The OCD Collaborative Genetics Study (NIMH Study 16 - Excerpts from description provided by study)

 

INTRODUCTION

Obsessive-compulsive disorder (OCD) [MIM 164230] is a neuropsychiatric condition characterized by recurrent, intrusive thoughts (obsessions) and repetitive behaviors that the individual feels driven to perform (compulsions). Individuals with OCD recognize that these thoughts and behaviors are excessive and unreasonable and attempt to suppress them. The obsessions and compulsions cause marked distress, are time consuming, and significantly interfere with social and occupational functioning [APA, 1994]. In many cases, symptoms first appear in childhood and early adolescence, and the majority of cases have onset before 20 years of age [Rasmussen and Eisen, 1992]. The lifetime prevalence of the disorder is estimated to be 1-3% in adults, based on population surveys in the United States and other countries [Karno, et al., 1998; Weissman, et al., 1994].

The OCD Collaborative Genetics Study (OCGS), which commenced in 2001, is an ongoing collaboration among investigators at six sites in the United States: Providence (Butler Hospital/Brown University); New York City (Columbia University); Baltimore (Johns Hopkins University) (JHU); Boston (Massachusetts General Hospital/Harvard Medical School); Bethesda, Maryland (NIMH); and Los Angeles (UCLA). Johns Hopkins University is the coordinating center for the study, which is funded by NIMH (R01 MH50214), under the auspices of the NIMH Genetics Initiative (www-grb.nimh.nih.gov/gi/html). The aims of the OCGS are to: (1) conduct diagnostic evaluations and obtain blooc specimens from a large sample of sibling pairs affected with OCD, their parents, and additional affected relatives (by extension through affected relatives); (2) conduct a genome-wide scan with microsatellite markers at the laboratory of the Center for Inherited Disease Research; (3) fine map regions that support linkage with a high-density set of markers; (4) make DNA samples and diagnostic information available to other scientists through the NIMH-sponsored cell repository (Center for Genetic Studies); and (5) refine the OCD phenotype by identifying clinical subtypes and dimensions that may be useful for future clinical and genetic studies of OCD.

Sample Recruitment and Inclusion: The OCGS targeted families with OCD-affected sibling pairs, and extended these when possible through affected first and second-degree relatives; in addition, two sites (Baltimore and New York) also collected other pedigrees with multiple affected relatives when these were available. Subjects were recruited into the study from outpatient and inpatient clinics, referrals from clinicians in the community, websites, media advertisements, self-help groups, and the Obsessive Compulsive Foundation (OCF) annual conventions. Recruitment efforts were focused on individuals living in the local area or patients presenting for treatment at the site; Johns Hopkins also budgeted resources for ascertainment and evaluation of subjects throughout the United States (several Canadian families also participated). Family history interviews were conducted to determine that there were at least two OCD affected siblings and two biological parents in the family who were willing to participate, and to identify additional affected relatives for extended pedigree families. All first- and second degree relatives were considered for inclusion, and families were extended through the first-degree relatives of all affected cases. To be considered affected, a subject had to meet DSM-IV OCD criteria at any time in his/her life. Probands were included if, in addition to meeting DSM-IV criteria, their first onset of obsessions and/or compulsions occurred before the age of 18.

Probands with schizophrenia, severe mental retardation, Tourette disorder, or OCD which occurred exclusively in the context of depression (secondary OCD) were excluded. Subjects had to be at least 7-years old to participate in the study.

Clinical Assessments: Diagnostic assessments were conducted by psychiatrists or PhD-level clinicians experienced with clinical evaluations. Examiners used the OCGS Assessment Package, modified and developed for the study, as a semi-structured format for the evaluation of psychopathology. The OCD section was adapted from the SADS-LA-R [Mannuzza, et al., 1986; Fyer, et al., 1990] and includes: (1) detailed screening questions; (2) the Yale Brown Obsessive Compulsive Scale (YBOCS) symptom checklist [Goodman, et al., 1989], refined to include the age of onset and level of severity (i.e., amount of time and level of distress during the worst period) of each symptom; (3) a modified version of the Yale Brown Obsessive Compulsive Scale (YBOCS) [Goodman, et al., 1989], to assess severity based on the amount of time, extent of interference, degree of distress, extent of resistance, and degree of control that the subject had over obsessions and compulsions during the worst episode); (4) additional questions on onset, course, and history of treatment for these symptoms. A similar section was developed for assessing tics, Tourette disorder, and other tic disorders. The Structured Clinical Interview for DSM-IV [Spitzer, et al., 1992] was used for assessing other major Axis I diagnoses. A semi-structured assessment protocol was used for additional diagnoses of interest in OCD (pathologic nail biting, pathological skin picking, trichotillomania, gambling, kleptomania, and pyromania). The Family Informant Schedule and Criteria [Mannuzza, et al., 1985] was used to obtain additional information about each subject from a knowledgeable informant. For subjects who had received psychiatric treatment, consent was obtained to review relevant medical records and to contact treatment providers, if such information was deemed useful for making diagnoses. Examiners completed a narrative formulation for each case. All psychiatric diagnoses were made according to strict DSM-IV criteria [APA, 1994]. If all criteria required for having the disorder were met, then a "definite" diagnosis was given. If any necessary criterion was clearly not met, then the diagnosis was considered "absent." If the diagnostician was uncertain about a necessary criterion, and the majority of necessary criteria were present, then the diagnosis was made at the "probable" level. If the diagnosticians could not be sure of the presence or absence of a given diagnosis, then it was recorded as "unknown." In adults, relevant items from the Structured Instrument for the Diagnosis of DSM-IV Personality Disorders [Pfohl, et al., 1989] were used for the assessment of criteria for schizoid, avoidant, dependent, and obsessive-compulsive personality; each trait was rated 0 (not present), 1 (sub threshold), 2 (present), or 3 (strongly present). In addition, adult subjects self-completed the NEO-PI-R questionnaire for the assessment of dimensions of the five-factor model of personality (neuroticism, extraversion, openness, agreeableness, and conscientious) and the facets [Costa and McCrae, 1992].

Diagnostic Consensus Procedure: At each site, each case was reviewed independently by two expert diagnosticians who reviewed all case materials and completed a Diagnostic Assignment Checklist form. Any disagreements between the two diagnosticians regarding diagnoses or age of onset of diagnoses (within 2 years) were resolved between the two. Materials were then reviewed by one of the five consensus psychiatrists at JHU. Any disagreements between the sites and JHU were resolved before the case materials were edited and sent for data entry.

DNA Collection: In most cases, blood was collected from each participant at the time of the diagnostic interview, or by the individual's physician or local phlebotomy laboratory at a later time. Blood was sent directly to the NIMH Cell Repository at Rutgers University.


 

The OCD Collaborative Genetics Association Study (OCGAS) (NIMH Study 66 - Excerpts from description provided by study)

 

INTRODUCTION

Obsessive-compulsive disorder (OCD) [MIM 164230] is a neuropsychiatric condition characterized by persistent, intrusive, senseless thoughts and impulses (obsessions) and repetitive, intentional behaviors that the individual feels driven to perform (compulsions). Patients with the disorder recognize that their thoughts and behaviors are excessive and unreasonable, and they struggle to resist them. The obsessions and compulsions cause marked distress, are time consuming, and significantly interfere with social and occupational functioning (APA, 1994). In many cases, symptoms first appear in childhood and early adolescence, and the majority of cases have onset before 20 years of age (Rasmussen and Eisen, 1992). The lifetime prevalence of OCD is estimated to be 1-3%, based on population-based surveys conducted in the United States and other counties (Weissman, et al., 1994).

The OCD Collaborative Genetic Association Study (OCGAS), which commenced in 2007, is a collaboration among investigators at several sites in the United States: Butler Hospital/Brown University; Columbia University; Johns Hopkins University; Massachusetts General Hospital/Harvard Medical School; University of California, Los Angeles; University of Southern California; and NIMH. Johns Hopkins University is the coordinating center for the study, which is funded by NIMH (R01 MH071507), under the auspices of the NIMH Genetics Initiative. The aims of the study are to assess and collect DNA from 2000 trios (cases and both parents) of early-onset OCD; to genotype the first 1000 trios using a dense genome-wide SNP panel and conduct genome-wide association analyses; to replicate the findings in 1000 independent trios; to combine the estimates in these two stages; and to make the clinical and biological materials publicly available.

Sample Recruitment and Inclusion: Affected probands were recruited from adult and pediatric OCD outpatients and inpatients clinics, referrals from clinicians in the community, websites, media advertisements, self-help groups, and local and national meetings. At each site, recruitment efforts were focused on individuals living in the local area, or patients presenting for treatment at the site. In addition, the Johns Hopkins site budgeted resources for ascertainment and evaluation of participants throughout the U.S., and also collected other pedigrees with multiple affected relatives when these were available. To be considered affected, an individual had to meet DSM-IV OCD criteria at any time in his/her life, with first onset of obsessions and/or compulsions before the age of 18 years. Probands with schizophrenia, severe mental retardation, Tourette disorder, or OCD which occurred exclusively in the context of major depression (i.e., secondary OCD) were excluded. Individuals had to be at least 7 years old to participate in the study.

Clinical Assessment: Diagnostic assessment were conducted by PhD-level clinicians, using the Structural Clinical Interview for DSM-IV (SCID) as a semi-structured interview for making major Axis I diagnoses (SCID-IV) (First et al., 1996). The OCD section was expanded to include a detailed screening procedure, as well as the checklist of obsessions and compulsions from the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) that has been refined to include the age of onset and severity of each symptom (Goodman, et al., 1989). Y-BOCS scores for the worst episode (lifetime) are generated. Course and treatment response variables are included. A similar model for recording tics and Tourette disorder was developed. A semi-structured protocol was used for additional diagnoses of interest in OCD (pathological nail biting, pathological skin picking, trichotillomania, gambling, kleptomania, and pyromania). An informant interview, the Family Informant Schedule and Criteria (FISC), was used to obtain additional information from each interviewed participant (Mannuzza, et al., 1985). The Diagnostic Assignment Checklist was used to document the criteria for the diagnoses. The K-SADS-E was used as the semi-structured instrument for diagnostic interview of children (Orvaschel and Puig-Antich, 1987). A case narrative was completed for all interviewed participants. All psychiatric diagnoses were made according to strict DSM-IV criteria (APA, 1994). If all criteria required for having the disorder were met, then a "definite" diagnosis was given. If any necessary criterion was clearly not met, then the diagnosis was considered "absent". If the diagnostician was uncertain about a necessary criterion, but the majority of necessary criteria were present, then a "probable" diagnosis was made. If the diagnostician was not sure of the presence or absence of a given diagnosis, then it was recorded as unknown. The Structured Instrument for the Diagnosis of DSM-IV Personality Disorder (SIDP) was used to evaluate the presence of all DSM-IV characteristics for diagnosing obsessive-compulsive, avoidant, dependent, and schizotypal personality disorders (Pfohl, et al., 1995). In addition, adult participants self-completed the: 1) NEO-FFI-3 questionnaire for the assessment of general personality dimensions according to the five-factor model (neuroticism, extraversion, openness, agreeableness, and conscientiousness) (Costa and McCrae, 2010); 2) the BRIEF-A questionnaire for the assessment of executive functions (Roth, Isquith, and Gioia, 2005); and 3) the Social Responsiveness Scale - Adult Research Version for the assessment of autism spectrum behaviors (Constantino, 2005). Parental informants completed the BRIEF (Gioia, et al., 2000) and Social Responsiveness Scale (SRS-2) (Constantino and Gruber, 2012) forms for participants younger than 18 years.

Diagnostic Consensus Procedure: At each site, each case was reviewed independently by expert diagnosticians who reviewed case materials and completed a Diagnostic Assignment Checklist. Any disagreements regarding the presence or age of onset (within 5 years) of diagnoses were resolved. Diagnostic materials were then reviewed by one of the five consensus psychiatrists at JHU. Any disagreements between the sites and JHU were resolved before the case materials were edited and data entered.

DNA Collection: In most cases, blood was collected from each participant at the time of the diagnostic interview, or by the individual's physician or local phlebotomy laboratory at a later time. Blood was sent directly to the NIMH Cell Repository at Rutgers University.

Information

Diagnostic Interview for Study 66 only

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