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

Mattheisen M, Samuels JF, Wang Y, Greenberg BD, Fyer AJ, McCracken JT, Geller DA, Murphy DL, Knowles JA, Grados MA, Riddle MA, Rasmussen SA, McLaughlin NC, Nurmi EL, Askland KD, Qin HD, Cullen BA, Piacentini J, Pauls DL, Bienvenu OJ, Stewart SE, Liang KY, Goes FS, Maher B, Pulver AE, Shugart YY, Valle D, Lange C, Nestadt G - Mol. Psychiatry (2014)

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Biomedicine and Center for Integrated Sequencing (iSEQ), Aarhus University, Aarhus, Denmark [2] Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA [3] Department of Genomic Mathematics, University of Bonn, Bonn, Germany.

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.

No MeSH data available.


Related in: MedlinePlus

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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Figure 2: 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.

Mentions: Analysis of the 549 123 autosomal markers revealed a nominally significant result at the level of α=0.05 for 27 283 markers. Among these, 456 markers reached a P-value of less than 0.001 and 54 markers were identified with a P<0.0001. As expected due to the stringent study design, no evidence for population stratification was observed (see also Supplementary Figure S1). Figure 1 shows the ‘Manhattan’ plot of the association results across the autosomal genome and Table 1 reports the association between single SNPs and OCD with P<1×10−5. No marker tested for association met the standard of genome-wide significance. The smallest P-value for our study was observed with a marker on chromosome 9 (rs4401971) at a P-value of 4.13×10−7. This SNP is 1.28 Mb from the 5′ end of the protein tyrosine phosphatase, receptor type, D gene (PTPRD, isoform 1; according to RefSeq). The second most significantly associated SNP (rs6876547, P=1.76×10−6) is located in a region of cadherin clusters and it is of note, that a second, independent SNP (rs6452234, P=1.13×10−5, r2<0.2, distance ~650kb) is located in the same region. The nearest flanking protein coding genes are the cadherin 9, type 2 (CDH9, 1 308 kb) and the cadherin 10, type 2 (CDH10, 927 kb) genes. A ‘regional association plot’ of these two top regions is provided in Figure 2.


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

Mattheisen M, Samuels JF, Wang Y, Greenberg BD, Fyer AJ, McCracken JT, Geller DA, Murphy DL, Knowles JA, Grados MA, Riddle MA, Rasmussen SA, McLaughlin NC, Nurmi EL, Askland KD, Qin HD, Cullen BA, Piacentini J, Pauls DL, Bienvenu OJ, Stewart SE, Liang KY, Goes FS, Maher B, Pulver AE, Shugart YY, Valle D, Lange C, Nestadt G - Mol. Psychiatry (2014)

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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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4231023&req=5

Figure 2: 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.
Mentions: Analysis of the 549 123 autosomal markers revealed a nominally significant result at the level of α=0.05 for 27 283 markers. Among these, 456 markers reached a P-value of less than 0.001 and 54 markers were identified with a P<0.0001. As expected due to the stringent study design, no evidence for population stratification was observed (see also Supplementary Figure S1). Figure 1 shows the ‘Manhattan’ plot of the association results across the autosomal genome and Table 1 reports the association between single SNPs and OCD with P<1×10−5. No marker tested for association met the standard of genome-wide significance. The smallest P-value for our study was observed with a marker on chromosome 9 (rs4401971) at a P-value of 4.13×10−7. This SNP is 1.28 Mb from the 5′ end of the protein tyrosine phosphatase, receptor type, D gene (PTPRD, isoform 1; according to RefSeq). The second most significantly associated SNP (rs6876547, P=1.76×10−6) is located in a region of cadherin clusters and it is of note, that a second, independent SNP (rs6452234, P=1.13×10−5, r2<0.2, distance ~650kb) is located in the same region. The nearest flanking protein coding genes are the cadherin 9, type 2 (CDH9, 1 308 kb) and the cadherin 10, type 2 (CDH10, 927 kb) genes. A ‘regional association plot’ of these two top regions is provided in Figure 2.

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Biomedicine and Center for Integrated Sequencing (iSEQ), Aarhus University, Aarhus, Denmark [2] Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA [3] Department of Genomic Mathematics, University of Bonn, Bonn, Germany.

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.

No MeSH data available.


Related in: MedlinePlus