The Genetics of Obsessive Compulsive Disorder and Related OCD Spectrum Disorders

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OCD is a severe, heritable condition with a lifetime prevalence of about two percent in world populations. First-degree family members and OCD probands are at a ten-fold higher risk of developing OCD and related disorders. The mode of inheritance is incompletely understood but is likely complex, involving multiple genetic loci of small to moderate effect. Our Laboratory has played a leading role in studies of OCD and of its genetics for over 25 years, and was one of the founding sites of multi-center, genome-wide project for studies of OCD, partial results of which have recently been reported in the group's publications noted below as well as in our previous annual reports. In addition, a series of association studies that has identified and evaluated several genes in OCD and related disorders is continuing. In our Lab's collaborative investigations, we have also worked to clarify the fundamental phenotypical features of OCD and related disorders, sometimes designated 'OCD spectrum disorders', in reports published in the last several years. We currently have a multifaceted array of compulsive phenotypical features that cut across traditional diagnostic designations (DSM-IV and DSM-5). Examples of some sub-disorders that can contribute to OCD but can be found without classic OCD features include our recent and prior studies of Tourette's disorder, ADHD, head trauma and hoarding as well as of comorbid affective disorders, including bipolar disorder. Bipolar disorder is also the subject of direct and molecular genetic studies in continuing collaborative investigations with the Bipolar Genetics Consortium group. Studies are ongoing of the role of serotonin, the SLC6A4 gene and other major serotonin genes plus SLC1A1 in OCD and related disorders such as Tourette disorder (in which 50% of patients meet diagnostic criteria for OCD). A manuscript was published last year about the multiple common and rare SLC6A4 variants found to be associated with Tourette's Disorder including the 5HTTLPR, rs25531, rs25532 and SERT I425V variants (Moya et al., 2013). The relationship of SLC6A4 variants to different SRI treatment responses in humans represents an additional illustration of gene-based influences on serotonergic pharmacologic responses, i.e., a new SERT-based pharmacogenomics, directly relevant to the treatment of human neuropsychiatric disorders such as OCD and depression as well as to other serotonin-related human disorders, as we have recently reviewed. Recent evidence from treatment and genetic studies suggest that another neurotransmitter system may contribute to OCD. As with SERT in the serotonin system, the neuronal glutamate transporter is a major regulator of glutamate availability. This glutamate transporter, EAAT3, is encoded by the gene SLC1A1 located within the chromosomal region 9p24. Recent evidence from 9p24 gene linkage analyses and candidate gene studies has suggested probable involvement of SLC1A1 in the development of OCD. Our large case-control study of SLC1A1 included a total of over 500 OCD probands and controls collected by our Lab. In addition, SLC1A1 expression and data were recently evaluated to gain further insights into SLC1A1 function. We are currently continuing further lab-based studies of this gene using transgenic techniques in mice. Dr. Moya, formerly from our Lab, has created conditional Slc1a1 mice, one set of which has this gene deleted and another set which preferentially overexpresses this gene in the forebrain. The rational for creating these two opposite functional Slc1a1 mice was based on l findings from the human SLC1A1 studies regarding whether this gene might be hypofunctional or hyperfunctional in OCD. These investigations, taken together, indicate that SLC1A1, like SLC6A4, is a susceptibility gene for OCD. The expression and database-mining approach that we used provide new and useful complementary model approaches to strengthen future GWAS and candidate rare functional gene studies in neuropsychiatric and other disorders, which represent a large public health burden. In fact, seven neuropsychiatric disorders, including OCD, were listed in a World Health Organizations report as among the leading causes of years of extended disability among adults. Thus these studies are expected to have a considerable public health impact. Of note is that our group continues to share our 25+ year collection of DNA and phenotype data with collaborators in the Obsessive-Compulsive Disorder Collaborative Genetics Study (OCGAS) and the Obsessive-Compulsive Foundation (OCF) groups, as well as with other intramural and extramural individual collaborators, thus enhancing the global search for underlying contributions to OCD and related disorders that are of major public health concerns. Many papers that were published in the last year that are listed below resulted from these collaborative studies. The OCF collaborational GWAS was conceived to compliment the earlier OCGS family-based genome linkage study of 299 OCD-affected sibling pairs together with other family members and now constitutes more than 1100 individuals. The OCGS studies generated more than 20 publications to date, the most recent two last year. Citations numbers of other papers that have referenced our scientific reports now number over 35,000. The protocol number for this Annual Report is 96-M-0124 and the NCT number is NCT00001548.