Glutamate transporter gene SLC1A1 associated with obsessive-compulsive disorder
Arnold PD, Sicard T, Burroughs E, Richter MA, Kennedy JL;
Commented by , 25 Jul 2006
Background
Two previous studies have linked obsessive-compulsive disorder (OCD) to chromosomal region 9p24. This region contains the glutamate transporter gene SLC1A1 (glutamate transporter gene solute carrier family 1, member 1). Since glutamate may be involved in the pathogenesis of OCD, the SLC1A1 gene may be a candidate gene for OCD.
Aims of the study
To determine whether one or more sequence variants in the SLC1A1 gene region are associated with OCD.
Method
A family-based candidate gene association study, involving 157 probands with OCD and their first-degree relatives. Nine single nucleotide polymorphisms (SNP) spaced throughout the SLC1A1 gene region were genotyped.
Results
A significant association was detected between OCD and two sequence variants in the SLC1A1 region. In addition, a specific 2-marker haplotype within this block was significantly associated with OCD in transmissions to male but not to female offspring
Professor Pull's comments
Glutamatergic dysfunction has been incriminated in the pathogenesis of OCD for several reasons. In particular, several functional neuroimaging studies have reported metabolic hyperactivity in the cortico-striato-thalamo-cortical circuitry in patients with OCD and recent magnetic resonance spectroscopy studies have provided evidence of elevated glutamate levels in several brain regions in patients suffering from OCD.
In addition, glutamate modulating agents have been found to hold promise for the treatment of the disorder.
The present study provides support for the presence of glutamatergic dysfunction in OCD. In another study published in the current issue of the Archives of General Psychiatry, Dickels et al. (ref. 1) also found a significant association between OCD and two common adjacent nucleotide polymorphisms in the SLC1A1 region. However, and although some of the same SNPs were used in both studies, the findings for specific SNPs did not replicate across the two studies.
As in the Arnold et al study, a significant association was detected for a haplotype within this block, again in male but not in female offspring.
Provided that they are replicated in larger samples of patients, the findings may profoundly change our understanding of OCD and have major implication for the treatment of the disorder.
However, as pointed out by Leckman and Kim (ref. 2), in a commentary to the articles by Arnold et al and Dickel et al, also appearing in the current issue of the Archives of General Psychiatry, the potential association between SLC1A1 and OCD also raises a number of as yet unanswered questions, such as in particular:
- what are the functional variants contributing to the OCD phenotype?
- what are the interactive genes?
- how do we understand the robust sex effect?
- what endophenotypes are most closely associated with these variants?
- can we create a valid animal model?
- what might such an association tell us with regard to treatment?
In spite of these limitations and unanswered questions, the studies by Arnold et al and Dickel et al are major investigations. The results of the two studies add to a growing body of data suggesting that SLC1A1 is a primary candidate gene for OCD and that glutamatergic dysfunction may be involved in the pathogenesis of the disorder.
References
1. Dickel DE, Veenstra-VanderWeele J, Cox NJ, Wu X, Fischer DJ, Van Etten-Lee M, et al. Association testing of the positional and functional candidate gene SLC1A1/EAAC1 in early-onset obsessive-compulsive disorder. Archives of General Psychiatry 2006; 63(7); 778-785
2. Leckman JF, Kim YS. A primary candidate gene for obsessive-compulsive disorder. Archives of General Psychiatry 2006; 63(7); 717-718