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. 2015 Mar;20(3):337-44.
doi: 10.1038/mp.2014.43. Epub 2014 May 13.

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

M Mattheisen  1 , J F Samuels  2 , Y Wang  2 , B D Greenberg  3 , A J Fyer  4 , J T McCracken  5 , D A Geller  6 , D L Murphy  7 , J A Knowles  8 , M A Grados  2 , M A Riddle  2 , S A Rasmussen  3 , N C McLaughlin  3 , E L Nurmi  5 , K D Askland  3 , H-D Qin  9 , B A Cullen  2 , J Piacentini  5 , D L Pauls  6 , O J Bienvenu  2 , S E Stewart  10 , K-Y Liang  11 , F S Goes  2 , B Maher  11 , A E Pulver  2 , Y Y Shugart  9 , D Valle  12 , C Lange  13 , G Nestadt  2
Affiliations

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

M Mattheisen et al. Mol Psychiatry. 2015 Mar.

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 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 × 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 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 × 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.

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Conflict of interest statement

Conflict of interest

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1. Manhattan plot for OCGAS GWAS
Shown 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 × 10−5) and a thin red line indicates genome-wide significance (5 × 10−8).
Figure 2
Figure 2. Regional association plots for top regions in OCGAS GWAS
The 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.
Figure 2
Figure 2. Regional association plots for top regions in OCGAS GWAS
The 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.
Figure 2
Figure 2. Regional association plots for top regions in OCGAS GWAS
The 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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