Genome-Wide Association Study of Obsessive-Compulsive Symptoms including 33,943 individuals from the general population

Nora I. Strom; Christie L. Burton; Conrad Iyegbe; Talisa Silzer; Lilit Antonyan; René Pool; Mathieu Lemire; James J. Crowley; Jouke Jan Hottenga; Volen Z. Ivanov; Henrik Larsson; Paul Lichtenstein; Patrik Magnusson; Christian Rück; Russell Schachar; Hei Man Wu; Danielle Cath; Jennifer Crosbie; David Mataix-Cols; Dorret I. Boomsma; Manuel Mattheisen; Sandra M. Meier; Dirk J.A. Smit; Paul D. Arnold

doi:10.1038/s41380-024-02489-6

Genome-Wide Association Study of Obsessive-Compulsive Symptoms including 33,943 individuals from the general population

Nora I. Strom^*, Christie L. Burton, Conrad Iyegbe, Talisa Silzer, Lilit Antonyan, René Pool, Mathieu Lemire, James J. Crowley, Jouke Jan Hottenga, Volen Z. Ivanov, Henrik Larsson, Paul Lichtenstein, Patrik Magnusson, Christian Rück, Russell Schachar, Hei Man Wu, Danielle Cath, Jennifer Crosbie, David Mataix-Cols, Dorret I. BoomsmaManuel Mattheisen, Sandra M. Meier, Dirk J.A. Smit, Paul D. Arnold

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

While 1–2% of individuals meet the criteria for a clinical diagnosis of obsessive-compulsive disorder (OCD), many more (~13–38%) experience subclinical obsessive-compulsive symptoms (OCS) during their life. To characterize the genetic underpinnings of OCS and its genetic relationship to OCD, we conducted the largest genome-wide association study (GWAS) meta-analysis of parent- or self-reported OCS to date (N = 33,943 with complete phenotypic and genome-wide data), combining the results from seven large-scale population-based cohorts from Sweden, the Netherlands, England, and Canada (including six twin cohorts and one cohort of unrelated individuals). We found no genome-wide significant associations at the single-nucleotide polymorphism (SNP) or gene-level, but a polygenic risk score (PRS) based on the OCD GWAS previously published by the Psychiatric Genetics Consortium (PGC-OCD) was significantly associated with OCS (P_fixed = 3.06 × 10⁻⁵). Also, one curated gene set (Mootha Gluconeogenesis) reached Bonferroni-corrected significance (N_genes = 28, Beta = 0.79, SE = 0.16, P_bon = 0.008). Expression of genes in this set is high at sites of insulin mediated glucose disposal. Dysregulated insulin signaling in the etiology of OCS has been suggested by a previous study describing a genetic overlap of OCS with insulin signaling-related traits in children and adolescents. We report a SNP heritability of 4.1% (P = 0.0044) in the meta-analyzed GWAS, and heritability estimates based on the twin cohorts of 33–43%. Genetic correlation analysis showed that OCS were most strongly associated with OCD (r_G = 0.72, p = 0.0007) among all tested psychiatric disorders (N = 11). Of all 97 tested phenotypes, 24 showed a significant genetic correlation with OCS, and 66 traits showed concordant directions of effect with OCS and OCD. OCS have a significant polygenic contribution and share genetic risk with diagnosed OCD, supporting the hypothesis that OCD represents the extreme end of widely distributed OCS in the population.

Original language	English
Pages (from-to)	2714-2723
Number of pages	10
Journal	Molecular Psychiatry
Volume	29
Issue number	9
Early online date	28 Mar 2024
DOIs	https://doi.org/10.1038/s41380-024-02489-6
Publication status	Published - Sept 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

Funding

We acknowledge The Swedish Twin Registry (STR) for data access. The STR is managed by Karolinska Institutet and receives funding through the Swedish Research Council under the grant no 2017-00641. The computations/data handling were enabled by resources provided by the Swedish National Infrastructure for Computing (SNIC) at Uppmax partially funded by the Swedish Research Council through grant agreement no. 2018-05973. The Netherlands Twin Register (NTR) warmly thanks all twin families for their participation. NTR is supported by multiple grants from the Netherlands Organizations for Scientific Research (NWO) and Medical Research (ZonMW): Netherlands Twin Registry Repository (NWO 480-15-001/674); the Biobank-based integrative omics study (BIOS) funded by BBMRI-NL (NWO projects 184.021.007 and 184.033.111); the European Science Council (ERC) Genetics of Mental Illness (ERC Advanced, 230374, PI Boomsma); the Royal Netherlands Academy of Science Professor Award (PAH/6635) to DIB; Rutgers University Cell and DNA Repository (NIMH U24 MH06845706), the Avera Institute, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH R01 HD042157-01A1). Part of the genotyping was funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health and Grand Opportunity grants 1RC2 MH089951). TwinsUK is funded by the Wellcome Trust, Medical Research Council, Versus Arthritis, European Union Horizon 2020, Chronic Disease Research Foundation (CDRF), Zoe Ltd, the National Institute for Health and Care Research (NIHR) Clinical Research Network (CRN) and Biomedical Research Centre based at Guy\u2019s and St Thomas\u2019 NHS Foundation Trust in partnership with King\u2019s College London. Spit for Science was supported by the Canadian Institutes of Health Research (RJS, MOP\u201093696 and PDA, MOP\u2010106573). PDA is supported by the Alberta Innovates Translational Health Chair in Child and Youth Mental Health. DM-C receives royalties for contributing articles to UpToDate, Wolters Kluwer Health, outside of the submitted work. RJS has consulted to E. Lilly, Highland Therapeutics and eHave. HL reports receiving grants from Shire Pharmaceuticals; personal fees from and serving as a speaker for Medice, Shire/Takeda Pharmaceuticals and Evolan Pharma AB; and sponsorship for a conference on attention-deficit/hyperactivity disorder from Shire/Takeda Pharmaceuticals and Evolan Pharma AB, all outside the submitted work. HL is editorin-chief of JCPP Advances. PA receives research funding from Biohaven Pharmaceuticals, unrelated to the submitted work. All other authors report no potential conflict of interest.

Funders	Funder number
Medical Research Council
National Institute for Health and Care Research
European Science Council
Genetics of Mental Illness
Wellcome Trust
Avera Institute
Karolinska Institutet
California Dairy Research Foundation
ZonMw
Medical Research
Alberta Innovates
Biohaven Pharmaceuticals
Versus Arthritis
European Union Horizon 2020, Chronic Disease Research Foundation
Not added	230374
Netherlands Twin Registry Repository	480-15-001/674
Not added	480-15-001
BBMRI-NL	184.033.111, 184.021.007
Vetenskapsrådet	2018-05973, 2017-00641
National Institutes of Health	1RC2 MH089951, R01 HD042157-01A1
Royal Netherlands Academy of Science	PAH/6635
National Institute of Mental Health	U24 MH06845706
Canadian Institutes of Health Research	MOP‐106573, MOP‐93696

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Strom, N. I., Burton, C. L., Iyegbe, C., Silzer, T., Antonyan, L., Pool, R., Lemire, M., Crowley, J. J., Hottenga, J. J., Ivanov, V. Z., Larsson, H., Lichtenstein, P., Magnusson, P., Rück, C., Schachar, R., Wu, H. M., Cath, D., Crosbie, J., Mataix-Cols, D., ... Arnold, P. D. (2024). Genome-Wide Association Study of Obsessive-Compulsive Symptoms including 33,943 individuals from the general population. Molecular Psychiatry, 29(9), 2714-2723. https://doi.org/10.1038/s41380-024-02489-6

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title = "Genome-Wide Association Study of Obsessive-Compulsive Symptoms including 33,943 individuals from the general population",

abstract = "While 1–2% of individuals meet the criteria for a clinical diagnosis of obsessive-compulsive disorder (OCD), many more (~13–38%) experience subclinical obsessive-compulsive symptoms (OCS) during their life. To characterize the genetic underpinnings of OCS and its genetic relationship to OCD, we conducted the largest genome-wide association study (GWAS) meta-analysis of parent- or self-reported OCS to date (N = 33,943 with complete phenotypic and genome-wide data), combining the results from seven large-scale population-based cohorts from Sweden, the Netherlands, England, and Canada (including six twin cohorts and one cohort of unrelated individuals). We found no genome-wide significant associations at the single-nucleotide polymorphism (SNP) or gene-level, but a polygenic risk score (PRS) based on the OCD GWAS previously published by the Psychiatric Genetics Consortium (PGC-OCD) was significantly associated with OCS (Pfixed = 3.06 × 10−5). Also, one curated gene set (Mootha Gluconeogenesis) reached Bonferroni-corrected significance (Ngenes = 28, Beta = 0.79, SE = 0.16, Pbon = 0.008). Expression of genes in this set is high at sites of insulin mediated glucose disposal. Dysregulated insulin signaling in the etiology of OCS has been suggested by a previous study describing a genetic overlap of OCS with insulin signaling-related traits in children and adolescents. We report a SNP heritability of 4.1% (P = 0.0044) in the meta-analyzed GWAS, and heritability estimates based on the twin cohorts of 33–43%. Genetic correlation analysis showed that OCS were most strongly associated with OCD (rG = 0.72, p = 0.0007) among all tested psychiatric disorders (N = 11). Of all 97 tested phenotypes, 24 showed a significant genetic correlation with OCS, and 66 traits showed concordant directions of effect with OCS and OCD. OCS have a significant polygenic contribution and share genetic risk with diagnosed OCD, supporting the hypothesis that OCD represents the extreme end of widely distributed OCS in the population.",

author = "Strom, {Nora I.} and Burton, {Christie L.} and Conrad Iyegbe and Talisa Silzer and Lilit Antonyan and Ren{\'e} Pool and Mathieu Lemire and Crowley, {James J.} and Hottenga, {Jouke Jan} and Ivanov, {Volen Z.} and Henrik Larsson and Paul Lichtenstein and Patrik Magnusson and Christian R{\"u}ck and Russell Schachar and Wu, {Hei Man} and Danielle Cath and Jennifer Crosbie and David Mataix-Cols and Boomsma, {Dorret I.} and Manuel Mattheisen and Meier, {Sandra M.} and Smit, {Dirk J.A.} and Arnold, {Paul D.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = sep,

doi = "10.1038/s41380-024-02489-6",

language = "English",

volume = "29",

pages = "2714--2723",

journal = "Molecular Psychiatry",

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Strom, NI, Burton, CL, Iyegbe, C, Silzer, T, Antonyan, L, Pool, R, Lemire, M, Crowley, JJ, Hottenga, JJ, Ivanov, VZ, Larsson, H, Lichtenstein, P, Magnusson, P, Rück, C, Schachar, R, Wu, HM, Cath, D, Crosbie, J, Mataix-Cols, D, Boomsma, DI, Mattheisen, M, Meier, SM, Smit, DJA & Arnold, PD 2024, 'Genome-Wide Association Study of Obsessive-Compulsive Symptoms including 33,943 individuals from the general population', Molecular Psychiatry, vol. 29, no. 9, pp. 2714-2723. https://doi.org/10.1038/s41380-024-02489-6

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T1 - Genome-Wide Association Study of Obsessive-Compulsive Symptoms including 33,943 individuals from the general population

AU - Strom, Nora I.

AU - Burton, Christie L.

AU - Iyegbe, Conrad

AU - Silzer, Talisa

AU - Antonyan, Lilit

AU - Pool, René

AU - Lemire, Mathieu

AU - Crowley, James J.

AU - Hottenga, Jouke Jan

AU - Ivanov, Volen Z.

AU - Larsson, Henrik

AU - Lichtenstein, Paul

AU - Magnusson, Patrik

AU - Rück, Christian

AU - Schachar, Russell

AU - Wu, Hei Man

AU - Cath, Danielle

AU - Crosbie, Jennifer

AU - Mataix-Cols, David

AU - Boomsma, Dorret I.

AU - Mattheisen, Manuel

AU - Meier, Sandra M.

AU - Smit, Dirk J.A.

AU - Arnold, Paul D.

PY - 2024/9

Y1 - 2024/9

N2 - While 1–2% of individuals meet the criteria for a clinical diagnosis of obsessive-compulsive disorder (OCD), many more (~13–38%) experience subclinical obsessive-compulsive symptoms (OCS) during their life. To characterize the genetic underpinnings of OCS and its genetic relationship to OCD, we conducted the largest genome-wide association study (GWAS) meta-analysis of parent- or self-reported OCS to date (N = 33,943 with complete phenotypic and genome-wide data), combining the results from seven large-scale population-based cohorts from Sweden, the Netherlands, England, and Canada (including six twin cohorts and one cohort of unrelated individuals). We found no genome-wide significant associations at the single-nucleotide polymorphism (SNP) or gene-level, but a polygenic risk score (PRS) based on the OCD GWAS previously published by the Psychiatric Genetics Consortium (PGC-OCD) was significantly associated with OCS (Pfixed = 3.06 × 10−5). Also, one curated gene set (Mootha Gluconeogenesis) reached Bonferroni-corrected significance (Ngenes = 28, Beta = 0.79, SE = 0.16, Pbon = 0.008). Expression of genes in this set is high at sites of insulin mediated glucose disposal. Dysregulated insulin signaling in the etiology of OCS has been suggested by a previous study describing a genetic overlap of OCS with insulin signaling-related traits in children and adolescents. We report a SNP heritability of 4.1% (P = 0.0044) in the meta-analyzed GWAS, and heritability estimates based on the twin cohorts of 33–43%. Genetic correlation analysis showed that OCS were most strongly associated with OCD (rG = 0.72, p = 0.0007) among all tested psychiatric disorders (N = 11). Of all 97 tested phenotypes, 24 showed a significant genetic correlation with OCS, and 66 traits showed concordant directions of effect with OCS and OCD. OCS have a significant polygenic contribution and share genetic risk with diagnosed OCD, supporting the hypothesis that OCD represents the extreme end of widely distributed OCS in the population.

AB - While 1–2% of individuals meet the criteria for a clinical diagnosis of obsessive-compulsive disorder (OCD), many more (~13–38%) experience subclinical obsessive-compulsive symptoms (OCS) during their life. To characterize the genetic underpinnings of OCS and its genetic relationship to OCD, we conducted the largest genome-wide association study (GWAS) meta-analysis of parent- or self-reported OCS to date (N = 33,943 with complete phenotypic and genome-wide data), combining the results from seven large-scale population-based cohorts from Sweden, the Netherlands, England, and Canada (including six twin cohorts and one cohort of unrelated individuals). We found no genome-wide significant associations at the single-nucleotide polymorphism (SNP) or gene-level, but a polygenic risk score (PRS) based on the OCD GWAS previously published by the Psychiatric Genetics Consortium (PGC-OCD) was significantly associated with OCS (Pfixed = 3.06 × 10−5). Also, one curated gene set (Mootha Gluconeogenesis) reached Bonferroni-corrected significance (Ngenes = 28, Beta = 0.79, SE = 0.16, Pbon = 0.008). Expression of genes in this set is high at sites of insulin mediated glucose disposal. Dysregulated insulin signaling in the etiology of OCS has been suggested by a previous study describing a genetic overlap of OCS with insulin signaling-related traits in children and adolescents. We report a SNP heritability of 4.1% (P = 0.0044) in the meta-analyzed GWAS, and heritability estimates based on the twin cohorts of 33–43%. Genetic correlation analysis showed that OCS were most strongly associated with OCD (rG = 0.72, p = 0.0007) among all tested psychiatric disorders (N = 11). Of all 97 tested phenotypes, 24 showed a significant genetic correlation with OCS, and 66 traits showed concordant directions of effect with OCS and OCD. OCS have a significant polygenic contribution and share genetic risk with diagnosed OCD, supporting the hypothesis that OCD represents the extreme end of widely distributed OCS in the population.

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Genome-Wide Association Study of Obsessive-Compulsive Symptoms including 33,943 individuals from the general population

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