Association Testing of the Positional and Functional Candidate Gene SLC1A1/EAAC1 in Early-Onset Obsessive-compulsive Disorder

Dickel, Diane E.; Veenstra‐VanderWeele, Jeremy; Cox, Nancy J.; Wu, Xiaolin; Fischer, Daniel J.; Etten-Lee, Michelle Van; Himle, Joseph A.; Leventhal, Bennett L.; Cook, Edwin H.; Hanna, Gregory L.

doi:10.1001/archpsyc.63.7.778

Cited by 263 publications

(211 citation statements)

References 55 publications

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“…It should also be noted that the recent association between 5-HTTLPR and OCD by Hu et al was observed in a case-control as well as in a family-based association study, the latter of which is not susceptible to hidden population stratification. Thus, the lack of association in our study warrants further analyses in large family-based OCD samples such as the OCD Collaborative Genetics Study ) before it will point toward the need to analyze other candidate regions such as 9p, 3q, 7p, 1q, 15q, 6q, and 13q (Hanna et al, 2002;Shugart et al, 2006;Willour et al, 2004) and polymorphisms involved in other neurotransmitters such as glutamate (Arnold et al, 2006;Dickel et al, 2006;Rosenberg and Keshavan, 1998), neuromodulators, and developmental signals potentially of importance in OCD such as glutamate.…”

Section: Discussionmentioning

confidence: 84%

A Large Case–Control Study of Common Functional SLC6A4 and BDNF Variants in Obsessive–Compulsive Disorder

Wendland

Kruse

Cromer

et al. 2007

Neuropsychopharmacol

101

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Both serotonin transporter (SLC6A4) and brain-derived neurotrophic factor (BDNF) genes have shown positive associations with obsessive-compulsive disorder (OCD) and some other psychiatric disorders, but these results have not been consistently replicated. To explore the hypothesis that this variability might result from the effects of differing combinations of overlooked variants within SLC6A4 together with small OCD and control sample sizes, we studied three common functional polymorphisms (5-HTTLPR, STin2, and the newly discovered SNP, rs25531) in the largest sample size of OCD patients (N ¼ 347) and controls (N ¼ 749) ever investigated. During methods development, we found evidence for potential SLC6A4 genotyping problems with earlier methodology, a third possible contributor to variability in earlier studies. A fourth possible explanation might be SLC6A4 Â BDNF interactions, which prompted us to investigate combined genotypes of BDNF V66M with the three SLC6A4 loci. Except for a nominal association with rs25531 alone, which did not survive correction for multiple comparisons, we found no evidence for any of these other variants being associated alone or together with OCD, and we therefore also examined clinical OCD subtypes within the sample to evaluate clinical heterogeneity. Subgroups based on the age of OCD onset, gender, familiality, factor analysis-derived symptom dimensions, or comorbidity with other psychiatric disorders failed to identify SLC6A4-or BDNF-associated phenotypes, with one exception of overall number of comorbid anxiety disorders being significantly associated with 5-HTTLPR/rs25531. We conclude that despite their attractiveness as candidate genes in OCD, our data provide no support for association in this large OCD patient sample and point toward the need to examine other genes as candidates for risk determinants in OCD.

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Section: Discussionmentioning

confidence: 84%

A Large Case–Control Study of Common Functional SLC6A4 and BDNF Variants in Obsessive–Compulsive Disorder

Wendland

Kruse

Cromer

et al. 2007

Neuropsychopharmacol

101

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“…This is equivalent to overtransmission of the C allele under the dominant model. A haplotype previously identified for association with OCD [Dickel et al, 2006], including this SNP (rs301430-rs301979), was also significant under a recessive model. The T-G haplotype type was undertransmitted to individuals with autism.…”

Section: Discussionmentioning

confidence: 68%

“…Dickel et al [2006] reported that two of the nine SNPs they tested, including rs3780412 from the Arnold paper (P 5 0.04) and rs301430, which showed significant overtransmission of the C allele (P 5 0.03), were significantly associated with OCD. Only rs3780412 was associated with OCD when they restricted their sample to males only.…”

Section: Discussionmentioning

confidence: 99%

“…This finding was replicated in 42 pedigrees with early onset OCD [Willour et al, 2004]. Subsequently, three studies have reported an association between markers at SLC1A1 and OCD [Arnold, Sicard, Burroughs, Richter, & Kennedy, 2006;Dickel et al, 2006;Stewart et al, 2007a]. The Autism Genome Project, a largescale, collaborative autism genetics research project, identified SLC1A1 in a genome-wide linkage scan of autism due to its proximity to a linkage peak at 9p24.1, and its role in glutamate function [Szatmari et al, 2007].…”

Section: Introductionmentioning

confidence: 98%

“…The aim of the study was to examine if previously associated SNPs in SLC1A1 were associated with autism. Of note, these three SNPs were associated with OCD in one or more of the previous association studies [Arnold et al, 2006;Dickel et al, 2006;Stewart et al, 2007a]. We tested each marker and a previously identified haplotype (rs301430-rs301979) for association in a strictly defined autism sample.…”

Section: Introductionmentioning

confidence: 99%

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Family‐based association testing of OCD‐associated SNPs of SLC1A1 in an autism sample

et al. 2008

Self Cite

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Reports identified the neuronal glutamate transporter gene, SLC1A1 (OMIM 133550, chromosome 9p24), as a positional and functional candidate gene for obsessive-compulsive disorder (OCD). The presence of obsessions and compulsions similar to OCD in autism, the identification of this region in a genome-wide linkage analysis of individuals with autism spectrum disorders (ASDs), and the hypothesized role of glutamate in ASDs make SLC1A1 a candidate gene for ASD as well. To test for association between SLC1A1 and autism, we typed three single nucleotide polymorphisms (SNPs, rs301430, rs301979, rs301434) previously associated with OCD in 86 strictly defined trios with autism. Family-Based Association Tests (FBAT) with additive and recessive models were used to check for association. Additionally, an rs301430-rs301979 haplotype identified for OCD was investigated. FBAT revealed nominally significant association between autism and one SNP under a recessive model. The G allele of rs301979 was undertransmitted (equivalent to overtransmission of the C allele under a dominant model) to individuals with autism (Z 5 À2.47, P 5 0.01). The G allele was also undertransmitted in the T-G haplotype under the recessive model (Z 5 À2.41, P 5 0.02). Both findings were also observed in the male-only sample. However, they did not withstand correction for multiple comparisons.

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Association of the Glutamate Transporter Gene SLC1A1 With Atypical Antipsychotics–Induced Obsessive-compulsive Symptoms

Kwon¹,

Joo²,

Nam³

et al. 2009

Arch Gen Psychiatry

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Association Testing of the Positional and Functional Candidate Gene SLC1A1/EAAC1 in Early-Onset Obsessive-compulsive Disorder

Abstract: The 3' region of SLC1A1 may contain a susceptibility allele for early-onset OCD, with differential effects in males and females. The results also provide further support for the involvement of a glutamatergic dysfunction in the pathogenesis of early-onset OCD.

Cited by 263 publications

References 55 publications

A Large Case–Control Study of Common Functional SLC6A4 and BDNF Variants in Obsessive–Compulsive Disorder

A Large Case–Control Study of Common Functional SLC6A4 and BDNF Variants in Obsessive–Compulsive Disorder

Family‐based association testing of OCD‐associated SNPs of SLC1A1 in an autism sample

Association of the Glutamate Transporter Gene SLC1A1 With Atypical Antipsychotics–Induced Obsessive-compulsive Symptoms

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