A haplotype containing quantitative trait loci for SLC1A1 gene expression and its association with obsessive-compulsive disorder.
BACKGROUND
Recent evidence from linkage analyses and follow-up candidate gene studies supports the involvement of SLC1A1, which encodes the neuronal glutamate transporter, in the development of obsessive-compulsive disorder (OCD).


OBJECTIVE
To determine the role of genetic variation of SLC1A1 in OCD in a large case-control study and to better understand how SLC1A1 variation affects functionality.


METHODS
A case-control study.


METHODS
Publicly accessible SLC1A1 expression and genotype data.


METHODS
Three hundred twenty-five OCD probands and 662 ethnically and sex-matched controls.


METHODS
Probands were assessed with the Structured Clinical Interview for DSM-IV, the Yale-Brown Obsessive Compulsive Scale, and the Saving Inventory-Revised. Six single-nucleotide polymorphisms (SNPs) were genotyped. Multiple testing corrections for single-marker and haplotype analyses were performed by permutation.


RESULTS
Gene expression of SLC1A1 is heritable in lymphoblastoid cell lines. We identified 3 SNPs in or near SLC1A1 that correlated with gene expression levels, 1 of which had previously been associated with OCD. Two of these SNPs also predicted expression levels in human brain tissue, and 1 SNP was further functional in reporter gene studies. Two haplotypes at 3 SNPs, rs3087879, rs301430, and rs7858819, were significantly associated with OCD after multiple-testing correction and contained 2 SNPs associated with expression levels. In addition, another SNP correlating with SLC1A1 gene expression, rs3933331, was associated with an OCD-hoarding subphenotype as assessed by 2 independent, validated scales.


CONCLUSIONS
Our case-control data corroborate previous smaller family-based studies that indicated that SLC1A1 is a susceptibility locus for OCD. The expression and genotype database-mining approach we used provides a potentially useful complementary approach to strengthen future candidate gene studies in neuropsychiatric and other disorders.
Wendland
Jens R
JR
Laboratory of Clinical Science, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. wendlandj@mail.nih.gov
Moya
Pablo R
PR
Timpano
Kiara R
KR
Anavitarte
Adriana P
AP
Kruse
Matthew R
MR
Wheaton
Michael G
MG
Ren-Patterson
Renee F
RF
Murphy
Dennis L
DL
D000328:Adult; D000483:Alleles; D001921:Brain / Q000378:metabolism; D016022:Case-Control Studies; D002460:Cell Line; D050580:Excitatory Amino Acid Transporter 3 / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009771:Obsessive-Compulsive Disorder / Q000175:diagnosis / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
D050580:Excitatory Amino Acid Transporter 3