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

Molecular Psychiatry volume 23, pages 1181–1188 (2018)Cite this article

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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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Acknowledgements

The OCD Collaborative Genetics Association Study (OCGAS) is a collaborative research study and was funded by the following NIMH Grant Numbers: MH071507 (GN), MH079489 (DAG), MH079487 (JM), MH079488 (AF) and MH079494 (JK). Yao Shugart and Wei Guo were also supported by the Intramural Research Program of the NIMH (MH002930-06)

The International Obsessive Compulsive Foundation Genetics Collaborative (IOCDF-GC) was supported by a grant from the David Judah Foundation (a private, nonindustry-related foundation established by a family affected by OCD), MH079489 (DLP), MH073250 (DLP), S40024 (JMS), MH 085057 (JMS), and MH087748 (CAM).

We thank the Psychiatric Genomics Consortium (PGC) for the use of their servers for data integration and analysis, the many families who have participated in the study, as well as the clinicians, study managers and clinical interviewers at the respective study sites for their efforts in participant recruitment and clinical assessments.

The views expressed here do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government.

Author contributions

Analytic group: Wei Guo, Dongmei Yu, Lea Davis, Stephan Ripke and Yin Yao Shugart; interpretation of data and manuscript preparation: Paul Arnold, Lea Davis, E.M. Derks, Wei Guo, James Knowles, Carol A Mathews, Rainald Moessner, Gerald Nestadt, Jeremiah M Scharf, Yin Yao Shugart and Dongmei Yu.

Author information

Author notes

  1. Paul D Arnold, Kathleen D Askland, Cristina Barlassina, Laura Bellodi, O J Bienvenu, Donald Black, Michael Bloch, Helena Brentani, Christie L Burton, Beatriz Camarena, Carolina Cappi, Danielle Cath, Maria Cavallini, David Conti, Edwin Cook, Vladimir Coric, Bernadette A Cullen, Danielle Cusi, Lea K Davis, Richard Delorme, Damiaan Denys, Eske Derks, Valsamma Eapen, Christopher Edlund, Lauren Erdman, Peter Falkai, Martijn Figee, Abigail J Fyer, Daniel A Geller, Fernando S Goes, Hans Grabe, Marcos A Grados, Benjamin D Greenberg, Edna Grünblatt, Wei Guo, Gregory L Hanna, Sian Hemmings, Ana G Hounie, Michael Jenicke, Clare Keenan, James Kennedy, Ekaterina A Khramtsova, Anuar Konkashbaev, James A Knowles, Janice Krasnow, Cristophe Lange, Nuria Lanzagorta, Marion Leboyer, Leonhard Lennertz, Bingbin Li, K-Y Liang, Christine Lochner, Fabio Macciardi, Brion Maher, Wolfgang Maier, Maurizio Marconi, Carol A Mathews, Manuel Matthesien, James T McCracken, Nicole C McLaughlin, Euripedes C Miguel, Rainald Moessner, Dennis L Murphy, Benjamin Neale, Gerald Nestadt, Paul Nestadt, Humberto Nicolini, Ericka Nurmi, Lisa Osiecki, David L Pauls, John Piacentini, Danielle Posthuma, Ann E Pulver, H-D Qin, Steven A Rasmussen, Scott Rauch, Margaret A Richter, Mark A Riddle, Stephan Ripke, Stephan Ruhrmann, Aline S Sampaio, Jack F Samuels, Jeremiah M Scharf, Yin Yao Shugart, Jan Smit, Daniel Stein, S Evelyn Stewart, Maurizio Turiel, Homero Vallada, Jeremy Veenstra-VanderWeele, Michael Wagner, Susanne Walitza, Y Wang, Jens Wendland, Nienke Vulink, Dongmei Yu and Gwyneth Zai: Members of the International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) and OCD Collaborative Genetics Association Studies (OCGAS) are listed before Reference section.

Authors and Affiliations

  1. , E-mail:,

    James A Knowles

  2. , E-mail:,

    Gerald Nestadt

Consortia

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

  • Paul D Arnold
  • , Kathleen D Askland
  • , Cristina Barlassina
  • , Laura Bellodi
  • , O J Bienvenu
  • , Donald Black
  • , Michael Bloch
  • , Helena Brentani
  • , Christie L Burton
  • , Beatriz Camarena
  • , Carolina Cappi
  • , Danielle Cath
  • , Maria Cavallini
  • , David Conti
  • , Edwin Cook
  • , Vladimir Coric
  • , Bernadette A Cullen
  • , Danielle Cusi
  • , Lea K Davis
  • , Richard Delorme
  • , Damiaan Denys
  • , Eske Derks
  • , Valsamma Eapen
  • , Christopher Edlund
  • , Lauren Erdman
  • , Peter Falkai
  • , Martijn Figee
  • , Abigail J Fyer
  • , Daniel A Geller
  • , Fernando S Goes
  • , Hans Grabe
  • , Marcos A Grados
  • , Benjamin D Greenberg
  • , Edna Grünblatt
  • , Wei Guo
  • , Gregory L Hanna
  • , Sian Hemmings
  • , Ana G Hounie
  • , Michael Jenicke
  • , Clare Keenan
  • , James Kennedy
  • , Ekaterina A Khramtsova
  • , Anuar Konkashbaev
  • , James A Knowles
  • , Janice Krasnow
  • , Cristophe Lange
  • , Nuria Lanzagorta
  • , Marion Leboyer
  • , Leonhard Lennertz
  • , Bingbin Li
  • , K-Y Liang
  • , Christine Lochner
  • , Fabio Macciardi
  • , Brion Maher
  • , Wolfgang Maier
  • , Maurizio Marconi
  • , Carol A Mathews
  • , Manuel Matthesien
  • , James T McCracken
  • , Nicole C McLaughlin
  • , Euripedes C Miguel
  • , Rainald Moessner
  • , Dennis L Murphy
  • , Benjamin Neale
  • , Gerald Nestadt
  • , Paul Nestadt
  • , Humberto Nicolini
  • , Ericka Nurmi
  • , Lisa Osiecki
  • , David L Pauls
  • , John Piacentini
  • , Danielle Posthuma
  • , Ann E Pulver
  • , H-D Qin
  • , Steven A Rasmussen
  • , Scott Rauch
  • , Margaret A Richter
  • , Mark A Riddle
  • , Stephan Ripke
  • , Stephan Ruhrmann
  • , Aline S Sampaio
  • , Jack F Samuels
  • , Jeremiah M Scharf
  • , Yin Yao Shugart
  • , Jan Smit
  • , Daniel Stein
  • , S Evelyn Stewart
  • , Maurizio Turiel
  • , Homero Vallada
  • , Jeremy Veenstra-VanderWeele
  • , Michael Wagner
  • , Susanne Walitza
  • , Y Wang
  • , Jens Wendland
  • , Nienke Vulink
  • , Dongmei Yu
  •  & Gwyneth Zai

Corresponding authors

Correspondence to James A Knowles or Gerald Nestadt.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Members of the IOCDF-GC and OCGAS consortia Paul D Arnold (IOCDF-GC), Kathleen D Askland (OCGAS and IOCDF-GC), Cristina Barlassina (IOCDF-GC), Laura Bellodi (IOCDF-GC), OJ Bienvenu (OCGAS and IOCDF-GC), Donald Black (IOCDF-GC), Michael Bloch (IOCDF-GC), Helena Brentani (IOCDF-GC), Christie L Burton (IOCDF-GC), Beatriz Camarena (IOCDF-GC), Carolina Cappi (IOCDF-GC), Danielle Cath (IOCDF-GC), Maria Cavallini (IOCDF-GC), David Conti (OCGAS), Edwin Cook (IOCDF-GC), Vladimir Coric (IOCDF-GC), Bernadette A Cullen (OCGAS and IOCDF-GC), Danielle Cusi (IOCDF-GC), Lea K Davis (IOCDF-GC), Richard Delorme (IOCDF-GC), Damiaan Denys (IOCDF-GC), Eske Derks (IOCDF-GC), Valsamma Eapen (IOCDF-GC), Christopher Edlund (IOCDF-GC), Lauren Erdman (IOCDF-GC), Peter Falkai (IOCDF-GC), Martijn Figee (IOCDF-GC), Abigail J Fyer (OCGAS and IOCDF-GC), Daniel A Geller (IOCDF-GC and OCGAS), Fernando S Goes (OCGAS), Hans Grabe (IOCDF-GC), Marcos A Grados (OCGAS and IOCDF-GC), Benjamin D Greenberg (OCGAS and IOCDF-GC), Edna Grünblatt (IOCDF-GC), Wei Guo (OCGAS), Gregory L Hanna (IOCDF-GC), Sian Hemmings (IOCDF-GC), Ana G Hounie (IOCDF-GC), Michael Jenicke (IOCDF-GC), Clare Keenan (IOCDF-GC), James Kennedy (IOCDF-GC), Ekaterina A Khramtsova (IOCDF-GC), Anuar Konkashbaev (IOCDF-GC), James A Knowles (IOCDF-GC and OCGAS), Janice Krasnow (IOCDF-GC and OCGAS), Cristophe Lange (OCGAS), Nuria Lanzagorta (IOCDF-GC), Marion Leboyer (IOCDF-GC), Leonhard Lennertz (IOCDF-GC), Bingbin Li (OCGAS), K-Y Liang (OCGAS and IOCDF-GC), Christine Lochner (IOCDF-GC), Fabio Macciardi (IOCDF-GC), Brion Maher (OCGAS), Wolfgang Maier (IOCDF-GC), Maurizio Marconi (IOCDF-GC), Carol A Mathews (IOCDF-GC), Manuel Matthesien (OCGAS), James T McCracken (OCGAS and IOCDF-GC), Nicole C McLaughlin (OCGAS and IOCDF-GC), Euripedes C Miguel (IOCDF-GC), Rainald Moessner (IOCDF-GC), Dennis L Murphy (OCGAS and IOCDF-GC), Benjamin Neale (IOCDF-GC), Gerald Nestadt (OCGAS and IOCDF-GC), Paul Nestadt (IOCDF-GC and OCGAS), Humberto Nicolini (OCDF-GC), Ericka Nurmi (OCGAS), Lisa Osiecki (IOCDF-GC), David L Pauls (IOCDF-GC and OCGAS), John Piacentini (OCGAS and IOCDF-GC), Danielle Posthuma (IOCDF-GC), Ann E Pulver (OCGAS), H-D Qin (OCGAS), Steven A Rasmussen (OCGAS and IOCDF-GC), Scott Rauch (IOCDF-GC), Margaret A Richter (IOCDF-GC), Mark A Riddle (OCGAS and IOCDF-GC), Stephan Ripke (Psychiatric Genomics Consortium), Stephan Ruhrmann (IOCDF-GC), Aline S Sampaio (IOCDF-GC), Jack F Samuels (OCGAS and IOCDF-GC), Jeremiah M Scharf (IOCDF-GC), Yin Yao Shugart (OCGAS and IOCDF-GC), Jan Smit (IOCDF-GC), Daniel Stein (IOCDF-GC), S Evelyn Stewart (IOCDF-GC and OCGAS), Maurizio Turiel (IOCDF-GC), Homero Vallada (IOCDF-GC), Jeremy Veenstra-VanderWeele (IOCDF-GC), Michael Wagner (IOCDF-GC), Susanne Walitza (IOCDF-GC), Y Wang (OCGAS and IOCDF-GC), Jens Wendland (IOCDF-GC), Nienke Vulink (IOCDF-GC), Dongmei Yu (IOCDF-GC), Gwyneth Zai (IOCF-GC).

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

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