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. Author manuscript; available in PMC: 2018 Apr 15.
Published in final edited form as: J Neurol Sci. 2017 Jan 12;375:71–72. doi: 10.1016/j.jns.2017.01.040

C9orf72 hexanucleotide repeat expansions are not a common cause of obsessive-compulsive disorder

Karissa C Arthur 1,2,*, Alberto M Rivera 1,3, Jack Samuels 4, Ying Wang 4, Marcos Grados 4, Fernando S Goes 4, Brion Maher 4, Gerald Nestadt 4, Bryan J Traynor 1,5
PMCID: PMC5800785  NIHMSID: NIHMS845348  PMID: 28320191

Abstract

Obsessive-compulsive disorder (OCD) is a polygenic neuropsychiatric disorder characterized by repetitive thoughts and behaviors that cause distress. The pathogenic repeat expansion [GGGGCC]n found at the C9orf72 locus is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), and has also been documented in patients with psychosis and schizophrenia. Furthermore, obsessions and compulsions have been identified in patients diagnosed with ALS and/or FTD and carrying the pathogenic repeat expansion. Here, we performed genetic screening for the C9orf72 repeat expansion on 573 patients diagnosed with OCD. None of the patients were found to carry the expansion. The results show that patients with OCD do not commonly carry the pathogenic repeat expansion and therefore should not be routinely screened. OCD and psychotic patients who do test positive for the C9orf72, however, should be closely observed for the later development of FTD and ALS.

Keywords: C9orf72, Obsessive-Compulsive Disorder, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia

1. Introduction

Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder characterized by repetitive thoughts and behaviors that cause distress [1]. It is a relatively common disorder with a lifetime prevalence of about 2.3% in the United States population [2]. Recent studies support the hypothesis that OCD is a polygenic disorder, and genes in the glutamatergic, serotonergic, and dopaminergic systems have been identified as important [3].

A [GGGGCC]n hexanucleotide repeat expansion at the C9orf72 locus is the most common genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) [4,5]. This repeat expansion has also been identified in patients diagnosed with psychosis and schizophrenia [6,7,8]. Furthermore, obsessions and compulsions have been identified in patients diagnosed with ALS and/or FTD and carrying the pathogenic repeat expansion [9,10]. However, it is unclear whether the C9orf72 repeat expansion is a common cause of patients with OCD in isolation. In order to investigate the frequency of the hexanucleotide repeat in patients with OCD, we performed genetic screening on 573 patients diagnosed with OCD.

2. Materials and Methods

A total of 573 participants in the Johns Hopkins University (JHU) site of the OCD Collaborative Genetics Association Study were included [11]. An Institutional Review Board has approved the use of human subjects for this study, and consent forms were obtained from all patients participating in the study. All patients were diagnosed with OCD according to DSM-IV criteria [1]. 226 (39.4%) of the participants were male, and 347 (60.6%) were female. The median age was 35 years (range, 7 to 84). Most (n = 546) of the participants were white, 4 were African-American, 9 were Latino, 9 were of other ethnicities, and ethnicity was missing for 5 individuals. A total of 378 (66%) of the cases had a family history of OCD (i.e., 1 or more relatives with OCD).

DNA samples were arrayed on seven 96-well plates. Each of these seven plates also contained a control sample known to carry a pathogenic C9orf72 repeat expansion. The C9orf72 hexanucleotide repeat was genotyped according to the previously described repeat-primed polymerase chain reaction (PCR) assay [5]. The resulting PCR amplicons were analyzed on an Applied Biosystems 3730cl DNA Analyzer (Life Technologies, Grand Island, N.Y., USA). The C9orf72 hexanucleotide expansion was considered pathogenic if it contained more than 30 repeats and had the typical sawtooth wave pattern [5].

3. Results

None of the 573 patients diagnosed with OCD carried a pathogenic C9orf72 repeat expansion. The control tested positive on all plates.

4. Discussion

This study shows that patients with OCD do not commonly harbor the pathogenic C9orf72 repeat expansion. Our data, together with the high occurrence of behavioral FTD among C9orf72 carriers, leads us to speculate that this type of repeat expansion is not a common cause of isolated neuropsychiatric syndromes. Instead, we postulate that the cases with psychosis, schizophrenia or OCD reported in the literature may be misdiagnosed cases of behavioral variant FTD. Under this paradigm, their neuropsychiatric symptoms were the initial manifestation of frontal lobe dysfunction and such patients would likely manifest additional symptoms of frontal lobe dysfunction or motor neuron degeneration if followed longitudinally.

In this regard, several clinical aspects of published cases of C9orf72-related neuropsychiatric disease are noteworthy. First, one of the patients diagnosed with schizophrenia reported by Galimberti et al. (2014) had a family history of early-onset dementia. The second patient developed severe cognitive impairment over the course of his illness and a CT scan of his brain showed diffuse brain atrophy [6]. Similarly, two of the four patients who tested positive for the expansion in the study performed by Watson et al. (2016) had a family history of an ill-defined neurological disorder [8]. Second, many of these cases manifested symptoms late in life, well past the peak age of symptom onset for these neuropsychiatric diseases [6,8].

We conclude that patients with isolated neuropsychiatric syndromes should not be routinely screened for the C9orf72 repeat expansion unless there is a family history of early-onset dementia or their symptoms occur late in life. Furthermore, OCD and psychotic patients who do test positive for the C9orf72 should be closely observed for the later development of FTD and ALS.

Highlights.

  • DNA from patients with OCD were tested for the C9orf72 repeat expansion.

  • None of the cases tested positive.

  • The C9orf72 repeat expansion is not a common cause of OCD.

Acknowledgments

This work was supported in part by the Intramural Research Program of the US National Institutes of Health (NIH), National Institute on Aging [Z01-AG000949-02], National Institute of Neurological Disorders and Stroke, and the National Institute of Mental Health, JHU site of the OCGAS [MH071507]. This research was made possible through the National Institutes of Health (NIH) Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation, The American Association for Dental Research, The Howard Hughes Medical Institute, and the Colgate-Palmolive Company, as well as other private donors. For a complete list, please visit the Foundation website at: http://fnih.org/work/education-training-0/medical-research-scholars-program.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Disclosure statement

BJT has a patent pending on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72.

Author Contributions

B.J.T. and G.N. designed the study. J.S., Y.W., M.G., F.G., B.M., and G.N. were involved in patient identification and DNA extraction. K.C.A. and A.M.R. performed C9orf72 screening. K.C.A. wrote the paper. All authors were involved in critical revisions of the manuscript.

References

  • 1.American Psychiatric Association. Diagnostic and statistical manual of mental disorders DSM-IV-TR. 4th., text revision. Washington, DC: Author; 2000. [Google Scholar]
  • 2.Ruscio AM, Stein DJ, Chiu WT, Kessler RC. The epidemiology of obsessive-compulsive disorder in the National Comorbidity Survey Replication. Mol Psychiatry. 2010;15:53–63. doi: 10.1038/mp.2008.94. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Pauls DL, Abramovitch A, Rauch SL, Geller DA. Obsessive-compulsive disorder: an integrative genetic and neurobiological perspective. Nature Rev Neurosci. 2014;15:410–424. doi: 10.1038/nrn3746. [DOI] [PubMed] [Google Scholar]
  • 4.DeJesus-Hernandez M, Mackenzie IR, Boeve BF, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72:245–256. doi: 10.1016/j.neuron.2011.09.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Renton AE, Majounie E, Waite A, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011;72:257–268. doi: 10.1016/j.neuron.2011.09.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Galimberti D, Reif A, Dell'Osso B, et al. The C9ORF72 hexanucleotide repeat expansion is a rare cause of schizophrenia. Neurobiol Aging. 2014;35:1214-e7. doi: 10.1016/j.neurobiolaging.2013.12.004. [DOI] [PubMed] [Google Scholar]
  • 7.Snowden JS, Rollinson S, Lafon C, Harris J, et al. Psychosis, C9ORF72 and dementia with Lewy bodies. J Neurol Neurosurg Psychiatry. 2012;83:1031–1032. doi: 10.1136/jnnp-2012-303032. [DOI] [PubMed] [Google Scholar]
  • 8.Watson A, Pribadi M, Chowdari K, et al. C9orf72 repeat expansions that cause frontotemporal dementia are detectable among patients with psychosis. Psychiatry Res. 2016;235:200–202. doi: 10.1016/j.psychres.2015.12.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Calvo A, Moglia C, Canosa A, et al. Amyotrophic lateral sclerosis/frontotemporal dementia with predominant manifestations of obsessive–compulsive disorder associated to GGGGCC expansion of the c9orf72 gene. J Neurol. 2012;259:2723–2725. doi: 10.1007/s00415-012-6640-1. [DOI] [PubMed] [Google Scholar]
  • 10.Snowden JS, Rollinson S, Thompson JC, et al. Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain. 2012;135:693–708. doi: 10.1093/brain/awr355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Mattheisen M, Samuels JF, Wang Y, et al. Genome-Wide Association Study in obsessive-compulsive disorder: results from the OCGAS. Mol Psychiatry. 2015;20:337–344. doi: 10.1038/mp.2014.43. [DOI] [PMC free article] [PubMed] [Google Scholar]

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