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Meta-analysis of genome-wide association studies of anxiety disorders.

Otowa T, Hek K, Lee M, Byrne EM, Mirza SS, Nivard MG, Bigdeli T, Aggen SH, Adkins D, Wolen A, Fanous A, Keller MC, Castelao E, Kutalik Z, der Auwera SV, Homuth G, Nauck M, Teumer A, Milaneschi Y, Hottenga JJ, Direk N, Hofman A, Uitterlinden A, Mulder CL, Henders AK, Medland SE, Gordon S, Heath AC, Madden PA, Pergadia ML, van der Most PJ, Nolte IM, van Oort FV, Hartman CA, Oldehinkel AJ, Preisig M, Grabe HJ, Middeldorp CM, Penninx BW, Boomsma D, Martin NG, Montgomery G, Maher BS, van den Oord EJ, Wray NR, Tiemeier H, Hettema JM - Mol. Psychiatry (2016)

Bottom Line: Meta-analysis for each phenotype combined results across the nine samples for over 18 000 unrelated individuals.Each meta-analysis identified a different genome-wide significant region, with the following markers showing the strongest association: for case-control contrasts, rs1709393 located in an uncharacterized non-coding RNA locus on chromosomal band 3q12.3 (P=1.65 × 10(-8)); for FS, rs1067327 within CAMKMT encoding the calmodulin-lysine N-methyltransferase on chromosomal band 2p21 (P=2.86 × 10(-9)).Independent replication and further exploration of these findings are needed to more fully understand the role of these variants in risk and expression of ADs.Molecular Psychiatry advance online publication, 12 January 2016; doi:10.1038/mp.2015.197.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.

ABSTRACT

Anxiety disorders (ADs), namely generalized AD, panic disorder and phobias, are common, etiologically complex conditions with a partially genetic basis. Despite differing on diagnostic definitions based on clinical presentation, ADs likely represent various expressions of an underlying common diathesis of abnormal regulation of basic threat-response systems. We conducted genome-wide association analyses in nine samples of European ancestry from seven large, independent studies. To identify genetic variants contributing to genetic susceptibility shared across interview-generated DSM-based ADs, we applied two phenotypic approaches: (1) comparisons between categorical AD cases and supernormal controls, and (2) quantitative phenotypic factor scores (FS) derived from a multivariate analysis combining information across the clinical phenotypes. We used logistic and linear regression, respectively, to analyze the association between these phenotypes and genome-wide single nucleotide polymorphisms. Meta-analysis for each phenotype combined results across the nine samples for over 18 000 unrelated individuals. Each meta-analysis identified a different genome-wide significant region, with the following markers showing the strongest association: for case-control contrasts, rs1709393 located in an uncharacterized non-coding RNA locus on chromosomal band 3q12.3 (P=1.65 × 10(-8)); for FS, rs1067327 within CAMKMT encoding the calmodulin-lysine N-methyltransferase on chromosomal band 2p21 (P=2.86 × 10(-9)). Independent replication and further exploration of these findings are needed to more fully understand the role of these variants in risk and expression of ADs.Molecular Psychiatry advance online publication, 12 January 2016; doi:10.1038/mp.2015.197.

No MeSH data available.


Related in: MedlinePlus

Manhattan plots of meta-analysis results for (a) case-control and (b) factor score phenotypes. Red horizontal line indicates the genome-wide significant p-value 5×10−8; blue line indicates the suggestive p-value=1×10−5.
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Figure 2: Manhattan plots of meta-analysis results for (a) case-control and (b) factor score phenotypes. Red horizontal line indicates the genome-wide significant p-value 5×10−8; blue line indicates the suggestive p-value=1×10−5.

Mentions: We performed an inverse-variance weighted, fixed-effects meta-analysis with all discovery GWAS data including approximately 6.5M common SNPs after applying post-imputation QC to each study. The genomic inflation factor λ ranged from 0.990 to 1.038 for all studies. The Q-Q plots of the meta-analyses for the CC and FS phenotypes are presented in Figure 1. Meta-analytic inflation factors were 1.03 and 1.02, suggesting little effect of population stratification. Manhattan plots are presented in Figure 2. Table 2 lists the LD-independent, genome-wide significant SNPs and associated regions. For the CC model, the strongest association was observed at rs1709393 located in an intron of an uncharacterized non-coding RNA locus LOC152225 on chromosome 3q12.3 (P=1.65×10−8; Q=0.027). Allelic frequencies were very similar across studies and ranged between 0.55 and 0.60. The most significant SNP in the FS model was rs1067327 on chromosome 2p21 within CAMKMT encoding the calmodulin-lysine N-methyltransferase (P=2.86×10−9; Q=0.0017) with LD extending into several adjacent genes. Allelic frequencies were consistent across studies, ranging from 0.32 to 0.36. Both of these SNPs were imputed with very high quality across studies (R2>0.93). As indicted in the forest plots (Supplementary Figure S1), no heterogeneity of effects was observed for either SNP. Figure 3 displays the regional SNP plots for these two genome-wide significant loci.


Meta-analysis of genome-wide association studies of anxiety disorders.

Otowa T, Hek K, Lee M, Byrne EM, Mirza SS, Nivard MG, Bigdeli T, Aggen SH, Adkins D, Wolen A, Fanous A, Keller MC, Castelao E, Kutalik Z, der Auwera SV, Homuth G, Nauck M, Teumer A, Milaneschi Y, Hottenga JJ, Direk N, Hofman A, Uitterlinden A, Mulder CL, Henders AK, Medland SE, Gordon S, Heath AC, Madden PA, Pergadia ML, van der Most PJ, Nolte IM, van Oort FV, Hartman CA, Oldehinkel AJ, Preisig M, Grabe HJ, Middeldorp CM, Penninx BW, Boomsma D, Martin NG, Montgomery G, Maher BS, van den Oord EJ, Wray NR, Tiemeier H, Hettema JM - Mol. Psychiatry (2016)

Manhattan plots of meta-analysis results for (a) case-control and (b) factor score phenotypes. Red horizontal line indicates the genome-wide significant p-value 5×10−8; blue line indicates the suggestive p-value=1×10−5.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4940340&req=5

Figure 2: Manhattan plots of meta-analysis results for (a) case-control and (b) factor score phenotypes. Red horizontal line indicates the genome-wide significant p-value 5×10−8; blue line indicates the suggestive p-value=1×10−5.
Mentions: We performed an inverse-variance weighted, fixed-effects meta-analysis with all discovery GWAS data including approximately 6.5M common SNPs after applying post-imputation QC to each study. The genomic inflation factor λ ranged from 0.990 to 1.038 for all studies. The Q-Q plots of the meta-analyses for the CC and FS phenotypes are presented in Figure 1. Meta-analytic inflation factors were 1.03 and 1.02, suggesting little effect of population stratification. Manhattan plots are presented in Figure 2. Table 2 lists the LD-independent, genome-wide significant SNPs and associated regions. For the CC model, the strongest association was observed at rs1709393 located in an intron of an uncharacterized non-coding RNA locus LOC152225 on chromosome 3q12.3 (P=1.65×10−8; Q=0.027). Allelic frequencies were very similar across studies and ranged between 0.55 and 0.60. The most significant SNP in the FS model was rs1067327 on chromosome 2p21 within CAMKMT encoding the calmodulin-lysine N-methyltransferase (P=2.86×10−9; Q=0.0017) with LD extending into several adjacent genes. Allelic frequencies were consistent across studies, ranging from 0.32 to 0.36. Both of these SNPs were imputed with very high quality across studies (R2>0.93). As indicted in the forest plots (Supplementary Figure S1), no heterogeneity of effects was observed for either SNP. Figure 3 displays the regional SNP plots for these two genome-wide significant loci.

Bottom Line: Meta-analysis for each phenotype combined results across the nine samples for over 18 000 unrelated individuals.Each meta-analysis identified a different genome-wide significant region, with the following markers showing the strongest association: for case-control contrasts, rs1709393 located in an uncharacterized non-coding RNA locus on chromosomal band 3q12.3 (P=1.65 × 10(-8)); for FS, rs1067327 within CAMKMT encoding the calmodulin-lysine N-methyltransferase on chromosomal band 2p21 (P=2.86 × 10(-9)).Independent replication and further exploration of these findings are needed to more fully understand the role of these variants in risk and expression of ADs.Molecular Psychiatry advance online publication, 12 January 2016; doi:10.1038/mp.2015.197.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.

ABSTRACT

Anxiety disorders (ADs), namely generalized AD, panic disorder and phobias, are common, etiologically complex conditions with a partially genetic basis. Despite differing on diagnostic definitions based on clinical presentation, ADs likely represent various expressions of an underlying common diathesis of abnormal regulation of basic threat-response systems. We conducted genome-wide association analyses in nine samples of European ancestry from seven large, independent studies. To identify genetic variants contributing to genetic susceptibility shared across interview-generated DSM-based ADs, we applied two phenotypic approaches: (1) comparisons between categorical AD cases and supernormal controls, and (2) quantitative phenotypic factor scores (FS) derived from a multivariate analysis combining information across the clinical phenotypes. We used logistic and linear regression, respectively, to analyze the association between these phenotypes and genome-wide single nucleotide polymorphisms. Meta-analysis for each phenotype combined results across the nine samples for over 18 000 unrelated individuals. Each meta-analysis identified a different genome-wide significant region, with the following markers showing the strongest association: for case-control contrasts, rs1709393 located in an uncharacterized non-coding RNA locus on chromosomal band 3q12.3 (P=1.65 × 10(-8)); for FS, rs1067327 within CAMKMT encoding the calmodulin-lysine N-methyltransferase on chromosomal band 2p21 (P=2.86 × 10(-9)). Independent replication and further exploration of these findings are needed to more fully understand the role of these variants in risk and expression of ADs.Molecular Psychiatry advance online publication, 12 January 2016; doi:10.1038/mp.2015.197.

No MeSH data available.


Related in: MedlinePlus