Revealing the complex genetic architecture of obsessive-compulsive disorder using meta-analysis

International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC), OCD Collaborative Genetics Association Studies (OCGAS)

Research output: Contribution to journalArticle

Abstract

Two obsessive-compulsive disorder (OCD) genome-wide association studies (GWASs) have been published by independent OCD consortia, the International Obsessive-Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) and the OCD Collaborative Genetics Association Study (OCGAS), but many of the top-ranked signals were supported in only one study. We therefore conducted a meta-analysis from the two consortia, investigating a total of 2688 individuals of European ancestry with OCD and 7037 genomically matched controls. No single-nucleotide polymorphisms (SNPs) reached genome-wide significance. However, in comparison with the two individual GWASs, the distribution of P-values shifted toward significance. The top haplotypic blocks were tagged with rs4733767 (P=7.1 × 10 -7; odds ratio (OR)=1.21; confidence interval (CI): 1.12-1.31, CASC8/CASC11), rs1030757 (P=1.1 × 10 -6; OR=1.18; CI: 1.10-1.26, GRID2) and rs12504244 (P=1.6 × 10 -6; OR=1.18; CI: 1.11-1.27, KIT). Variants located in or near the genes ASB13, RSPO4, DLGAP1, PTPRD, GRIK2, FAIM2 and CDH20, identified in linkage peaks and the original GWASs, were among the top signals. Polygenic risk scores for each individual study predicted case-control status in the other by explaining 0.9% (P=0.003) and 0.3% (P=0.0009) of the phenotypic variance in OCGAS and the European IOCDF-GC target samples, respectively. The common SNP heritability in the combined OCGAS and IOCDF-GC sample was estimated to be 0.28 (s.e.=0.04). Strikingly, ∼65% of the SNP-based heritability in the OCGAS sample was accounted for by SNPs with minor allele frequencies of ≥40%. This joint analysis constituting the largest single OCD genome-wide study to date represents a major integrative step in elucidating the genetic causes of OCD.

Original languageEnglish (US)
Pages (from-to)1181-1188
Number of pages8
JournalMolecular Psychiatry
Volume23
Issue number5
DOIs
StatePublished - May 1 2018

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Obsessive-Compulsive Disorder
Meta-Analysis
Genetic Association Studies
Single Nucleotide Polymorphism
Genome-Wide Association Study
Odds Ratio
Confidence Intervals
Genome
Gene Frequency
Case-Control Studies

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC), & OCD Collaborative Genetics Association Studies (OCGAS) (2018). Revealing the complex genetic architecture of obsessive-compulsive disorder using meta-analysis. Molecular Psychiatry, 23(5), 1181-1188. https://doi.org/10.1038/mp.2017.154

Revealing the complex genetic architecture of obsessive-compulsive disorder using meta-analysis. / International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC); OCD Collaborative Genetics Association Studies (OCGAS).

In: Molecular Psychiatry, Vol. 23, No. 5, 01.05.2018, p. 1181-1188.

Research output: Contribution to journalArticle

International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) & OCD Collaborative Genetics Association Studies (OCGAS) 2018, 'Revealing the complex genetic architecture of obsessive-compulsive disorder using meta-analysis', Molecular Psychiatry, vol. 23, no. 5, pp. 1181-1188. https://doi.org/10.1038/mp.2017.154
International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC), OCD Collaborative Genetics Association Studies (OCGAS). Revealing the complex genetic architecture of obsessive-compulsive disorder using meta-analysis. Molecular Psychiatry. 2018 May 1;23(5):1181-1188. https://doi.org/10.1038/mp.2017.154
International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) ; OCD Collaborative Genetics Association Studies (OCGAS). / Revealing the complex genetic architecture of obsessive-compulsive disorder using meta-analysis. In: Molecular Psychiatry. 2018 ; Vol. 23, No. 5. pp. 1181-1188.
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abstract = "Two obsessive-compulsive disorder (OCD) genome-wide association studies (GWASs) have been published by independent OCD consortia, the International Obsessive-Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) and the OCD Collaborative Genetics Association Study (OCGAS), but many of the top-ranked signals were supported in only one study. We therefore conducted a meta-analysis from the two consortia, investigating a total of 2688 individuals of European ancestry with OCD and 7037 genomically matched controls. No single-nucleotide polymorphisms (SNPs) reached genome-wide significance. However, in comparison with the two individual GWASs, the distribution of P-values shifted toward significance. The top haplotypic blocks were tagged with rs4733767 (P=7.1 × 10 -7; odds ratio (OR)=1.21; confidence interval (CI): 1.12-1.31, CASC8/CASC11), rs1030757 (P=1.1 × 10 -6; OR=1.18; CI: 1.10-1.26, GRID2) and rs12504244 (P=1.6 × 10 -6; OR=1.18; CI: 1.11-1.27, KIT). Variants located in or near the genes ASB13, RSPO4, DLGAP1, PTPRD, GRIK2, FAIM2 and CDH20, identified in linkage peaks and the original GWASs, were among the top signals. Polygenic risk scores for each individual study predicted case-control status in the other by explaining 0.9{\%} (P=0.003) and 0.3{\%} (P=0.0009) of the phenotypic variance in OCGAS and the European IOCDF-GC target samples, respectively. The common SNP heritability in the combined OCGAS and IOCDF-GC sample was estimated to be 0.28 (s.e.=0.04). Strikingly, ∼65{\%} of the SNP-based heritability in the OCGAS sample was accounted for by SNPs with minor allele frequencies of ≥40{\%}. This joint analysis constituting the largest single OCD genome-wide study to date represents a major integrative step in elucidating the genetic causes of OCD.",
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AU - International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC)

AU - OCD Collaborative Genetics Association Studies (OCGAS)

AU - Arnold, Paul D.

AU - Askland, Kathleen D.

AU - Barlassina, Cristina

AU - Bellodi, Laura

AU - Bienvenu, Oscar J

AU - Black, Donald

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AU - Cath, Danielle

AU - Cavallini, Maria

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AU - Cook, Edwin

AU - Coric, Vladimir

AU - Cullen, Bernadette A.

AU - Cusi, Danielle

AU - Davis, Lea K.

AU - Delorme, Richard

AU - Denys, Damiaan

AU - Derks, Eske

AU - Eapen, Valsamma

AU - Edlund, Christopher

AU - Erdman, Lauren

AU - Falkai, Peter

AU - Figee, Martijn

AU - Fyer, Abigail J.

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AU - Goes, Fernando S

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AU - Grados, Marco

AU - Greenberg, Benjamin D.

AU - Grünblatt, Edna

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AU - Hounie, Ana G.

AU - Jenicke, Michael

AU - Keenan, Clare

AU - Kennedy, James

AU - Khramtsova, Ekaterina A.

AU - Konkashbaev, Anuar

AU - Knowles, James A.

AU - Maher, Brion

AU - Nestadt, Gerald

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AU - Samuels, Jack

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AB - Two obsessive-compulsive disorder (OCD) genome-wide association studies (GWASs) have been published by independent OCD consortia, the International Obsessive-Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) and the OCD Collaborative Genetics Association Study (OCGAS), but many of the top-ranked signals were supported in only one study. We therefore conducted a meta-analysis from the two consortia, investigating a total of 2688 individuals of European ancestry with OCD and 7037 genomically matched controls. No single-nucleotide polymorphisms (SNPs) reached genome-wide significance. However, in comparison with the two individual GWASs, the distribution of P-values shifted toward significance. The top haplotypic blocks were tagged with rs4733767 (P=7.1 × 10 -7; odds ratio (OR)=1.21; confidence interval (CI): 1.12-1.31, CASC8/CASC11), rs1030757 (P=1.1 × 10 -6; OR=1.18; CI: 1.10-1.26, GRID2) and rs12504244 (P=1.6 × 10 -6; OR=1.18; CI: 1.11-1.27, KIT). Variants located in or near the genes ASB13, RSPO4, DLGAP1, PTPRD, GRIK2, FAIM2 and CDH20, identified in linkage peaks and the original GWASs, were among the top signals. Polygenic risk scores for each individual study predicted case-control status in the other by explaining 0.9% (P=0.003) and 0.3% (P=0.0009) of the phenotypic variance in OCGAS and the European IOCDF-GC target samples, respectively. The common SNP heritability in the combined OCGAS and IOCDF-GC sample was estimated to be 0.28 (s.e.=0.04). Strikingly, ∼65% of the SNP-based heritability in the OCGAS sample was accounted for by SNPs with minor allele frequencies of ≥40%. This joint analysis constituting the largest single OCD genome-wide study to date represents a major integrative step in elucidating the genetic causes of OCD.

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