Genetic meta-analysis of obsessive–compulsive disorder and self-report compulsive symptoms

Dirk J.A. Smit; Danielle Cath; Nuno R. Zilhão; Hill F. Ip; Damiaan Denys; Anouk den Braber; Eco J.C. de Geus; Karin J.H. Verweij; Jouke Jan Hottenga; Dorret I. Boomsma

doi:10.1002/ajmg.b.32777

Genetic meta-analysis of obsessive–compulsive disorder and self-report compulsive symptoms

Dirk J.A. Smit^*
, Danielle Cath
, Nuno R. Zilhão
, Hill F. Ip
, Damiaan Denys
, Anouk den Braber
, Eco J.C. de Geus
, Karin J.H. Verweij
, Jouke Jan Hottenga
, Dorret I. Boomsma

^*Corresponding author for this work

Amsterdam University Medical Centers
University of Groningen
GGZ-Drenthe
Icelandic Heart Association
Vrije Universiteit Amsterdam

Research output: Contribution to journal › Article › peer-review

30 Citations (Scopus)

Abstract

We investigated whether obsessive–compulsive (OC) symptoms from a population-based sample could be analyzed to detect genetic variants influencing obsessive–compulsive disorder (OCD). We performed a genome-wide association studies (GWAS) on the obsession (rumination and impulsions) and compulsion (checking, washing, and ordering/precision) subscales of an abbreviated version of the Padua Inventory (N = 8,267 with genome-wide genotyping and phenotyping). The compulsion subscale showed a substantial and significant positive genetic correlation with an OCD case–control GWAS (r_G = 0.61, p =.017) previously published by the Psychiatric Genomics Consortium (PGC-OCD). The obsession subscale and the total Padua score showed no significant genetic correlations (r_G = −0.02 and r_G = 0.42, respectively). A meta-analysis of the compulsive symptoms GWAS with the PGC-OCD revealed no genome-wide significant Single-Nucleotide Polymorphisms (SNPs combined N = 17,992, indicating that the power is still low for individual SNP effects). A gene-based association analysis, however, yielded two novel genes (WDR7 and ADCK1). The top 250 genes in the gene-based test also showed a significant increase in enrichment for psychiatric and brain-expressed genes. S-Predixcan testing showed that for genes expressed in hippocampus, amygdala, and caudate nucleus significance increased in the meta-analysis with compulsive symptoms compared to the original PGC-OCD GWAS. Thus, the inclusion of dimensional symptom data in genome-wide association on clinical case–control GWAS of OCD may be useful to find genes for OCD if the data are based on quantitative indices of compulsive behavior. SNP-level power increases were limited, but aggregate, gene-level analyses showed increased enrichment for brain-expressed genes related to psychiatric disorders, and increased association with gene expression in brain tissues with known emotional, reward processing, memory, and fear-formation functions.

Original language	English
Pages (from-to)	208-216
Number of pages	9
Journal	American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Volume	183
Issue number	4
DOIs	https://doi.org/10.1002/ajmg.b.32777
Publication status	Published - 1 Jun 2020
Externally published	Yes

Keywords

OCD
Padua Inventory-revised
gene expression
genome-wide association study (GWAS)
obsessive–compulsive symptoms

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10.1002/ajmg.b.32777

Cite this

Smit, D. J. A., Cath, D., Zilhão, N. R., Ip, H. F., Denys, D., den Braber, A., de Geus, E. J. C., Verweij, K. J. H., Hottenga, J. J., & Boomsma, D. I. (2020). Genetic meta-analysis of obsessive–compulsive disorder and self-report compulsive symptoms. American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, 183(4), 208-216. https://doi.org/10.1002/ajmg.b.32777

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title = "Genetic meta-analysis of obsessive–compulsive disorder and self-report compulsive symptoms",

abstract = "We investigated whether obsessive–compulsive (OC) symptoms from a population-based sample could be analyzed to detect genetic variants influencing obsessive–compulsive disorder (OCD). We performed a genome-wide association studies (GWAS) on the obsession (rumination and impulsions) and compulsion (checking, washing, and ordering/precision) subscales of an abbreviated version of the Padua Inventory (N = 8,267 with genome-wide genotyping and phenotyping). The compulsion subscale showed a substantial and significant positive genetic correlation with an OCD case–control GWAS (rG = 0.61, p =.017) previously published by the Psychiatric Genomics Consortium (PGC-OCD). The obsession subscale and the total Padua score showed no significant genetic correlations (rG = −0.02 and rG = 0.42, respectively). A meta-analysis of the compulsive symptoms GWAS with the PGC-OCD revealed no genome-wide significant Single-Nucleotide Polymorphisms (SNPs combined N = 17,992, indicating that the power is still low for individual SNP effects). A gene-based association analysis, however, yielded two novel genes (WDR7 and ADCK1). The top 250 genes in the gene-based test also showed a significant increase in enrichment for psychiatric and brain-expressed genes. S-Predixcan testing showed that for genes expressed in hippocampus, amygdala, and caudate nucleus significance increased in the meta-analysis with compulsive symptoms compared to the original PGC-OCD GWAS. Thus, the inclusion of dimensional symptom data in genome-wide association on clinical case–control GWAS of OCD may be useful to find genes for OCD if the data are based on quantitative indices of compulsive behavior. SNP-level power increases were limited, but aggregate, gene-level analyses showed increased enrichment for brain-expressed genes related to psychiatric disorders, and increased association with gene expression in brain tissues with known emotional, reward processing, memory, and fear-formation functions.",

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AU - Smit, Dirk J.A.

AU - Cath, Danielle

AU - Zilhão, Nuno R.

AU - Ip, Hill F.

AU - Denys, Damiaan

AU - den Braber, Anouk

AU - de Geus, Eco J.C.

AU - Verweij, Karin J.H.

AU - Hottenga, Jouke Jan

AU - Boomsma, Dorret I.

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AB - We investigated whether obsessive–compulsive (OC) symptoms from a population-based sample could be analyzed to detect genetic variants influencing obsessive–compulsive disorder (OCD). We performed a genome-wide association studies (GWAS) on the obsession (rumination and impulsions) and compulsion (checking, washing, and ordering/precision) subscales of an abbreviated version of the Padua Inventory (N = 8,267 with genome-wide genotyping and phenotyping). The compulsion subscale showed a substantial and significant positive genetic correlation with an OCD case–control GWAS (rG = 0.61, p =.017) previously published by the Psychiatric Genomics Consortium (PGC-OCD). The obsession subscale and the total Padua score showed no significant genetic correlations (rG = −0.02 and rG = 0.42, respectively). A meta-analysis of the compulsive symptoms GWAS with the PGC-OCD revealed no genome-wide significant Single-Nucleotide Polymorphisms (SNPs combined N = 17,992, indicating that the power is still low for individual SNP effects). A gene-based association analysis, however, yielded two novel genes (WDR7 and ADCK1). The top 250 genes in the gene-based test also showed a significant increase in enrichment for psychiatric and brain-expressed genes. S-Predixcan testing showed that for genes expressed in hippocampus, amygdala, and caudate nucleus significance increased in the meta-analysis with compulsive symptoms compared to the original PGC-OCD GWAS. Thus, the inclusion of dimensional symptom data in genome-wide association on clinical case–control GWAS of OCD may be useful to find genes for OCD if the data are based on quantitative indices of compulsive behavior. SNP-level power increases were limited, but aggregate, gene-level analyses showed increased enrichment for brain-expressed genes related to psychiatric disorders, and increased association with gene expression in brain tissues with known emotional, reward processing, memory, and fear-formation functions.

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KW - genome-wide association study (GWAS)

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JO - American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics

JF - American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics

IS - 4

ER -

Genetic meta-analysis of obsessive–compulsive disorder and self-report compulsive symptoms

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Keywords

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