Genome-wide association study of obsessive-compulsive disorder

Abstract

Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1,465 cases, 5,557 ancestry-matched controls and 400 complete trios remained, with a common set of 469,410 autosomal and 9,657 X-chromosome SNPs. Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two p-values were located within DLGAP1 (p=2.49×10-6 and p=3.44×10-6), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a p-value=3.84 × 10-8. However, when trios were meta-analyzed with the combined case-control samples, the p-value for this variant was 3.62×10-5, losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation-QTLs (p<0.001) and frontal lobe eQTLs (p=0.001) was observed within the top-ranked SNPs (p<0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD.

Preliminary investigation of the role of BTB domain-containing 3 gene in the proliferation and metastasis of hepatocellular carcinoma

“…Within this gene, there is a BTB (broad-complex, tramtrack and bric-à-brac) structural domain (amino acids 113-219), a nuclear localization signal region (amino acids 55-70), and a structural domain containing BACK (amino acids 226-335) and PHR (amino acids 226-335) regions. At present, there have been limited studies investigating the function of the BTBD3 gene (13)(14)(15)(16)(17)(18)(19)(20). A previous study by Zhang et al (13), investigating the function of hsa-let-7i in colon cancer metastasis, is the only study to have suggested the BTBD3 gene may be the target of hsa-let-7i.…”

Comparative genomic evidence for self-domestication inHomo sapiens

“…DLGAP1, a scaffold-protein-coding gene at the postsynaptic density, is in fact selected for in AMHs and in the horse. This gene has been implicated in obsessive-compulsive disorders and interacts significantly with Shank proteins, mutations in which have been linked to autism spectrum disorders with impaired social interaction and communication [66][67][68] . DLGAP1 interacts with the glutamate receptor GRIK2, implicated in obsessive-compulsive disorders 69 .…”

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.…”