SNOMEDCT: 191736004; ICD10CM: F42, F42.8, F42.9; ICD9CM: 300.3;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 13q14.2 | {Obsessive-compulsive disorder, susceptibility to} | 164230 | Autosomal dominant | 3 | HTR2A | 182135 |
| 17q11.2 | {Obsessive-compulsive disorder} | 164230 | Autosomal dominant | 3 | SLC6A4 | 182138 |
A number sign (#) is used with this entry because susceptibility to obsessive-compulsive disorder (OCD) has been associated with single-nucleotide polymorphisms (SNPs) in the SLC6A4 serotonin transporter gene (182138) and in the promoter region of the serotonin 5-HT2A receptor (HTR2A; 182135).
Obsessive-compulsive disorder (OCD) is characterized by recurring obsessions and/or compulsions and has been estimated to affect nearly 5 million people in the United States (Karno et al., 1988). Evidence for a strong genetic component in OCD comes from twin studies, family genetics studies, and segregation analyses, as reviewed by Alsobrook et al. (2002).
Zhang et al. (2002) suggested that hoarding is likely to be an evolutionarily conserved trait that, in times of adversity, was associated with increased survival and reproductive fitness. However, extreme forms of this trait are associated with marked disability and poor response to treatment (Black et al., 1998; Mataix-Cols et al., 1999).
Leckman et al. (1994) found higher levels of oxytocin (167050) in the lumbar spinal fluid of patients with obsessive-compulsive disorder but no personal or family history of tics, than in normal controls or patients with obsessive-compulsive disorder in the presence of Tourette syndrome. In contrast to previous reports, they found similar concentrations of arginine vasopressin (192340) in the spinal fluid of all 3 groups.
Using semistructured diagnostic interviews, Hanna et al. (2005) assessed 33 familial and 17 sporadic OCD probands ranging in age from 10 to 19 years with onset of symptoms before age 15. The first- and second-degree relatives of the probands were also assessed. Ordering compulsions were significantly more common in familial OCD probands. Aberrant grooming behaviors, in particular skin picking, were significantly more frequent in the familial subgroup. Anxiety disorders other than OCD, in particular phobic disorders, were also significantly more frequent in the familial subgroup. Hanna et al. (2005) concluded that familial and sporadic early-onset OCD may be differentiated by the presence of ordering compulsions, aberrant grooming behaviors, and anxiety disorders other than OCD.
Investigations by means of segregation analyses in each of 5 studies had found evidence of a gene of major effect when relatives were classified according to the presence or absence of OCD as a binary outcome. For example, Nestadt et al. (2000) conducted complex segregation analyses of OCD in 153 families (80 cases and 73 control families) that were ascertained in the Johns Hopkins OCD Family Study, and found strong evidence for a major autosomal dominant gene with significant sex effects.
Weissbecker et al. (1989) studied a 3-generation family in which obsessive-compulsive disorder appeared to be segregating as an autosomal dominant characteristic. Although it has been suggested that OCD represents an alternative expression of the gene responsible for Tourette syndrome (137580), the disorder in this family appeared to be clinically distinct. They suggested linkage to GC (139200).
Hoarding is a component of the obsessive-compulsive disorder; tic-related obsessive-compulsive disorder appears to constitute a distinct phenotype (Leckman et al., 2000). Zhang et al. (2002) performed a genomewide scan of hoarding in 77 sib pairs in which both sibs also had Tourette syndrome. Twenty-six pairs were concordant for hoarding, 28 were discordant for hoarding, and 23 with concordant for being unaffected with hoarding. Treating the hoarding as either a dichotomous or a quantitative trait, they found evidence of linkage to chromosome 4q34-q35 in a region where a Tourette syndrome locus had previously been mapped.
Hanna et al. (2002) performed a genome scan for mapping of early-onset obsessive-compulsive disorder using families ascertained through pediatric probands. A maximum multipoint lod score of 2.25, using a dominant model, was obtained for 9p. However, with fine mapping and additional subjects, the lod score decreased to 1.97. Other regions requiring further study with larger samples were found. Willour et al. (2004) likewise found strongest evidence of linkage with dominant parameters and found evidence of linkage in the 9p24 region identified by Hanna et al. (2002). Pedigree-based association analyses also implicated the 9p24 candidate region by identification of 2 markers with modest evidence for association. Analysis under dominant parameters yielded a parametric signal peak at marker D9S1792 with an HLOD of 2.26. Nonparametric linkage signal peaked at marker D9S1813 with an NPL of 2.52 (p =.006).
Ross et al. (2011) performed genomewide linkage analysis of 3 families from Costa Rica in which at least 2 individuals had OCD. The strongest evidence for linkage was on chromosome 15q14 (lod score of 3.13), using parametric linkage analysis with a recessive model. Each family had a haplotype that cosegregated with OCD across a 7-Mb interval within this region, which contains 18 brain-expressed genes. Exonic sequencing of the strongest candidate gene in this region, RYR3 (180903), did not reveal any variants that cosegregated with OCD in all 3 families.
Karayiorgou et al. (1997, 1999) found an association between OCD and catechol-O-methyltransferase (COMT; 116790); the homozygous low activity genotype of the COMT gene was associated with risk for OCD in males. Alsobrook et al. (2002) used a family-based genetic design in haplotype relative risk (HRR) and transmission-disequilibrium (TDT) analyses of the association between OCD and COMT. Fifty-six OCD probands and their parents were genotyped for the COMT locus. Analysis of allele and genotype frequencies between the proband genotypes and the control (parental nontransmitted) genotypes failed to replicate the previous finding of gender divergence and gave no evidence of overall association; furthermore, no linkage was detected by TDT. However, further analysis of the COMT allele frequencies by proband gender gave evidence of a mildly significant association with the low activity COMT allele in female probands (p = 0.049), but not in male probands.
Walitza et al. (2002) performed an association analysis of the -1438G-A promoter polymorphism in the HTR2A gene (182135.0002) in 55 children and adolescents with OCD and in 223 controls consisting of unrelated students. Statistically significant differences in genotype (p less than 0.05) and allele frequencies (p less than 0.05) were observed that suggested an association of the -1438A allele with OCD.
Ozaki et al. (2003) described association between an ile425-to-val (I425V; 182138.0002) polymorphism of the serotonin transporter gene (SLC6A4) and OCD and some other 'serotonin-related disorders' in 2 unrelated families. Of 7 family members with the mutation, 6 had OCD and 1 had obsessive-compulsive personality disorder; several of them also met diagnostic criteria for other disorders, including Asperger syndrome (see 608638), social phobia, anorexia nervosa (see 606788), tic disorder, and alcohol (103780) and other substance abuse/dependence. The 4 most clinically affected individuals had both the I425V mutation and the L allele of SLC6A4 (182138.0001), suggesting a gene dose effect given that the L allele transcribes more efficiently.
Hu et al. (2006) found that the gain-of-function homozygous L(A)L(A) genotype of SLC6A4 was approximately twice as common in 169 whites with obsessive-compulsive disorder than in 253 ethnically matched controls. Hu et al. (2006) performed a replication study in 175 trios consisting of probands with OCD and their parents. The L(A) allele was 2-fold overtransmitted to the patients with OCD. The SLC6A4 L(A)L(A) genotype exerted a moderate (1.8-fold) effect on risk of OCD, thus establishing a role for the HTT gene in OCD.
Associations Pending Confirmation
For discussion of a possible association between variation in expression of the NTRK3 gene and hoarding, see 191316.
For discussion of a possible association between variation in the BDNF gene and protection against OCD, see 113505.0002.
Welch et al. (2007) found that mice generated to be null for Sapap3 (611413) exhibited increased anxiety and compulsive grooming behavior leading to facial hair loss and skin lesions and that both behaviors were alleviated by a selective serotonin reuptake inhibitor. Electrophysiologic, structural, and biochemical studies of Sapap3 mutant mice revealed defects in corticostriatal synapses. Furthermore, lentiviral-mediated selective expression of Sapap3 in the striatum rescued the synaptic and behavioral defects of Sapap3 mutant mice. Welch et al. (2007) concluded that their findings demonstrated a critical role for Sapap3 at corticostriatal synapses and emphasized the importance of corticostriatal circuitry in obsessive-compulsive-like behaviors.
Shmelkov et al. (2010) found that transgenic mice with inactivation of the Slitrk5 gene (609680) developed OCD-like behaviors, including excessive self-grooming bordering on self-mutilation and increased anxiety in the open maze test. These behaviors were alleviated by the selective serotonin reuptake inhibitor fluoxetine. Slitrk5-null mice showed selective overactivation of the orbitofrontal cortex, decreased volume of the striatum associated with decreased dendritic complexity of neurons in the striatum, and downregulation of glutamate receptor subunit. Extracellular recordings showed deficient corticostriatal neurotransmission.
Alsobrook, J. P., II, Zohar, A. H., Leboyer, M., Chabane, N., Ebstein, R. P., Pauls, D. L. Association between the COMT locus and obsessive-compulsive disorder in females but not males. Am. J. Med. Genet. 114: 116-120, 2002. [PubMed: 11840516] [Full Text: https://doi.org/10.1002/ajmg.10040]
Black, D. W., Monahan, P., Gable, J., Blum, N., Clancy, G., Baker, P. Hoarding and treatment response in 38 nondepressed subjects with obsessive-compulsive disorder. J. Clin. Psychiat. 59: 420-425, 1998. [PubMed: 9721822] [Full Text: https://doi.org/10.4088/jcp.v59n0804]
Hanna, G. L., Fischer, D. J., Chadha, K. R., Himle, J. A., Van Etten, M. Familial and sporadic subtypes of early-onset obsessive-compulsive disorder. Biol. Psychiat. 57: 895-900, 2005. [PubMed: 15820710] [Full Text: https://doi.org/10.1016/j.biopsych.2004.12.022]
Hanna, G. L., Veenstra-VanderWeele, J., Cox, N. J., Boehnke, M., Himle, J. A., Curtis, G. C., Leventhal, B. L., Cook, E. H., Jr. Genome-wide linkage analysis of families with obsessive-compulsive disorder ascertained through pediatric probands. Am. J. Med. Genet. 114: 541-552, 2002. [PubMed: 12116192] [Full Text: https://doi.org/10.1002/ajmg.10519]
Hu, X.-Z., Lipsky, R. H., Zhu, G., Akhtar, L. A., Taubman, J., Greenberg, B. D., Xu, K., Arnold, P. D., Richter, M. A., Kennedy, J. L., Murphy, D. L., Goldman, D. Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. Am. J. Hum. Genet. 78: 815-826, 2006. [PubMed: 16642437] [Full Text: https://doi.org/10.1086/503850]
Karayiorgou, M., Altemus, M., Galke, B., Goldman, D., Murphy, D., Ott, J., Gogos, J. Genotype determining low catechol-O-methyltransferase activity as a risk factor for obsessive-compulsive disorder. Proc. Nat. Acad. Sci. 94: 4572-4575, 1997. [PubMed: 9114031] [Full Text: https://doi.org/10.1073/pnas.94.9.4572]
Karayiorgou, M., Sobin, C., Blundell, M. L., Galke, B. L., Malinova, L., Goldberg, P., Ott, J., Gogos, J. A. Family-based association studies support a sexually dimorphic effect of COMT and MAOA on genetic susceptibility to obsessive-compulsive disorder. Biol. Psychiat. 45: 1178-1189, 1999. [PubMed: 10331110] [Full Text: https://doi.org/10.1016/s0006-3223(98)00319-9]
Karno, M., Golding, J. M., Sorenson, S. B., Burnam, M. A. The epidemiology of obsessive-compulsive disorder in five U.S. communities. Arch. Gen. Psychiat. 45: 1094-1099, 1988. [PubMed: 3264144] [Full Text: https://doi.org/10.1001/archpsyc.1988.01800360042006]
Leckman, J. F., Goodman, W. K., North, W. G., Chappell, P. B., Price, L. H., Pauls, D. L., Anderson, G. M., Riddle, M. A., McSwiggan-Hardin, M., McDougle, C. J., Barr, L. C., Cohen, D. J. Elevated cerebrospinal fluid levels of oxytocin in obsessive-compulsive disorder: comparison with Tourette's syndrome and healthy controls. Arch. Gen. Psychiat. 51: 782-792, 1994. [PubMed: 7524462] [Full Text: https://doi.org/10.1001/archpsyc.1994.03950100030003]
Leckman, J. F., McDougle, C. J., Pauls, D. L., Peterson, B. S., Grice, D. E., King, R. A., Scahill, L., Price, L. H., Rasmussen, S. A. Tic-related versus non-tic related obsessive-compulsive disorder.In: Goodman, W. K.; Rudorfer, M. V.; Mazur, J. D. (eds) : Obsessive-Compulsive Disorder: Contemporary Issues in Treatment. New York: Lawrence Erlbaum 2000. Pp. 43-68.
Mataix-Cols, D., Rauch, S. L., Manzo, P. A., Jenike, M. A., Baer, L. Use of factor-analyzed symptom dimensions to predict outcome with serotonin reuptake inhibitors and placebo in the treatment of obsessive-compulsive disorder. Am. J. Psychiat. 156: 1409-1416, 1999. [PubMed: 10484953] [Full Text: https://doi.org/10.1176/ajp.156.9.1409]
Nestadt, G., Lan, T., Samuels, J., Riddle, M., Bienvenu, O. J., III, Liang, K. Y., Hoehn-Saric, R., Cullen, B., Grados, M., Beaty, T. H., Shugart, Y. Y. Complex segregation analysis provides compelling evidence for a major gene underlying obsessive-compulsive disorder and for heterogeneity by sex. Am. J. Hum. Genet. 67: 1611-1616, 2000. [PubMed: 11058433] [Full Text: https://doi.org/10.1086/316898]
Ozaki, N., Goldman, D., Kaye, W. H., Plotnicov, K., Greenberg, B. D., Lappalainen, J., Rudnick, G., Murphy, D. L. Serotonin transporter missense mutation associated with a complex neuropsychiatric phenotype. Molec. Psychiat. 8: 933-936, 2003. [PubMed: 14593431] [Full Text: https://doi.org/10.1038/sj.mp.4001365]
Ross, J., Badner, J., Garrido, H., Sheppard, B., Chavira, D. A., Grados, M., Woo, J. M., Doo, P., Umana, P., Fournier, E., Murray, S. S., Mathews, C. A. Genomewide linkage analysis in Costa Rican families implicates chromosome 15q14 as a candidate region for OCD. Hum. Genet. 130: 795-805, 2011. [PubMed: 21691774] [Full Text: https://doi.org/10.1007/s00439-011-1033-6]
Shmelkov, S. V., Hormigo, A., Jing, D., Proenca, C. C., Bath, K. G., Milde, T., Shmelkov, E., Kushner, J. S., Baljevic, M., Dincheva, I., Murphy, A. J., Valenzuela, D. M., Gale, N. W., Yancopoulos, G. D., Ninan, I., Lee, F. S., Rafii, S. Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive-like behaviors in mice. Nature Med. 16: 598-602, 2010. [PubMed: 20418887] [Full Text: https://doi.org/10.1038/nm.2125]
Walitza, S., Wewetzer, C., Warnke, A., Gerlach, M., Geller, F., Gerber, G., Gorg, T., Herpertz-Dahlmann, B., Schulz, E., Remschmidt, H., Hebebrand, J., Hinney, A. 5-HT(2A) promoter polymorphism -1438G/A in children and adolescents with obsessive-compulsive disorders. Molec. Psychiat. 7: 1054-1057, 2002. [PubMed: 12476319] [Full Text: https://doi.org/10.1038/sj.mp.4001105]
Weissbecker, K., Baxter, L., Schwartz, J., Sparkes, R. S., Spence, M. A. Linkage analysis of obsessive compulsive disorder. (Abstract) Cytogenet. Cell Genet. 51: 1105 only, 1989.
Welch, J. M., Lu, J., Rodriguiz, R. M., Trotta, N. C., Peca, J., Ding, J.-D., Feliciano, C., Chen, M., Adams, J. P., Luo, J., Dudek, S. M., Weinberg, R. J., Calakos, N., Wetsel, W. C., Feng, G. Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Nature 448: 894-900, 2007. [PubMed: 17713528] [Full Text: https://doi.org/10.1038/nature06104]
Willour, V. L., Yao Shugart, Y., Samuels, J., Grados, M., Cullen, B., Bienvenu, O. J., III, Wang, Y., Liang, K.-Y., Valle, D., Hoehn-Saric, R., Riddle, M., Nestadt, G. Replication study supports evidence for linkage to 9p24 in obsessive-compulsive disorder. Am. J. Hum. Genet. 75: 508-513, 2004. [PubMed: 15272418] [Full Text: https://doi.org/10.1086/423899]
Zhang, H., Leckman, J. F., Pauls, D. L., Tsai, C.-P., Kidd, K. K., Campos, M. R., Tourette Syndrome Association International Consortium for Genetics. Genomewide scan of hoarding in sib pairs in which both sibs have Gilles de la Tourette syndrome. Am. J. Hum. Genet. 70: 896-904, 2002. [PubMed: 11840360] [Full Text: https://doi.org/10.1086/339520]