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

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 >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 < 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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Journal
Molecular Psychiatry
Published
2024-10-27
DOI
https://doi.org/10.1038/s41380-024-02763-7
Citations
11
Primary Topic
Genomic variations and chromosomal abnormalities
Type
article
Field-Weighted Citation Impact
6.05

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article

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

Cynthia Marie Bulik, Bjarne Hansen, Kira D. Höffler, Kerstin Lindblad‐Toh et al.
11 citations
Molecular Psychiatry
Genomic variations and chromosomal abnormalities
6.05
article

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

Cynthia Marie Bulik, Bjarne Hansen, Kira D. Höffler, Kerstin Lindblad‐Toh, Bengt T. Fundín, Mikael Landén, Nora I. Strom, Anna K. Kähler, Paul Lichtenstein, James J. Crowley, John Wallert, Jan Haavik, Elinor K. Karlsson, Thorstein Olsen Eide, Gerd Kvale, Kristen Hagen, Elles de Schipper, Matthew Halvorsen, Christian Rück, Hyun Ji Noh, Long Long Chen, Tetyana Zayats, Kathleen M. Morrill, David Mataix‐Cols, Manuel Mattheisen, Julia Bäckman, Diana R. Djurfeldt, Nancy L. Pedersen
article en
11 citations

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<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 >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 < 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.

Molecular PsychiatryVol. 30(4)
Broad Institute (US), University of North Carolina at Chapel Hill (US), Uppsala University (SE), Dalhousie University (CA), UMass Memorial Health Care (US), University of Massachusetts Chan Medical School (US), Lund University (SE), Aarhus University (DK), Norwegian University of Science and Technology (NO), Science for Life Laboratory (SE), Haukeland University Hospital (NO), Karolinska Institutet (SE), Humboldt-Universität zu Berlin (DE), Molde Hospital (NO), Stockholm Health Care Services (SE), Senter for Krisepsykologi (NO), University of Bergen (NO), Ludwig-Maximilians-Universität München (DE), University of Gothenburg (SE)
Trond Mohn stiftelse, AFA Försäkring, Lundbeckfonden, Hjärnfonden, Karolinska Institutet, Stockholms Läns Landsting, Vetenskapsrådet, H. Lundbeck A/S, National Institutes of Health, Uppsala Multidisciplinary Center for Advanced Computational Science, Center for Innovative Medicine
Good health and well-being
Openalex Percentile: Top 3%
Genomic variations and chromosomal abnormalities
6.05
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