Obsessive-Compulsive Disorder Genetics: Current and Future Directions

Obsessive-compulsive disorder (OCD) is a complex genetic disorder with a lifetime prevalence of 1%−3% (1). Onset of OCD symptoms usually begins between ages 10 and 24 years, with most individuals having onset by age 19 years. Childhood onset has been reported in one-third to one-half of adults with OCD (2). OCD is a chronic disorder across the lifespan and is a leading global cause of nonfatal illness burden (3). OCD is equally prevalent in males and females, although onset tends to be earlier in males. Females may experience onset or worsening of symptoms during pregnancy or during the period before menstruation. The disorder is also equally prevalent in different races and ethnicities.

Other disorders are closely related to OCD, as recognized in DSM-5. Wayne Goodman (4), editor in chief of Obsessive Compulsive and Related Disorders, wrote:

Reclassification of these disorders under the rubric OCDR in DSM-5 not only recognizes shared symptom domains but also reflects slowly growing evidence of shared genetic components. Comorbidity of OCDRs with depression, bipolar disorder, schizophrenia, alcohol and/or substance abuse, attention-deficit hyperactivity disorder, and other anxiety or impulse control disorders has also been recognized, but little is known about shared genetic risks.

OCDRs Are Complex Multifactorial Disorders

OCDRs, as with all neuropsychiatric disorders (e.g., schizophrenia, major depression) and most common nonpsychiatric disorders (e.g., non–insulin-dependent diabetes, asthma), are viewed as genetically complex, multifactorial disorders. The term complex refers to the fact that it is unlikely that a major single gene predisposes to or directly causes the disorder; rather, many genes may make minor contributions to disease risk, and the combination of genes is likely to vary between individuals and populations. The term multifactorial refers to the fact that genes alone do not cause disease; rather, a combination of genes and environmental factors most likely underlies causation. Schizophrenia is a good example of a complex, multifactorial neuropsychiatric illness for which the genetic contribution is slowly being elucidated. Most recently, a whole-genome (i.e., all of the DNA/genes in an organism) study identified >100 different genomic regions as contributing to the disease (5). The exact mutations in these regions have not yet been identified. Although these results are promising, the >100 regions collectively explain only about 10% of the risk of schizophrenia. The remaining 90% may involve additional genes, genetic processes, or environmental or other random factors.

The goal of all genetic studies is to tease out what proportion of illness risk is likely to be genetic (as opposed to environmental and/or random) and, ultimately, to identify specific mutations or other causative variations. Historically, twin and family studies have been conducted to demonstrate that there are genetic contributions to the disorder. Genomic studies in which the DNA sequence is examined directly (or indirectly) are used to identify genomic regions shared by affected versus nonaffected relatives or, in studies of unrelated cases and unrelated controls, by cases more than controls. A case-control whole-genome design was used in the aforementioned schizophrenia study (5).

In all such studies, the disease entity (i.e., phenotype) of interest must be specified. For example, some studies use only a narrow disease definition (e.g., OCD only or Tourette’s syndrome only), whereas others use a broad definition (e.g., OCD and trichotillomania [TTM] and/or BDD, Tourette’s syndrome, etc.). These types of studies can not only identify associated genes/regions for a specific disorder but also can help elucidate the relationship of one disorder to another (e.g., Does Tourette’s syndrome share the same genes/regions as OCD?).

Another approach to phenotypic description involves specific findings (e.g., neuropsychological, neuroanatomical, neurocognitive) that cut across traditional disease boundaries. The focus is on objective, heritable, qualitative/quantitative, and enduring traits (i.e., not “state” dependent) that are coinherited (i.e., cosegregate) with illness yet are also present, albeit at intermediate levels, in unaffected relatives but are not present (or at the lowest levels) in unrelated, healthy individuals. An endophenotype, therefore, is presumed to be in the causal chain between observed behavioral phenotypes and the underlying etiology. For example, performance on neurocognitive tests may be used to tease out some of the differences that may be attributable to genetic variability between patients with OCD, their first-degree unaffected relatives, and unrelated healthy controls. These alternative phenotypes will be an increasingly important component of genomic studies as more stable, heritable endophenotypic traits are identified.

Twin and family studies as well as genome-wide studies have been conducted in OCD, Tourette’s syndrome/chronic tics, and other related disorders. Most studies have been performed on the OCD or Tourette’s syndrome/chronic tics phenotypes (few studies using endophenotypic end points have been conducted to date). In addition to genome-wide studies, analyses of particular genes that may be plausibly involved in disease causation or that may influence the effectiveness of pharmacologic treatments (i.e., “candidate genes”) have been performed. Animal models derived from gene knockouts, biochemical manipulations, or innate characteristics (i.e., naturally occurring) have also been investigated. An excellent review of the literature on the genetics of OCDR, including twin, family, and genome-wide case-control studies, was recently published (6). Likewise, Camilla d’Angelo et al. (7) authored an excellent review on OCD animal models. Below we present a summary of recent findings.

Twin and Family Studies

Twin and family studies examine the pattern of disease occurrence and co-occurrence (or recurrence) in related individuals to determine whether there is evidence of shared genetic risk factors. Shared environmental and random factors also contribute to disease risk, and studies are thus designed to specifically elucidate the genetically based risks.

Identical Versus Fraternal Twins

Twin studies examine the concordance of disease in monozygotic (identical) twins versus dizygotic (fraternal) twins to estimate the contribution of genes. Because monozygotic twins share all of their genes and dizygotic twins share only one-half of their genes on average (similar to any pair of siblings), rates of co-occurrence of disease in both monozygotic twins compared with dizygotic twins can be used to estimate genetic heritability. The advantage of using dizygotic twins instead of siblings is that they are more likely to share environmental exposures, including in utero, whereas siblings born years apart may not. Most studies of monozygotic versus dizygotic twins have used only OCD as the phenotype, but some studies have included related disorders or specific OCD symptom dimensions. Almost all studies to date have also used DSM designations that preceded publication of DSM-5. Most studies have reported monozygotic concordance rates around 0.50 and dizygotic rates around 0.20 (6).

As reviewed by Pauls et al. (8), twin studies of Tourette’s syndrome report concordances of 50%−77% for monozygotic twins compared with 10%−23% for dizygotic twins, depending on the diagnosis used. A later study found that concordance in monozygotic twins increases to nearly 100% when the phenotype is extended to include chronic tics, suggesting that Tourette’s syndrome and chronic tics share genetic predispositions.

Few studies have been performed on hoarding disorder (HD), BDD, TTM, and skin-picking disorder (SPD) alone. One HD study reported greater monozygotic than dizygotic concordance (0.44 versus 0.17) in male twins but no difference in female twins (9). The overall heritability of HD is estimated to be 51% (10). Few data exist for TTM, and widely divergent estimates of heritability were derived, from a high of 0.76 in one study (11) to only 32% in another report (10). SPD has an estimated heritability of approximately 40%−47% based on an initial study as well as a follow-up study (12). BDD heritability has also been estimated to be around 40%, although few studies have been performed (10).

Family Studies

Family studies estimate the likelihood that a disease or trait present in one family member will occur again in other family members. This estimate is commonly known as the recurrence risk. For OCD, first-degree relatives (i.e., biological parents, full siblings, and offspring) who share on average 50% of their genomes have an estimated recurrence risk between 10% and 20% based on studies performed over the past decade or so using more modern disease criteria (studies in the early 1980s showed higher risks). Some studies used only OCD as the phenotype of interest, whereas others used a broader definition that included subdiagnostic OCD symptoms. In general, the broader the phenotype definition, the greater the recurrence risk (6). Researchers have particularly focused on the subset of patients with early-onset OCD. Higher recurrence risks of OCD in first-degree relatives of pediatric-onset versus adult-onset cases have been reported, but this finding is not consistent. In addition, some studies that reported increased risk to relatives of pediatric-onset versus adult-onset cases had nonstatistically significant increases (6, 13).

As reviewed by Browne et al. (6), clustering of Tourette’s syndrome, chronic tics, TTM, and other disorders in families of individuals with OCD has also been documented. First-degree relatives of patients with OCD have been reported to have recurrence risks of 4%–14% for Tourette’s syndrome/chronic tics, up to 6% for BDD, 4% for TTM, and around 15% for other compulsive behaviors such as pathologic skin picking or nail biting. A twin study involving >1000 female twin pairs (i.e., >2000 participants) reported substantial (64%) genetic influences between OCD and BDD, with even higher estimates (82%) when BDD and OCD symptom dimensions (and not diagnoses, per se) were analyzed (14). Reciprocal studies that examined the relatives of individuals with OCD-related disorders but not OCD have shown increased risks of OCD in those relatives (6).

Candidate Gene Studies

Because evidence from twin- and family-based studies clearly demonstrates a genetic component to OCDRs, a wide range of studies have been conducted in an effort to identify specific disease-susceptibility genes. Research, including neuroimaging, treatment trials, and animal models, suggests that abnormalities in serotonin (5-HT), dopamine, and glutamate neurotransmission are involved (15–21). Some genes that have been putatively linked to OCD include those coding for catechol-O-methyltransferase, monoamine oxidase-A, brain-derived neurotrophic factor, myelin oligodendrocyte glycoprotein, GABA-type B receptor 1, and the mu opioid receptor, but these must be considered provisional associations at this time. Although some replicated associations of OCD with the glutamate transporter gene SLCL1A1 have been published (22–25), the most recent meta-analysis did not fully support significant associations (26).

The lack of significant and consistent findings in OCDR candidate gene studies is attributable in part to the relatively small sample sizes used in these studies. Even with meta-analyses that pool data from smaller studies, there is often inadequate statistical power to detect small contributions to disease risk.

Other sets of candidate genes include those involved in treatment response, such as genes coding for drug-metabolizing enzymes. These genes have been examined with the aim of identifying which patients, on the basis of their genetic profiles, might benefit from a particular treatment. Several excellent recent reviews have been published on this complex subject (27–29), which is beyond the scope of this article.

Genome-Wide and Family-Based Molecular Genetics Studies

In contrast with candidate gene studies, genome-wide studies in families or in unrelated case-control samples do not hypothesize the involvement of particular genes; rather, these studies survey the genome for disease association. The most popular study designs use a subset of known DNA variants that do not affect gene structure or function; rather, these variants are benign differences between individuals and population groups. These DNA “markers” can be used as figurative sign posts on a roadway, suggesting that there is a nearby gene/variant that differs between individuals with disease and those without. In other words, the marker and the putative disease-associated variant are linked and thereby inherited together.

A broad collaborative group (International OCD Foundation Genetics Collaboration [IOCDFGC]) performed the first genome-wide association study of OCD (30). This study involved 1465 patients suffering from OCD and 5557 ancestry-matched controls. The study also included 400 trios composed of an affected child and parents or genetically related parental surrogates. In the case-control analysis, the DLGAP1 gene, a member of the neuronal postsynaptic density complex, showed evidence of disease association. This is an intriguing result because deletion of the closely related Dlgap3 gene in mice results in compulsive/repetitive grooming behavior, leading to facial hair removal and skin lesions, as well as anxiety-like behavior (31). In an examination of the DLGAP3 gene sequence in 165 individuals with OCD and/or TTM, researchers found variants in 4.2% of these patients compared with 1.1% of the 178 controls (32).

In the IOCDFGC trio analysis, there was some evidence that a DNA marker near the BTBD3 gene, a key regulator of dendritic field orientation during development of the sensory cortex, was passed on to the affected child more often than by chance alone. However, there were no significantly associated DNA markers/genes when the case-control and trio samples were jointly examined (30).

A second collaborative study of OCD by the OCD Collaborative Genetics Study (OCGS) included 1406 cases from 1065 families; thus, multiple affected members of the same family were included (33). The PTPRD gene, whose protein product is an enzyme involved in the regulation of glutamatergic and GABAergic synapse formation, showed the strongest association, although this was below what is considered statistically significant (P<5×10⁻⁸; i.e., 1:500,000,000 odds of the result being due to chance) in genome-wide studies testing tens of thousands of markers.

Although neither of these two genome-wide studies identified unequivocal findings, it is noteworthy that there was some overlap when the genes/markers with the best evidence of association in the IOCDFGC study were compared with the OCGS analysis. This suggests that a subset of these markers/genes may truly be associated with OCD.

Scharf and colleagues (34) performed an analysis of Tourette’s syndrome cases in which a collagen gene variant had some evidence of association; however, this finding has yet to be replicated and failed to reach genome-wide statistical significance. Additional analyses have identified large genomic rearrangements in another collagen gene (COL8A1) as well as a gene (NRXN1) that has been associated with other neurodevelopmental disorders (35). Further studies are necessary to verify and extend these findings.

Cross-disorder (OCD and Tourette’s syndrome/chronic tics) analyses have been performed. Although some analyses support overlapping genetic signals between the disorders (36–38), the most recent analysis by Yu et al. (39) suggests a more complicated relationship in which there also are distinct genetic components to each disorder. In addition, the analysis by Yu et al. (39) showed that OCD with co-occurring Tourette’s syndrome or chronic tics may have a different underlying genetic susceptibility than OCD alone.

Several studies involving the sequencing of DNA in gene regions putatively associated with OCD and Tourette’s syndrome/chronic tics have been undertaken, including an analysis of the SLITRK6 gene. Members of this gene family are expressed predominantly in neural tissues and have neurite-modulating activity. Conflicting findings of an association with Tourette’s syndrome have been reported, but other preliminary results suggest that the gene may be associated with OCD and TTM (40–42).

Animal Models

A number of animal models of OCDRs have been developed through genetic or pharmacologic manipulations or through experimentally induced or naturally occurring behaviors. Gene knockouts (e.g., serotonin 2c receptor, dopamine transporter) in mice have produced animals with OCD-like behaviors, whereas knockouts of HoxB8, Slitrk5, or Sapap3 have resulted in mice with TTM and OCD symptoms [reviewed by Camilla d’Angelo et al. (7)]. As noted earlier, the Dlgap3 knockout mouse displays compulsive/repetitive grooming behavior, leading to facial hair removal and skin lesions, as well as anxiety-like behavior (31).

Pharmacologic manipulations (e.g., treatment with acute 5-HT1b agonists) in rodents have induced repeated checking, motor perseveration, and other compulsive behaviors, whereas specific environmental manipulations (e.g., food restriction) have induced hyperactivity and other aberrant behaviors (7). Naturally occurring behaviors such as acral lick dermatitis in dogs, hair pulling in cats, and feather picking in birds mimic human TTM and have been noted to develop especially after neglect or sensory deprivations. Other repetitive, compulsive animal behaviors include tail chasing, biting, circling, and nest building (7).

Some of these putative animal models are limited by the fact that they also have other aberrant behaviors or somatic conditions, such as obesity and hyperphagia in the 5-HT2c knockout mice. Moreover, not all subjects respond to treatment with serotonin selective reuptake inhibitors (SSRIs), which are effective in a significant proportion of patients with OCD. More recently developed models, such as the Sapap3 and the Slitrk5 knockout mice, do respond to SSRI treatment and continue to be investigated as useful models.

Epigenetic Studies

In addition to direct changes in DNA sequence that may disrupt normal gene activity, other types of genome variation can affect genes. The term epigenetics refers to external modifications to DNA that can alter when and how much of a gene’s product is produced (i.e., expressed). Thus, epigenetic changes do not alter the actual DNA sequence itself, but do affect gene regulation. Furthermore, epigenetic modifications can be heritability transmitted. Types of epigenetic mechanisms include X-chromosome inactivation, imprinting, DNA methylation, and chromatin remodeling. Data on epigenetic changes in OCDRs are emerging and suggest that expression of certain genes in the brains of patients with OCD may be affected, but no statistically significant, replicated findings have been published.

Need for Larger Sample Sizes

The complexity of OCD and its relationship to Tourette’s syndrome/chronic tics, HD, BDD, TTM, and SPD have been formally recognized in DSM-5; however, identifying the nature of the underlying genetic predisposition to these disorders may be both helped and hampered. Heterogeneity within and between the disorders (e.g., specific symptoms, symptom severity, comorbidities, early versus late onset), population variation (e.g., sex, race/ethnicity), probable involvement of many (possibly hundreds) genes each with small effects (“polygenes”), and the unknown contributions of unspecified environmental factors create a challenge for investigators. One clear principle, however, guides the field: the greater the sample size and the more phenotypic descriptors available (e.g., stable endophenotypes), the more likely the identification of genetic contributions. This has been demonstrated for schizophrenia in that initial genome-wide studies found six genome-wide significant hits with approximately 10,000 cases, 62 hits with 25,000 cases, and 128 at the current 36,989 cases with schizophrenia (5, 43).

Current and Future Directions

One goal of an ongoing research effort at the University of Southern California is to expand current case samples by adding 5000 individuals with primary OCD, HD, BDD, or other OCDRs. Biological samples (DNA, RNA) from participants along with clinical, demographic, and genotypic data will be made available to the greater research community.

Using a modern research design in which participants can join the research via secure internet avenues, we aim to reach affected individuals who may not come to the attention of academic research centers. Initial assessment of signs/symptoms and evaluation of severity are based on participants’ responses to online instruments and interviews (either in person or through secure phone or internet connections). Donation of biological samples (either blood or saliva) can also be done remotely without the need to visit a participating academic research center. All data and biological samples are deidentified. Participants must agree to broad sharing of deidentified data and samples and must also have the option of agreeing to ongoing follow-up and participation in future studies. A website for clinicians and patients is established for University of Southern California OCD research (keck.usc.edu/gpc-ocd).

As with all other complex, multifactorial illnesses, be they psychiatric or somatic, the participation of affected individuals is essential for identifying genetic susceptibility factors. We encourage all clinicians to stay abreast of research efforts through organizations such as the International OCD Foundation and to inform patients of resources and research studies available through such organizations (www.iocdf.org)