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

T. Otowa, K. Hek, M. Lee, E. M. Byrne, S. S. Mirza, M. G. Nivard, T. Bigdeli, S. H. Aggen, D. Adkins, Aaron Wolen, A. Fanous, M. C. Keller, E. Castelao, Z. Kutalik, S. V. Der Auwera, G. Homuth, M. Nauck, A. Teumer, Y. Milaneschi, J. J. Hottenga & 27 others N. Direk, A. Hofman, A. Uitterlinden, C. L. Mulder, A. K. Henders, S. E. Medland, S. Gordon, A. C. Heath, P. A.F. Madden, M. L. Pergadia, P. J. Van Der Most, I. M. Nolte, F. V.A. Van Oort, C. A. Hartman, A. J. Oldehinkel, M. Preisig, H. J. Grabe, C. M. Middeldorp, B. W.J.H. Penninx, D. Boomsma, N. G. Martin, G. Montgomery, B. S. Maher, E. J. Van Den Oord, N. R. Wray, H. Tiemeier, J. M. Hettema

Research output: Contribution to journalArticle

67 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1391-1399
Number of pages9
JournalMolecular Psychiatry
Volume21
Issue number10
DOIs
StatePublished - Oct 1 2016

Fingerprint

Genome-Wide Association Study
Anxiety Disorders
Meta-Analysis
Phenotype
Genome
Untranslated RNA
Phobic Disorders
Panic Disorder
Disease Susceptibility
Genetic Predisposition to Disease
Single Nucleotide Polymorphism
Linear Models
Multivariate Analysis
Logistic Models
Interviews

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Otowa, T., Hek, K., Lee, M., Byrne, E. M., Mirza, S. S., Nivard, M. G., ... Hettema, J. M. (2016). Meta-analysis of genome-wide association studies of anxiety disorders. Molecular Psychiatry, 21(10), 1391-1399. https://doi.org/10.1038/mp.2015.197

Meta-analysis of genome-wide association studies of anxiety disorders. / Otowa, T.; Hek, K.; Lee, M.; Byrne, E. M.; Mirza, S. S.; Nivard, M. G.; Bigdeli, T.; Aggen, S. H.; Adkins, D.; Wolen, Aaron; Fanous, A.; Keller, M. C.; Castelao, E.; Kutalik, Z.; Der Auwera, S. V.; Homuth, G.; Nauck, M.; Teumer, A.; Milaneschi, Y.; Hottenga, J. J.; Direk, N.; Hofman, A.; Uitterlinden, A.; Mulder, C. L.; Henders, A. K.; Medland, S. E.; Gordon, S.; Heath, A. C.; Madden, P. A.F.; Pergadia, M. L.; Van Der Most, P. J.; Nolte, I. M.; Van Oort, F. V.A.; Hartman, C. A.; Oldehinkel, A. J.; Preisig, M.; Grabe, H. J.; Middeldorp, C. M.; Penninx, B. W.J.H.; Boomsma, D.; Martin, N. G.; Montgomery, G.; Maher, B. S.; Van Den Oord, E. J.; Wray, N. R.; Tiemeier, H.; Hettema, J. M.

In: Molecular Psychiatry, Vol. 21, No. 10, 01.10.2016, p. 1391-1399.

Research output: Contribution to journalArticle

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, PAF, Pergadia, ML, Van Der Most, PJ, Nolte, IM, Van Oort, FVA, Hartman, CA, Oldehinkel, AJ, Preisig, M, Grabe, HJ, Middeldorp, CM, Penninx, BWJH, Boomsma, D, Martin, NG, Montgomery, G, Maher, BS, Van Den Oord, EJ, Wray, NR, Tiemeier, H & Hettema, JM 2016, 'Meta-analysis of genome-wide association studies of anxiety disorders', Molecular Psychiatry, vol. 21, no. 10, pp. 1391-1399. https://doi.org/10.1038/mp.2015.197
Otowa T, Hek K, Lee M, Byrne EM, Mirza SS, Nivard MG et al. Meta-analysis of genome-wide association studies of anxiety disorders. Molecular Psychiatry. 2016 Oct 1;21(10):1391-1399. https://doi.org/10.1038/mp.2015.197
Otowa, T. ; Hek, K. ; Lee, M. ; Byrne, E. M. ; Mirza, S. S. ; Nivard, M. G. ; Bigdeli, T. ; Aggen, S. H. ; Adkins, D. ; Wolen, Aaron ; Fanous, A. ; Keller, M. C. ; Castelao, E. ; Kutalik, Z. ; Der Auwera, S. V. ; Homuth, G. ; Nauck, M. ; Teumer, A. ; Milaneschi, Y. ; Hottenga, J. J. ; Direk, N. ; Hofman, A. ; Uitterlinden, A. ; Mulder, C. L. ; Henders, A. K. ; Medland, S. E. ; Gordon, S. ; Heath, A. C. ; Madden, P. A.F. ; Pergadia, M. L. ; Van Der Most, P. J. ; Nolte, I. M. ; Van Oort, F. V.A. ; Hartman, C. A. ; Oldehinkel, A. J. ; Preisig, M. ; Grabe, H. J. ; Middeldorp, C. M. ; Penninx, B. W.J.H. ; Boomsma, D. ; Martin, N. G. ; Montgomery, G. ; Maher, B. S. ; Van Den Oord, E. J. ; Wray, N. R. ; Tiemeier, H. ; Hettema, J. M. / Meta-analysis of genome-wide association studies of anxiety disorders. In: Molecular Psychiatry. 2016 ; Vol. 21, No. 10. pp. 1391-1399.
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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.",
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T1 - Meta-analysis of genome-wide association studies of anxiety disorders

AU - Otowa, T.

AU - Hek, K.

AU - Lee, M.

AU - Byrne, E. M.

AU - Mirza, S. S.

AU - Nivard, M. G.

AU - Bigdeli, T.

AU - Aggen, S. H.

AU - Adkins, D.

AU - Wolen, Aaron

AU - Fanous, A.

AU - Keller, M. C.

AU - Castelao, E.

AU - Kutalik, Z.

AU - Der Auwera, S. V.

AU - Homuth, G.

AU - Nauck, M.

AU - Teumer, A.

AU - Milaneschi, Y.

AU - Hottenga, J. J.

AU - Direk, N.

AU - Hofman, A.

AU - Uitterlinden, A.

AU - Mulder, C. L.

AU - Henders, A. K.

AU - Medland, S. E.

AU - Gordon, S.

AU - Heath, A. C.

AU - Madden, P. A.F.

AU - Pergadia, M. L.

AU - Van Der Most, P. J.

AU - Nolte, I. M.

AU - Van Oort, F. V.A.

AU - Hartman, C. A.

AU - Oldehinkel, A. J.

AU - Preisig, M.

AU - Grabe, H. J.

AU - Middeldorp, C. M.

AU - Penninx, B. W.J.H.

AU - Boomsma, D.

AU - Martin, N. G.

AU - Montgomery, G.

AU - Maher, B. S.

AU - Van Den Oord, E. J.

AU - Wray, N. R.

AU - Tiemeier, H.

AU - Hettema, J. M.

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