Comprehensive family-based association study of the glutamate transporter gene SLC1A1 in obsessive-compulsive disorder

Jack Samuels, Ying Wang, Mark A. Riddle, Benjamin D. Greenberg, Abby J. Fyer, James T. Mccracken, Scott L. Rauch, Dennis L. Murphy, Marco A. Grados, James A. Knowles, John Piacentini, Bernadette Cullen, O. Joseph Bienvenu, Steven A. Rasmussen, Daniel Geller, David L. Pauls, Kung Yee Liang, Yin Y. Shugart, Gerald Nestadt

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Abstract

SLC1A1 encodes a neuronal glutamate transporter and is a promising candidate gene for obsessive-compulsive disorder (OCD). Several independent research groups have reported significant associations between OCD and single nucleotide polymorphisms (SNPs) in this gene. Previously, we evaluated 13 SNPs in, or near, SLC1A1 and reported a strong association signal with rs301443, a SNP 7.5kb downstream of the gene [Shugart et al. (2009); Am J Med Genet Part B 150B:886-892]. The aims of the current study were first, to further investigate this finding by saturating the region around rs301443; and second, to explore the entire gene more thoroughly with a dense panel of SNP markers. We genotyped an additional 111 SNPs in or near SLC1A1, covering from 9kb upstream to 84kb downstream of the gene at average spacing of 1.7kb per SNP, and conducted family-based association analyses in 1,576 participants in 377 families. We found that none of the surrounding markers were in linkage disequilibrium with rs301443, nor were any associated with OCD. We also found that SNP rs4740788, located about 8.8kb upstream of the gene, was associated with OCD in all families (P=0.003) and in families with male affecteds (P=0.002). A three-SNP haplotype (rs4740788-rs10491734-rs10491733) was associated with OCD in the total sample (P=0.00015) and in families with male affecteds (P=0.0007). Although of nominal statistical significance considering the number of comparisons, these findings provide further support for the involvement of SLC1A1 in the pathogenesis of OCD.

Original languageEnglish (US)
Pages (from-to)472-477
Number of pages6
JournalAmerican Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Volume156
Issue number4
DOIs
StatePublished - Jun 1 2011

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Keywords

  • Candidate gene
  • Glutamate transporter
  • Obsessive-compulsive disorder

ASJC Scopus subject areas

  • Genetics(clinical)
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Samuels, J., Wang, Y., Riddle, M. A., Greenberg, B. D., Fyer, A. J., Mccracken, J. T., Rauch, S. L., Murphy, D. L., Grados, M. A., Knowles, J. A., Piacentini, J., Cullen, B., Bienvenu, O. J., Rasmussen, S. A., Geller, D., Pauls, D. L., Liang, K. Y., Shugart, Y. Y., & Nestadt, G. (2011). Comprehensive family-based association study of the glutamate transporter gene SLC1A1 in obsessive-compulsive disorder. American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, 156(4), 472-477. https://doi.org/10.1002/ajmg.b.31184