Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS.
paper
Cited
Public
- Authors
- Mattheisen, M; Samuels, J F; Wang, Y; Greenberg, B D; Fyer, A J; McCracken, J T; Geller, D A; Murphy, D L; Knowles, J A; Grados, M A; Riddle, M A; Rasmussen, S A; McLaughlin, N C; Nurmi, E L; Askland, K D; Qin, H-D; Cullen, B A; Piacentini, J; Pauls, D L; Bienvenu, O J; Stewart, S E; Liang, K-Y; Goes, F S; Maher, B; Pulver, A E; Shugart, Y Y; Valle, D; Lange, C; Nestadt, G
- Year
- 2015
- Journal
- Molecular psychiatry
- PMID
- 24821223
- DOI
- 10.1038/mp.2014.43
- PMCID
- PMC4231023
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 1065 families (containing 1406 patients with OCD), combined with population-based samples (resulting in a total sample of 5061 individuals), were studied. An integrative analyses pipeline was utilized, involving association testing at single-nucleotide polymorphism (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 Γ 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 noΒ SNPs were identified as associated with OCD at genome-wide significance level, follow-up analyses of genome-wide association study (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 Γ 10(-)(6), experiment-wide significant), as well as OFCC1 (P=6.29 Γ 10(-)(5)). The suggestive findings in this study await replication in larger samples.
Manhattan plot for OCGAS GWASShown are the result for the hybrid analysis of the within and between family component of the OCGAS GWAS. A thin blue line indicates level of suggestive evidence for association (1 Γ 10β5) and a thin red line indicates genome-wide significance (5 Γ 10β8).
Regional association plots for top regions in OCGAS GWASThe most associated marker in the region (see table 2 and S2, purple dot) is centered in a genomic window of 5 Mb (hg19). P-values for the OCGAS GWAS are given. The linkage disequilibrium (LD) strength (r2; data from the 1000 genomes project European samples) between the sentinel single nucleotide polymorphism and its flanking markers is demonstrated by the coloring of the dots for the neighboring markers (ranging from red = high to blue = low). The recombination rate (cM/Mb; second y axis) is plotted in blue. Plots are given for the a) chromosome 9 region harboring PTPRD (clump 1 in table 2), b) the chromosome 5 region (clump 2 in table 2), and c) the chromosome 16 region harboring the two genes that were identified in the gene-based analysis, IQCK and C16orf88.
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Next β
| Name | Type |
|---|---|
| 15q local | variant |
| 1q local | variant |
| 3q27-28 local | variant |
| 6q local | variant |
| 7p local | variant |
| 9p24 local | variant |
| ADHD | phenotype |
| Alzheimerβs disease | phenotype |
| anorexia nervosa | phenotype |
| ASD | phenotype |
| attention deficit hyperactivity disorder | phenotype |
| bipolar disorder | phenotype |
| brain tumor | phenotype |
| BTBD3 | gene |
| C16orf88 local | gene |
| Case-control subsample local | cohort |
| Case probands local | cohort |
| CDH10 | gene |
| CDH9 | gene |
| controls | cohort |
| dbGaP accession number phs000196.v2.p1 local | cohort |
| Dlgap1 | gene |
| DLGAP3 | gene |
| early neurodevelopment local | phenotype |
| Early Onset Obsessive-Compulsive Disorder local | phenotype |
| Early onset probands local | cohort |
| EREG | gene |
| family-based association testing local | drug |
| family-based sample | cohort |
| First-degree relatives of case probands local | cohort |
| frontal cortex | anatomy |
| genetic factors | cohort |
| GRIA4 | gene |
| GRIK2 | gene |
| HACE1 local | gene |
| Hopkins OCD family study local | cohort |
| Huntingtonβs disease | phenotype |
| Illumina HumanOMNI1-QUAD bead chip local | drug |
| Illumina HumanOmniExpress bead chips local | drug |
| International OCD Foundation Genetic Collaborative local | cohort |
| IOCDF-GC | cohort |
| IOCDF-GC GWAS local | cohort |
| IQCK | gene |
| JHU local | cohort |
| learning and memory | phenotype |
| long-term potentiation | phenotype |
| memory | phenotype |
| mental retardation | phenotype |
| metal | drug |
| miRNA set 1 local | drug |
| miRNA set 2 local | drug |
| NEUROD6 local | gene |
| neuropsychiatric disorders | phenotype |
| obsessive-compulsive disorder | phenotype |
| OCD | phenotype |
| OCD Collaborative Genetics Association Study | cohort |
| OCD Collaborative Genetics Study local | cohort |
| OCD GWAS study (this study) local | cohort |
| OCD Study Cohort local | cohort |
| OCGAS | cohort |
| OFCC1 local | gene |
| panic disorder | phenotype |
| parents | cohort |
| Parkinsonβs disease | phenotype |
| PBAT local | drug |
| Pde4d | gene |
| population | cohort |
| population-based analyses local | drug |
| population-based study cohorts local | cohort |
| probands | cohort |
| psychiatric traits | phenotype |
| PTPRD | gene |
| PTPRD-deficient Mice local | cohort |
| Restless Leg Syndrome local | phenotype |
| rs11081062 local | variant |
| rs11663827 local | variant |
| rs1544352 local | variant |
| rs2205748 local | variant |
| rs3866988 local | variant |
| rs4401971 local | variant |
| rs6131295 local | variant |
| rs6452234 local | variant |
| rs6876547 local | variant |
| schizophrenia | phenotype |
| Secondary OCD local | phenotype |
| second OCD GWAS local | cohort |
| siblings | cohort |
| Siblings of early onset probands local | cohort |
| singleton OCD cases local | cohort |
| SLC1A1 | gene |
| Slc1a2 | gene |
| SLITRK1 | gene |
| SLITRK3 local | gene |
| SLITRK5 local | gene |
| spatial learning | phenotype |
| Stewart et al OCD GWAS local | cohort |
| Sv2a | gene |
| top-ranked SNPs local | variant |
| Total sample of 5,061 individuals local | cohort |
| Tourette syndrome | phenotype |
| trioβcaseβcontrol sample local | cohort |
| TS | cohort |
| unrelated controls local | cohort |
| unselected controls local | cohort |
| weighted Z-score statistic local | drug |
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