Gene Candidate for Obsessive-compulsive Disorder Revealed

20 July 2006. Two research teams have independently found association of the solute carrier family 1 member 1 (SLC1A1) gene, which codes for a neuronal/epithelial excitatory amino acid transporter (EAAC1), with obsessive-compulsive disorder (OCD). The researchers report their findings in back-to-back papers in this month’s Archives of General Psychiatry. The studies may be of interest to schizophrenia researchers for several reasons. Not only do the two diseases have symptoms in common, including anxiety, delusions, and obsessive compulsions, but excitatory amino acid transporters are crucial in protecting neurons against glutamate toxicity in the brain. Glutamate is, of course, intimately tied to schizophrenia (see, for example, Current Hypothesis review by Bita Moghaddam, as well as Moghaddam, 2003), and excitatory amino acid transporters have been investigated for their potential role in schizophrenia pathology (Smith et al., 2001; McCullumsmith et al., 2002).

SLC1A1 lies on chromosome 9p24, the only genomic region whose linkage to OCD has been replicated. It was this connection that compelled the researchers to analyze this region further. Both groups used similar approaches, genotyping single nucleotide polymorphisms (SNPs) along the SLC1A1 locus and correlating those genotypes to OCD. A Canadian team led by James Kennedy at the University of Toronto genotyped nine SNPs in 157 OCD probands and 319 first-degree relatives. A U.S.-based team, led by Jeremy Veenstra-VanderWeele at the University of Illinois (now at Vanderbilt University, Nashville, Tennessee) and Greg Hanna of the University of Michigan at Ann Arbor, in collaboration with others at these institutions as well as the University of Chicago, also genotyped nine SNPs—including five distinct from the Canadian study—in 71 probands and their parents. Though both groups found SNPs associating with transmission of OCD, the polymorphisms they found were not the same.

In the Canadian study, first author Paul Daniel Arnold and colleagues found that two SNPs (rs301434 and rs301435), located in the same haplotype block, were significantly linked to OCD. They also found a two-marker haplotype (rs301434 and rs3087879) in the same block that had a significant association. In the American study, first author Diane Dickel, University of Chicago, and colleagues found that two different SNPs (rs3780412 and rs301430) were significantly linked to OCD transmission, as was a different two-SNP haplotype (T/C nucleotides at rs301430 and rs301979). Though the Canadian team also tested rs3780412 and rs301430, finding no association in their families, they did note that rs301430 segregates modestly with rs3087879, one of the SNPs in their two-SNP haplotype, supporting the association. The major difference between the two findings is that the American group focused on early-onset OCD, which might explain why the two groups found different genetic associations.

Both groups conclude that the evidence supports a role for SLC1A1 and glutamatergic neurotransmission in OCD. “We concur with the authors that their findings are promising,” write James Leckman and Young-Shin Kim, Yale University, New Haven, Connecticut, in an accompanying editorial. But efforts to replicate these findings in larger samples are clearly warranted, they add.

One notable feature of the link between SLC1A1 and OCD, which could not have been predicted a priori, is that the associations are limited to males. “How do we understand the robust sex effect?” is only one of the many queries addressed by Leckman and Kim. As with any new genetic link, the findings raise many questions and provide plenty of opportunities for new research. For example, how do these SNPs affect EAAC1 activity? With what other genes may SLC1A1 interact? Is there a link with neurodevelopment, which is increasingly becoming the focus of psychiatric research (see, for example, Lewis and Levitt, 2002)? And more importantly, can the findings lead to any new therapeutics? On the last note, Arnold and colleagues are somewhat optimistic. “It is also hoped that confirmation and further delineation of the association of SLC1A1 with OCD will lead to the development of novel pharmacological treatments of this common and debilitating neuropsychiatric condition,” they conclude.—Tom Fagan.

Reference:
Arnold PD, Sicard R, Burroughs E, Richter MA, Kennedy JL. Glutamate transporter gene SLC1A1 associated with obsessive-compulsive disorder. Arch. Gen. Psych. July, 2006;63:769-776. Abstract

Dickel DE, Veenstra-VanderWeele J, Cox NJ, Wu X, Fischer DJ, Van Etten-Lee M, Himle JA, Leventhal BL, Cook EH, Hanna GL. Association testing of the positional and functional candidate gene SLC1A1/EAAC1 in early-onset obsessive-compulsive disorder. Arch. Gen. Psych. July, 2006;63:778-785. Abstract

Leckman JF, Kim Y-S. A primary candidate gene for obsessive-compulsive disorder. Arch. Gen. Psych. July, 2006;63:717-719. Abstract

Perhaps the finding by these researchers may help explain the significant clinical improvement in OCD signs with the use of N-acetylcysteine recently reported by the Lafleur group . I refer to the study by Aoyama et al. in which they find that the neuronal glutathione deficiency with consequent oxidative stress and neurodegeneration in EAAC1-deficient mice is restored with the use of N-acetylcysteine. This benefit might indicate that these SNPs associated with OCD result in reduced EAAC1 activity. Another interesting study by Gu and colleagues finds that β amyloid inhibits Na(+)/K(+)-ATPase and EAAC1. Maybe you could kill two birds with one stone here, as Studer et al. find that N-acetylcysteine downregulates APP gene transcription in neuroblastoma cells. Perhaps a study reporting APP gene transcription in those with Down syndrome treated with N-acetylcysteine would be very beneficial.

References:

1. Aoyama K, Suh SW, Hamby AM, Liu J, Chan WY, Chen Y, Swanson RA. Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse. Nat Neurosci. 2006 Jan;9(1):119-26. Epub 2005 Nov 27. Abstract

2. Lafleur DL, Pittenger C, Kelmendi B, Gardner T, Wasylink S, Malison RT, Sanacora G, Krystal JH, Coric V. N-acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder. Psychopharmacology (Berl). 2006 Jan;184(2):254-6. Epub 2005 Dec 22. Abstract

3. Gu QB, Zhao JX, Fei J, Schwarz W. Modulation of Na(+),K(+) pumping and neurotransmitter uptake by beta-amyloid. Neuroscience. 2004;126(1):61-7. Abstract

4. Studer R, Baysang G, Brack C. N-Acetyl-L-Cystein downregulates beta-amyloid precursor protein gene transcription in human neuroblastoma cells. Biogerontology. 2001;2(1):55-60. Abstract

View all comments by Mary ReidComment by:  James L. Kennedy, SRF Advisor (Disclosure)
Submitted 22 July 2006
Posted 25 July 2006

Another intriguing link with schizophrenia is the relatively frequent occurrence of obsessional symptoms when schizophrenia patients are started on the newer antipsychotics clozapine or olanzapine (see, e.g., Ongur and Goff, 2005).

View all comments by James L. KennedyComment by:  Patricia Estani
Submitted 25 July 2006
Posted 25 July 2006
  I recommend the Primary PapersComment by:  Mary Reid
Submitted 13 October 2006
Posted 14 October 2006

Perhaps the study by Fournier and Robinson (2006), reporting that "SNAP-23 that lacks a domain required for SNARE complex assembly decreased the fraction of EAAC1 found on the cell surface and decreased total EAAC1 expression" may also have us suspect a role for SNAP-23(15q21-22)in OCD. Interesting that 15q21 is also a dyslexia locus.

View all comments by Mary Reid

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