The limited success identifying genetic determinants for OCD may be related to the etiological heterogeneity of OCD. Multiple approaches have been proposed to delineate more etiologically homogeneous groups within the broader definition of the disorder. Below we address some of the possible subtypes that may usefully be employed to identify genetic etiologies.
Age at onset (AAO) has proven useful in the clinical categorization of patients with respect to their genetic risk. Results from the Hopkins OCD Family Study and the Childhood OCD Family Study suggest an inverse relationship between age of onset of OCD in probands, and the risk of OCD in relatives. This is consistent with findings from other family studies[34
]. We found a significant inverse relationship between the proband’s AAO and the prevalence of OCD in their first-degree relatives (odds per year = 0.92 (0.85–0.99), p=0.02). Interestingly, this relationship was found for relatives of female, but not male, probands.
In addition to the increased familial risk, early-onset OCD has been distinguished from later-onset OCD, based on the nature of the OCD symptoms [104
], patterns of comorbidity [105
], course and treatment response[107
],and regional cerebral blood flow in frontal-subcortical circuits.[108
] Unfortunately, no twin study has compared age-at-onset concordance patterns. To date, there is no clinical or other type of variable with stronger support in OCD.
Family studies found that AAO of OCD before18 years indicates a substantially more familial subgroup[23
]. Using familiality as the outcome measure, the Hopkins group found evidence that an AAO earlier than 18 years was more useful than the standard phenotype[23
]. In the linkage study described above, age of onset was used as a covariate in covariate-based linkage analysis. The LOD score was 2.94 at D1S1679 (empirical P-value = 0.001). After stratifying the sample by age at onset it was determined that it was younger age at onset that increased the linkage estimate[109
Given our previous work of differential penetrance by gender (segregation analysis), we stratified the sample based on proband gender (78 male proband families; 141 female proband families), with a subsequent substantial increase in the linkage signal at 11p15[110
]. After genotyping additional microsatellite markers, at approximately a 1–2cM density, from 2.8cM to 15cM, the stratified analyses showed a LOD= 5.66 (p<0.00001) in the male group. This first stage fine-mapping reduced the 1-LOD support interval from 25.9Mb to 4Mb. This region contains plausible candidate genes, such as Dopamine D4 receptor (DRD4
), Tyrosine Hydroxylase (TH
), Neuronal Nicotinic, Alpha Polypeptide 10 (CHRNA10
), and the Cholecystokinin B Receptor (CCKBR
), amongst others.
In addition to age at onset and gender, several clinical features potentially may be useful for categorizing OCD into homogeneous phenotypes for etiologic investigation. Clinical characteristics that may distinguish a familial subtype of OCD include: tic disorders [34
], affective and anxiety disorders[33
], obsessive-compulsive personality disorder[115
], and specific obsessive-compulsive symptom classes[116
In a large sample of multiply-affected families, we identified three OCD classes: OCD ‘Simplex’, Comorbid OCD ‘tic-related’, and comorbid OCD “affective-related.” These classes suggest that the co-occurrence of other psychiatric disorders (e.g. tics, anxiety, and affective disorders) with OCD may be indicative of different phenotypic subgroups [131
]. It is possible that one or more of the above OCD subtypes represents a more homogenous genetic group yielding greater ability to detect genetic variation relevant to the disorder. The tic-related group points to the widely investigated relationship between Tourette Disease (TS) and OCD. There is compelling evidence that OCD is a familially related phenotype in families with TS [132
]. However, it has not been established whether those individuals with OCD in TS families share, or do not share, a genetic etiology with other cases of OCD.
Several groups have reported that OCD subjects with hoarding behaviors are clinically distinct from other individuals with OCD[120
]. The Hopkins OCD Family Study also found that relatives of hoarding OCD probands had a higher prevalence of hoarding behaviors[124
In addition to subtyping by individual clinical features, it may be fruitful to subtype based on symptom clusters. Consistent with several prior studies[125
], our research group found four or five OCD symptom dimensions using different statistical approaches on data collected with the Y-BOCS symptom checklist. In 221 OCD-affected individuals examined during the JHU OCD Family Study, Cullen et al[126
], using dichotomous factor analysis of 16 YBOCS symptom categories, found four symptom factors: aggressive/sexual/ religious obsessions; contamination/cleaning; symmetry/order and hoarding. These dimensions were differentially associated with onset of symptoms, treatment responsiveness, and comorbid diagnoses, as well as magnitude of sib-sib correlation[126
]. Similar dimensions were evident using principal components factor analysis of YBOCS symptom checklist categories in 418 OCD-affected individuals (251 affected sibling pairs) ascertained during the OCD Collaborative Genetics Study. These factors had significant sib-sib correlations, with the hoarding dimension being the most familial[127
]. More recently, using exploratory dichotomous factor analysis on individual YBOCS symptom checklist items in 485 adults ascertained in the OCGS, we found similar dimensions (as well as a taboo factor) and strong sib-sib correlations, especially for the hoarding factor[128
]. This structure has been replicated in children and adolescents[129
It has been reported that OCD subjects with hoarding behaviors were clinically different from other OCD subjects, and that hoarding was more frequent in their first-degree relatives[124
]. When families were stratified based on the presence of two or more relatives with compulsive hoarding (74 hoarding families; 145 non-hoarding families), we found suggestive linkage for the stratum with hoarding (LOD= 2.99; p= 0.0001).[130
]. The 1-LOD support region at 14q31-32 is 10.9Mb. This region contains the positional candidate genes Potassium Channel, Voltage-Gated, Subfamily H, Member 5 (KCNH5
), Potassium Channel, Subfamily K, Member 10 (KCNK10
), Estrogen Receptor 2 (ESR2
), Neurexin 3 (NRXN3
), and others. These analyses were repeated using OCD hoarding as the phenotypic outcome (i.e., ONLY subjects with OCD hoarding, regardless of the presence of any other OCD symptoms were the affected phenotype). This reduced the number of informative families to an N =60 but still there was a signal (LOD =1.6; p =0.003), albeit the peak was marginally proximal to the one using the stratified sample. The linkage signal on the X chromosome, when stratified for compulsive hoarding, was strengthened considerably (LOD=2.81, p=0.0002) suggesting that these two chromosomal regions are likely to harbour susceptibility genes for compulsive hoarding.