Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS

Abstract

Obsessive-compulsive disorder (OCD) is a psychiatric condition characterized by intrusive thoughts and urges and repetitive, intentional behaviors that cause significant distress and impair functioning. The OCD Collaborative Genetics Association Study (OCGAS) is comprised of comprehensively assessed OCD patients, with an early age of OCD onset. After application of a stringent quality control protocol, a total of 1 065 families (containing 1 406 patients with OCD), combined with population-based samples (resulting in a total sample of 5 061 individuals), were studied. An integrative analyses pipeline was utilized, involving association testing at SNP- and gene-levels (via a hybrid approach that allowed for combined analyses of the family- and population-based data). The smallest P-value was observed for a marker on chromosome 9 (near PTPRD, P=4.13×10−7). Pre-synaptic PTPRD promotes the differentiation of glutamatergic synapses and interacts with SLITRK3. Together, both proteins selectively regulate the development of inhibitory GABAergic synapses. Although no SNPs were identified as associated with OCD at genome-wide significance level, follow-up analyses of GWAS signals from a previously published OCD study identified significant enrichment (P=0.0176). Secondary analyses of high confidence interaction partners of DLGAP1 and GRIK2 (both showing evidence for association in our follow-up and the original GWAS study) revealed a trend of association (P=0.075) for a set of genes such as NEUROD6, SV2A, GRIA4, SLC1A2, and PTPRD. Analyses at the gene-level revealed association of IQCK and C16orf88 (both P<1×10−6, experiment-wide significant), as well as OFCC1 (P=6.29×10−5). The suggestive findings in this study await replication in larger samples.

The balancing act of GABAergic synapse organizers

“…Given that only the initial crucial functions of PTPd or Slitrk3 are revealed by the currently available KO mice, conditional KO mice of these proteins would help to elucidate their precise roles at inhibitory synapses [36,37]. Intriguingly, both Slitrk3 and PTPd have been implicated in obsessive-compulsive disorder (OCD) [38]. A co-crystal structure of the Slitrk1/PTPd complex has allowed analysis of the discrete molecular steps that drive Slitrk-mediated presynaptic differentiation [39].…”

Obsessive-Compulsive Disorder, Psychosis, and Bipolarity: A Longitudinal Cohort and Multigenerational Family Study

“…Taken together, these findings are suggestive of a shared etiology, probably of genetic origin, between OCD and disorders of the schizophrenia and bipolar spectrum. Because gene-searching efforts in OCD are lagging considerably behind, with only 2 small genome-wide association studies published to date, 43,44 there may be some value in the targeted exploration of genetic variants already known to confer risk to schizophrenia and bipolar disorder in patients with OCD.…”

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.…”