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Exome sequencing in obsessive–compulsive disorder reveals a burden of rare damaging coding variants

Abstract

Obsessive–compulsive disorder (OCD) affects 1–2% of the population, and, as with other complex neuropsychiatric disorders, it is thought that rare variation contributes to its genetic risk. In this study, we performed exome sequencing in the largest OCD cohort to date (1,313 total cases, consisting of 587 trios, 41 quartets and 644 singletons of affected individuals) and describe contributions to disease risk from rare damaging coding variants. In case–control analyses (n = 1,263/11,580), the most significant single-gene result was observed in SLITRK5 (odds ratio (OR) = 8.8, 95% confidence interval 3.4–22.5, P = 2.3 × 10−6). Across the exome, there was an excess of loss of function (LoF) variation specifically within genes that are LoF-intolerant (OR = 1.33, P = 0.01). In an analysis of trios, we observed an excess of de novo missense predicted damaging variants relative to controls (OR = 1.22, P = 0.02), alongside an excess of de novo LoF mutations in LoF-intolerant genes (OR = 2.55, P = 7.33 × 10−3). These data support a contribution of rare coding variants to OCD genetic risk.

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Fig. 1: Overview of analysis design.
Fig. 2: QQ plot from gene-based collapsing meta-analysis across 11 separate case–control clusters that reflect ancestry (total case–control n = 1,263/11,580).
Fig. 3: Enrichment of LoF variation across LOEUF deciles in 845 cases relative to 1,761 healthy controls (dots), with 95% CIs provided (bars).
Fig. 4: Enrichment of coding DNMs in 587 OCD trios relative to 1,911 healthy controls (dots), with 95% CIs for the estimates provided (bars) and two-sided unadjusted P values (right of dots).
Fig. 5: Results of gene-based tests combining DNM data and independent case–control data.

Data availability

Gene-based collapsing analysis summary statistics are provided in Supplementary Tables 4 and 5. DNMs detected across the 587 OCD trios and 41 quartets are provided in Supplementary Tables 8 and 9, respectively. Summary statistics from extTADA analysis (including LoF counts per gene in 476 OCD cases versus 1,761 healthy controls) are provided in Supplementary Table 16. Clinical data for cases and healthy family members sequenced as part of this study are available on dbGaP (https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000903.v1.p1).

Code availability

Extraction of sample-level coverage information and extraction of QC-passing genotypes was done using ATAV (https://github.com/igm-team/atav). Manipulation of PLINK files and subsetting according to genotype missingness were done using PLINK version 1.90_3.38 (https://www.cog-genomics.org/plink2/). Kinship analysis was performed using KING version 1.4 (http://people.virginia.edu/~wc9c/KING/). PCA was performed using FLASHPCA version 2.0 (https://github.com/gabraham/flashpca) in gene-based collapsing analysis and EIGENSOFT version 6.1.4 (https://data.broadinstitute.org/alkesgroup/EIGENSOFT/) in LoF rate comparisons. Calculation of trio-based coverage was done using mosdepth version 0.2.4 (https://github.com/brentp/mosdepth) and bedtools version 2.25.0 (https://github.com/arq5x/bedtools2/releases). Full analysis code written specifically for the analysis described in this manuscript is available in the Supplementary Software Appendix and is also available in a public repository (https://github.com/Halvee/OCD_WES_analysis_full_NatureNeuro2020).

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Acknowledgements

We are grateful to the research participants, as this study would not have been possible without their participation. This work was supported by the following National Institutes of Health grants: ‘Identifying de novo mutations causing OCD in trios by whole exome sequencing’ (MH099216—D.B.G. and G.N.); ‘Identification of rare variants of OCD’ (MH097971—D.B.G.; MH097993—G.N.). Data acquisition was made possible by the OCD Collaborative Genetics Association Study, funded by the following National Institute of Mental Health grants: MH071507 (D.G.), MH079489 (A.J.F.), MH079487 (J.M.), MH079494 (J.A.K.) and MH 071507 (G.N.).

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D.B.G. and G.N. conceived of and obtained funding for the research, and D.B.G. designed the experiments. J.F.S., J.K., D.G., A.J.F., B.D.G., J.T.M., O.J.B., J.A.K., M.A.R., M.A.G., P.S.N., Y.W., F.S.G. and B.M. collected samples, prepared samples for analysis or were involved in clinical evaluation. IGM staff members performed all experiments, and M.H. executed data analyses, with critical help provided by T.D.P. D.B.G., G.N., B.M., T.D.P., A.W.Z. and F.S.G. provided analysis suggestions. M.H. and D.B.G. performed the primary writing of the manuscript, with input from G.N., B.M., F.S.G., A.W.Z. and J.F.S. All authors approved the final manuscript.

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Correspondence to Gerald Nestadt or David B. Goldstein.

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D.B.G. reports equity holdings in precision medicine companies and consultancy payments from Gilead Sciences, AstraZeneca and GoldFinch Bio. All other authors declare no competing financial interests.

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Peer review information Nature Neuroscience thanks Ditte Demontis and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Halvorsen, M., Samuels, J., Wang, Y. et al. Exome sequencing in obsessive–compulsive disorder reveals a burden of rare damaging coding variants. Nat Neurosci 24, 1071–1076 (2021). https://doi.org/10.1038/s41593-021-00876-8

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