Meta‐analysis of association between obsessive‐compulsive disorder and the 3′ region of neuronal glutamate transporter gene SLC1A1

Abstract

The neuronal glutamate transporter gene SLC1A1 is a candidate gene for obsessive-compulsive disorder (OCD) based on linkage studies and convergent evidence implicating glutamate in OCD etiology. The 3' end of SLC1A1 is the only genomic region with consistently demonstrated OCD association, especially when analyzing male-only probands. However, specific allele associations have not been consistently replicated, and recent OCD genome-wide association and meta-analysis studies have not incorporated all previously associated SLC1A1 SNPs. To clarify the nature of association between SLC1A1 and OCD, pooled analysis was performed on all available relevant raw study data, comprising a final sample of 815 trios, 306 cases and 634 controls. This revealed weak association between OCD and one of nine tested SLC1A1 polymorphisms (rs301443; uncorrected P = 0.046; non-significant corrected P). Secondary analyses of male-affecteds only (N = 358 trios and 133 cases) demonstrated modest association between OCD and a different SNP (rs12682807; uncorrected P = 0.012; non-significant corrected P). Findings of this meta-analysis are consistent with the trend of previous candidate gene studies in psychiatry and do not clarify the putative role of SLC1A1 in OCD pathophysiology. Nonetheless, it may be important to further examine the potential associations demonstrated in this amalgamated sample, especially since the SNPs with modest associations were not included in the more highly powered recent GWAS or in a past meta-analysis including five SLC1A1 polymorphisms. This study underscores the need for much larger sample sizes in future genetic association studies and suggests that next-generation sequencing may be beneficial in examining the potential role of rare variants in OCD.

Imaging genetics in obsessive-compulsive disorder: Linking genetic variations to alterations in neuroimaging

“…Although the genetic studies show one of the highest effect sizes for association of the glutamatergic system and OCD, only few groups have reported findings related to imaging genetics in OCD and genetic variants of glutamatergic genes (Arnold et al, 2009a(Arnold et al, , 2009bWu et al, 2012). The results of these investigations coincide with findings from meta-analyses and GWAS; taken together, these observations support the involvement of the glutamatergic system in OCD (Stewart et al, 2013a(Stewart et al, , 2013bTaylor, 2013). The existing literature on imaging-genetic studies with respect to OCD provides evidence of increasing specificity of brain structure and/or activity findings exerted by variants in genes involved in the serotonergic (5-HTTLPR, HTR2A) and glutamatergic (SLC1A1, SAPAP) systems.…”

“…This stipulation led to the retrieval of a small collection of manuscripts describing association analyses of genetic variants with neuroimaging techniques in OCD (n = 8). The present study focused on the most significant and nominally significant genes associated with OCD as inclusion criteria by cross-referencing these publications with GWAS and meta-analyzed genetic association (Azzam and Mathews, 2003;Lin, 2007;Pooley et al, 2007;Stewart et al, 2013aStewart et al, , 2013bTaylor, 2013;Walitza et al, 2014b). A publication by Hoexter et al (2009) was not included in the review because it did not include genetic association results in addition to their findings of single-photon emission computed tomography or magnetic resonance imaging in OCD.…”

Obsessive Compulsive Disorder

“…Interestingly, they also found sexually dimorphic effect of MAO-A on genetic susceptibility to OCD. As mentioned above, an association between a glutamate transporter gene that encodes EAAT3 ( SLC1A1 ) and OCD was reported by several independent groups ( 56 -59 ), although a meta-analysis of these data did not identify signifi cant association ( 59 ). Glutamate system genes warrant further investigation as functional candidates for OCD, based on multiple lines of evidence, including: 1) elevated glutamate levels in brain regions within OCD patients in magnetic resonance spectroscopy studies ( 76 -78 ); 2) corticostriatal glutamatergic mediation of stereotypic behavior in mice ( 79 ) and results of glutamate modulating agent augmentation studies in OCD ( 80 , 81 ).…”

“…and several groups reported an association between this gene and OCD ( 56 -59 ). Most recently, a meta-analysis of SLC1A1 found only weak associations between OCD and a single nucleotide polymorphism (SNP) rs301443 in the overall sample and between OCD and SNP rs12682807 in males-only, neither of which maintained signifi cance following correction for multiple testing ( 59 ). The second genome-wide scan was performed in 219 families at an approximate density of 9 cM, and found suggestive signals from chromosomes 3q27-28, 7p, 1q, 15q, and 6q ( 54 ).…”

Dissecting OCD Circuits: From Animal Models to Targeted Treatments

“…One of the more consistently replicated genetic findings in OCD is an association with the neuronal glutamate transporter SLC1A1 (protein: EAAT3 or EAAC1) [18][19][20][21][22][23][24] , although a recent meta-analysis showed only a modest association of 2/9 SNPs with OCD 25 , and SLC1A1 has not emerged as a probable locus from recent GWAS studies 15,16 . Findings cluster in the 3′ region, with most evidence for association with the rs301430C allele.…”