kira D. and Djurfeldt, Diana R. and Chen, Long Long and Lindblad-Toh, Kerstin and Karlsson, Elinor K. and Pedersen, Nancy L. and Wallert, John and Bulik, Cynthia M. and Fundín, Bengt and Landén, Mikael and Kvale, Gerd and Hansen, Bjarne and Haavik, Jan and Mattheisen, Manuel and Rück, Christian and Mataix-Cols, David and Crowley, James J.}},
  issn         = {{1359-4184}},
  language     = {{eng}},
  publisher    = {{Springer Nature}},
  series       = {{Molecular Psychiatry}},
  title        = {{A burden of rare copy number variants in obsessive-compulsive disorder}},
  url          = {{http://dx.doi.org/10.1038/s41380-024-02763-7}},
  doi          = {{10.1038/s41380-024-02763-7}},
  year         = {{2024}},
}