Skip to main content

Significant concordance of genetic variation that increases both the risk for obsessive–compulsive disorder and the volumes of the nucleus accumbens and putamen

  • Derrek P. Hibar (a1), Joshua W. Cheung (a1), Sarah E. Medland (a2), Mary S. Mufford (a3), Neda Jahanshad (a1), Shareefa Dalvie (a4), Raj Ramesar (a5), Evelyn Stewart (a6), Odile A. van den Heuvel (a7), David L. Pauls (a8), James A. Knowles (a9), Dan J. Stein (a10), Paul M. Thompson (a1) and Enhancing Neuro Imaging Genetics through Meta Analysis (ENIGMA) Consortium and International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) (a1) (a2) (a3) (a1) (a4) (a5) (a6) (a7) (a8) (a9) (a10) (a1)...

Many studies have identified changes in the brain associated with obsessive–compulsive disorder (OCD), but few have examined the relationship between genetic determinants of OCD and brain variation.


We present the first genome-wide investigation of overlapping genetic risk for OCD and genetic influences on subcortical brain structures.


Using single nucleotide polymorphism effect concordance analysis, we measured genetic overlap between the first genome-wide association study (GWAS) of OCD (1465 participants with OCD, 5557 controls) and recent GWASs of eight subcortical brain volumes (13 171 participants).


We found evidence of significant positive concordance between OCD risk variants and variants associated with greater nucleus accumbens and putamen volumes. When conditioning OCD risk variants on brain volume, variants influencing putamen, amygdala and thalamus volumes were associated with risk for OCD.


These results are consistent with current OCD neurocircuitry models. Further evidence will clarify the relationship between putamen volume and OCD risk, and the roles of the detected variants in this disorder.

Declaration of interest

The authors have declared that no competing interests exist.

Corresponding author
Correspondence: Paul M. Thompson, PhD, Imaging Genetics Center and Institute for Neuroimaging and Informatics, Keck School of Medicine of the University of Southern California, University of Southern California, 4676 Admiralty Way, Marina del Rey, CA 90292, USA. Email:
Hide All

A full author list, including all affiliations, is available as supplementary material at

Hide All
1.Ruscio, AM, Stein, DJ, Chiu, WT, Kessler, RC. The epidemiology of obsessive-compulsive disorder in the National Comorbidity Survey Replication. Mol Psychiatry 2010; 15: 5363.
2.Ayuso-Mateos, JL. Global Burden of Obsessive-Compulsive Disorder in the Year 2000. World Health Organization, 2006.
3.Kariuki-Nyuthe, C, Gomez-Mancilla, B, Stein, DJ. Obsessive compulsive disorder and the glutamatergic system. Curr Opin Psychiatry 2014; 27: 32–7.
4.Wu, K, Hanna, GL, Rosenberg, DR, Arnold, PD. The role of glutamate signaling in the pathogenesis and treatment of obsessive-compulsive disorder. Pharmacol Biochem Behav 2012; 100: 726–35.
5.van Grootheest, DS, Cath, DC, Beekman, AT, Boomsma, DI. Twin studies on obsessive-compulsive disorder: a review. Twin Res Hum Genet 2005; 8: 450–8.
6.Iervolino, AC, Rijsdijk, FV, Cherkas, L, Fullana, MA, Mataix-Cols, D. A multivariate twin study of obsessive-compulsive symptom dimensions. Arch Gen Psychiatry 2011; 68: 637–44.
7.Moore, J, Smith, GW, Shevlin, M, O'Neill, FA. Alternative factor models and heritability of the Short Leyton Obsessional Inventory-Children's Version. J Abnorm Child Psychol 2010; 38: 921–34.
8.Bolton, D, Rijsdijk, F, Eley, TC, O'Connor, TG, Briskman, J, Perrin, S. Normative childhood repetitive routines and obsessive compulsive symptomatology in 6-year-old twins. J Child Psychol Psychiatry 2009; 50: 1139–46.
9.den Braber, A, van ’t Ent, D, Boomsma, DI, Cath, DC, Veltman, DJ, Thompson, PM, et al. White matter differences in monozygotic twins discordant or concordant for obsessive-compulsive symptoms: a combined diffusion tensor imaging/voxel-based morphometry study. Biol Psychiatry 2011; 70: 969–77.
10.den Braber, A, van ’t Ent, D, Cath, DC, Veltman, DJ, Boomsma, DI, de Geus, EJ. Brain activation during response interference in twins discordant or concordant for obsessive compulsive symptoms. Twin Res Hum Genet 2012; 15: 372–83.
11.den Braber, A, van ’t Ent, D, Cath, DC, Wagner, J, Boomsma, DI, de Geus, EJ. Brain activation during cognitive planning in twins discordant or concordant for obsessive-compulsive symptoms. Brain 2010; 133: 3123–40.
12.Hibar, DP, Stein, JL, Renteria, ME, Arias-Vasquez, A, Desriviéres, S, Jahanshad, N, et al. Common genetic variants influence human subcortical brain structures. Nature 2015; 520: 224–9.
13.Wu, K, Hanna, GL, Easter, P, Kennedy, JL, Rosenberg, DR, Arnold, PD. Glutamate system genes and brain volume alterations in pediatric obsessive-compulsive disorder: a preliminary study. Psychiatry Res 2013; 211: 214–20.
14.Stewart, SE, Yu, D, Scharf, JM, Neale, BM, Fagerness, JA, Mathews, CA, et al. Genome-wide association study of obsessive-compulsive disorder. Mol Psychiatry 2013; 18: 788–98.
15.Fischl, B, Salat, DH, Busa, E, Albert, M, Dieterich, M, Haselgrove, C, et al. Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron 2002; 33: 341–55.
16.Purcell, S, Neale, B, Todd-Brown, K, Thomas, L, Ferreira, MA, Bender, D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–75.
17.Nyholt, DR. SECA: SNP effect concordance analysis using genome-wide association summary results. Bioinformatics 2014; 30: 2086–8.
18.Andreassen, OA, Thompson, WK, Schork, AJ, Ripke, S, Mattingsdal, M, Kelsoe, JR, et al. Improved detection of common variants associated with schizophrenia and bipolar disorder using pleiotropy-informed conditional false discovery rate. Plos Genet 2013; 9: e1003455.
19.Benjamini, Y, Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser A 1995; 57: 289300.
20.Bulik-Sullivan, BK, Loh, PR, Finucane, HK, Ripke, S, Yang, J, Schizophrenia Working Group of the Psychiatric Genomics C, et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat Genet 2015; 47: 291–5.
21.Bulik-Sullivan, B, Finucane, HK, Anttila, V, Gusev, A, Day, FR, Loh, PR, et al. An atlas of genetic correlations across human diseases and traits. Nat Genet 2015; 47: 1236–41.
22.Shaw, P, Sharp, W, Sudre, G, Wharton, A, Greenstein, D, Raznahan, A, et al. Subcortical and cortical morphological anomalies as an endophenotype in obsessive-compulsive disorder. Mol Psychiatry 2015; 20: 224–31. Wit, SJ, Alonso, P, Schweren, L, Mataix-Cols, D, Lochner, C, Menchon, JM, et al. Multicenter voxel-based morphometry mega-analysis of structural brain scans in obsessive-compulsive disorder. Am J Psychiatry 2014; 171: 340–9.
24.Blokland, GA, de Zubicaray, GI, McMahon, KL, Wright, MJ. Genetic and environmental influences on neuroimaging phenotypes: a meta-analytical perspective on twin imaging studies. Twin Res Hum Genet 2012; 15: 351–71.
25.Radua, J, Mataix-Cols, D. Voxel-wise meta-analysis of grey matter changes in obsessive-compulsive disorder. Br J Psychiatry 2009; 195: 393402.
26.Rotge, JY, Guehl, D, Dilharreguy, B, Tignol, J, Bioulac, B, Allard, M, et al. Meta-analysis of brain volume changes in obsessive-compulsive disorder. Biol Psychiatry 2009; 65: 7583.
27.Denys, D, Mantione, M, Figee, M, van den Munckhof, P, Koerselman, F, Westenberg, H, et al. Deep brain stimulation of the nucleus accumbens for treatment-refractory obsessive-compulsive disorder. Arch Gen Psychiatry 2010; 67: 1061–8.
28.Kim, E, Naisbitt, S, Hsueh, YP, Rao, A, Rothschild, A, Craig, AM, et al. GKAP, a novel synaptic protein that interacts with the guanylate kinase-like domain of the PSD-95/SAP90 family of channel clustering molecules. J Cell Biol 1997; 136: 669–78.
29.Wan, Y, Ade, KK, Caffall, Z, Ilcim Ozlu, M, Eroglu, C, Feng, G, et al. Circuit-selective striatal synaptic dysfunction in the Sapap3 knockout mouse model of obsessive-compulsive disorder. Biol Psychiatry 2014; 75: 623–30.
30.Burguiere, E, Monteiro, P, Feng, G, Graybiel, AM. Optogenetic stimulation of lateral orbitofronto-striatal pathway suppresses compulsive behaviors. Science 2013; 340: 1243–6.
31.Blaydon, DC, Ishii, Y, O'Toole, EA, Unsworth, HC, Teh, MT, Ruschendorf, F, et al. The gene encoding R-spondin 4 (RSPO4), a secreted protein implicated in Wnt signaling, is mutated in inherited anonychia. Nat Genet 2006; 38: 1245–7.
32.Okerlund, ND, Cheyette, BN. Synaptic Wnt signaling-a contributor to major psychiatric disorders? J Neurodev Disord 2011; 3: 162–74.
33.Wasif, N, Ahmad, W. A novel nonsense mutation in RSPO4 gene underlies autosomal recessive congenital anonychia in a Pakistani family. Pediatr Dermatol 2013; 30: 139–41.
34.Jolles, P, Jolles, J. Whats new in lysozyme research - always a model system, today as yesterday. Mol Cell Biochem 1984; 63: 165–89.
35.Cao, MY, Davidson, D, Yu, J, Latour, S, Veillette, A. Clnk, a novel SLP-76-related adaptor molecule expressed in cytokine-stimulated hemopoietic cells. J Exp Med 1999; 190: 1527–34.
36.Utting, O, Sedgmen, BJ, Watts, TH, Shi, X, Rottapel, R, Iulianella, A, et al. Immune functions in mice lacking Clnk, an SLP-76-related adaptor expressed in a subset of immune cells. Mol Cell Biol 2004; 24: 6067–75.
37.Swedo, SE, Leonard, HL, Garvey, M, Mittleman, B, Allen, AJ, Perlmutter, S, et al. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry 1998; 155: 264–71.
38.Ramasamy, A, Trabzuni, D, Guelfi, S, Varghese, V, Smith, C, Walker, R, et al. Genetic variability in the regulation of gene expression in ten regions of the human brain. Nat Neurosci 2014; 17: 1418–28.
39.Stewart, SE, Mayerfeld, C, Arnold, PD, Crane, JR, O'Dushlaine, C, Fagerness, JA, et al. Meta-analysis of association between obsessive-compulsive disorder and the 3′ region of neuronal glutamate transporter gene SLC1A1. Am J Med Genet B 2013; 162B: 367–79.
40.Arnold, PD, Macmaster, FP, Hanna, GL, Richter, MA, Sicard, T, Burroughs, E, et al. Glutamate system genes associated with ventral prefrontal and thalamic volume in pediatric obsessive-compulsive disorder. Brain imaging and behavior. 2009; 3: 6476.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

The British Journal of Psychiatry
  • ISSN: 0007-1250
  • EISSN: 1472-1465
  • URL: /core/journals/the-british-journal-of-psychiatry
Please enter your name
Please enter a valid email address
Who would you like to send this to? *


Type Description Title
Supplementary materials

Hibar et al. supplementary material
Hibar et al. supplementary material 1

 Unknown (330 KB)
330 KB


Altmetric attention score

Significant concordance of genetic variation that increases both the risk for obsessive–compulsive disorder and the volumes of the nucleus accumbens and putamen

  • Derrek P. Hibar (a1), Joshua W. Cheung (a1), Sarah E. Medland (a2), Mary S. Mufford (a3), Neda Jahanshad (a1), Shareefa Dalvie (a4), Raj Ramesar (a5), Evelyn Stewart (a6), Odile A. van den Heuvel (a7), David L. Pauls (a8), James A. Knowles (a9), Dan J. Stein (a10), Paul M. Thompson (a1) and Enhancing Neuro Imaging Genetics through Meta Analysis (ENIGMA) Consortium and International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) (a1) (a2) (a3) (a1) (a4) (a5) (a6) (a7) (a8) (a9) (a10) (a1)...
Submit a response


No eLetters have been published for this article.


Reply to: Submit a response

Your details

Conflicting interests

Do you have any conflicting interests? *