OCD is a severe, heritable condition with a lifetime prevalence of about two percent of world populations. 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 a multi-center genome-wide study of OCD, the results of which have recently been reported in the group's publications noted below. In addition, a series of association studies that has identified and evaluated candidate genes in OCD and related disorders is continuing. There have been several recent major OCD genetic research results from our Lab. In our Lab's continuing and collaborative investigations of the role of serotonin and its major genes in OCD and related disorders, we resequenced the promoter region of SLC6A4 to search for additional and possibly functional variants. We discovered that a common single nucleotide polymorphism (SNP), rs25532, strongly modulated SERT expression in several cultured cell lines and in human post-mortem brain cortex. When this SNP and other SLC6A4 SNPs were included in haplotype (i.e., combinatorial) analyses, our group discovered a highly significant association in a large OCD case-control sample (Wendland et al., 2008).Thus, in keeping with our hypothesis of increased SERT functioning in OCD, a haplotype containing the higher-expressing variant at each locus was found to be significantly more common in OCD probands than in controls (Wendland et al., 2009). The strong 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 diseases such as fibromyalgia, irritable bowel syndrome and migraine. Recent evidence from treatment studies 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 is encoded by the gene SLC1A1 located at the chromosomal region 9p24. Recent evidence from 9p24 gene linkage analyses and five family-based candidate gene studies have indicated the likely involvement of SLC1A1 in the development of OCD. We undertook the first large case-control study of SLC1A1 that included over 300 OCD probands and over 650 matched controls collected by our Lab. In addition, SLC1A1 expression and genotype data were evaluated to gain further insights into SLC1A1 function. Six SNPs in or near SLC1A1 were genotyped. We found that gene expression of SLC1A1 is heritable in human cell lines. We identified three SNPs in or near SLC1A1 that correlated with gene expression levels. Additionally, two of these SNPs also predicted expression levels in human post-mortem brain tissue, and one SNP was found to have functional consequences in reporter gene studies (Wendland et al., 2009). Two haplotypes at three SNPs, rs3087879, rs301430, and rs7858819, were significantly associated with OCD after multiple testing corrections and contained two of the SNPs associated with expression levels. In addition, another SNP correlating with SLC1A1 gene expression, rs3933331, was associated with an OCD sub-phenotype, hoarding, as assessed by two independent, validated rating scales for hoarding. Thus, our case-control data corroborate previous smaller, family-based studies that, taken together, indicate that SLC1A1, like SLC6A4, is a susceptibility gene for OCD. The expression and database-mining approach that we used provides a new and useful complementary model approach to strengthen future candidate gene studies in neuropsychiatric and other disorders which represent a large public health burden. In fact, seven of these disorders, including OCD, were listed in the 2001 World Health Organizations report on the leading causes of years of extended disability among adults. In additional studies of the genetics of OCD, we focused on candidate genes for OCD based on animal models of some OCD-related compulsive behaviors. Recently, it was shown that mice deficient in the postsynaptic synapse-associated protein Sapap3 develop an OCD-like phenotype, which included compulsive grooming and increased anxiety-like behaviors. Interestingly, the phenotype of Sapap3 gene knock-out mice can be rescued by administering SRIs, the most effective group of therapeutic agents for OCD. We hypothesized that variants in human SAPAP3 could contribute to disorders in the OCD spectrum. To test this, we resequenced SAPAP3 in DNA samples from OCD patients and from others with related disorders in a case-control study, investigating the complete coding region and flanking intronic sequences of SAPAP3. Importantly, we detected seven novel non-synonymous variants. These SAPAP3 variants were present in 4.2% of diagnosed OCD and related disorder patients, but only in 1.1% of controls. Thus, we observed a significant case-control association in our moderately-sized sample (Zuchner et al., 2009). The majority of changes were missense mutations, while one variant was an in-frame insertion of five amino acids. Modeling analysis of these missense variants identified several variants with highly likely functional consequences. It is thus possible that a combination of relatively rare susceptibility variants may prove contributory to OCD, as suggested for some other disorders including autism as well as for OCD itself in our prior study of the SLC6A4 uncommon variant, Ileu425Val (Wendland et al., 2008). Our data is thus in support of the multiple rare variant/common disease hypothesis versus the common variant/common disease hypothesis highly debated currently in the scientific literature. The combination of the Sapap3 mouse model with compulsive behaviors and our recent, first case-control study of the SAPAP3 gene in humans with OCD demonstrates a role for SAPAP3 in OCD and compulsive behaviors. In fact, a follow-up study recently reported from our collaborative study of siblings who were both affected by OCD found that four of six SNPs investigated in SAPAP3 were nominally associated with specifically-studied grooming disorders, with high genotypic relative risks of 1.6-3.3. All three haplotypes that were identified were nominally associated with at least one grooming disorder. This study thus brings an even sharper focus on OCD subtypes or sub-populations that may be more closely related to specific single genes. Other studies by our group of OCD-related common and uncommon gene variants and also of other OCD phenotypic subtypes such as hoarding are noted in our list of recent publications, below. Also 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 (OCGS) 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. Multiple papers that were published in the last year that are listed below resulted from these collaborative studies. Other papers that were published with our collaborators that have helped to refine the phenotype for OCD and other neuropsychiatric disorders genetic studies are also listed.

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31
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2010
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$734,422
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U.S. National Institute of Mental Health
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Mattheisen, M; Samuels, J F; Wang, Y et al. (2015) Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS. Mol Psychiatry 20:337-44
Samuels, Jack; Shugart, Yin Yao; Wang, Ying et al. (2014) Clinical correlates and genetic linkage of social and communication difficulties in families with obsessive-compulsive disorder: Results from the OCD Collaborative Genetics Study. Am J Med Genet B Neuropsychiatr Genet 165B:326-36
McGrath, Lauren M; Yu, Dongmei; Marshall, Christian et al. (2014) Copy number variation in obsessive-compulsive disorder and tourette syndrome: a cross-disorder study. J Am Acad Child Adolesc Psychiatry 53:910-9
Rudnick, Gary; Krämer, Reinhard; Blakely, Randy D et al. (2014) The SLC6 transporters: perspectives on structure, functions, regulation, and models for transporter dysfunction. Pflugers Arch 466:25-42
Davis, Lea K; Yu, Dongmei; Keenan, Clare L et al. (2013) Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture. PLoS Genet 9:e1003864
Murphy, Dennis L; Maile, Michelle S; Vogt, Nicholas M (2013) 5HTTLPR: White Knight or Dark Blight? ACS Chem Neurosci 4:13-5
Murphy, Dennis L; Moya, Pablo R; Fox, Meredith A et al. (2013) Anxiety and affective disorder comorbidity related to serotonin and other neurotransmitter systems: obsessive-compulsive disorder as an example of overlapping clinical and genetic heterogeneity. Philos Trans R Soc Lond B Biol Sci 368:20120435
Stewart, S E; Yu, D; Scharf, J M et al. (2013) Genome-wide association study of obsessive-compulsive disorder. Mol Psychiatry 18:788-98
Ozomaro, Uzoezi; Cai, Guiqing; Kajiwara, Yuji et al. (2013) Characterization of SLITRK1 variation in obsessive-compulsive disorder. PLoS One 8:e70376
Stewart, S E; Mayerfeld, C; Arnold, P D et al. (2013) Meta-analysis of association between obsessive-compulsive disorder and the 3' region of neuronal glutamate transporter gene SLC1A1. Am J Med Genet B Neuropsychiatr Genet 162B:367-79

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