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.
Laboratory of Clinical Science, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. wendlandj@mail.nih.gov
Jens R
JR
Wendland
Pablo R
PR
Moya
Kiara R
KR
Timpano
Adriana P
AP
Anavitarte
Matthew R
MR
Kruse
Michael G
MG
Wheaton
Renee F
RF
Ren-Patterson
Dennis L
DL
Murphy
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