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 language | English (US) |
|---|---|
| Pages (from-to) | 1391-1399 |
| Number of pages | 9 |
| Journal | Molecular psychiatry |
| Volume | 21 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 1 2016 |
ASJC Scopus subject areas
- Molecular Biology
- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
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In: Molecular psychiatry, Vol. 21, No. 10, 01.10.2016, p. 1391-1399.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
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, A.
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.
N1 - Funding Information: This overall project was supported by NIH grant R01MH87646 to JMH. TO was supported by a research fellowship from the Japan Society for the Promotion of Science (no. 21-8373). Samples and associated phenotype data for the MGS study were collected under the following grants: NIMH Schizophrenia Genetics Initiative U01s: MH046276 (CR Cloninger), MH46289 (C Kaufmann), and MH46318 (MT Tsuang); and MGS Part 1 (MGS1) and Part 2 (MGS2) R01s: MH67257 (NG Buccola), MH59588 (BJ Mowry), MH59571 (PV Gejman), MH59565(R Freedman), MH59587 (F Amin), MH60870 (WF Byerley), MH59566 (DW Black), MH59586 (JM Silverman), MH61675 (DF Levinson) and MH60879 (CR Cloninger). Analyses in the Rotterdam Study were supported by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), The Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Ageing (NCHA) project No. 050-060-810. The work of HT is supported by Vidi (grant 017.106.370). The Rotterdam Study is funded by Erasmus Medical Center, Rotterdam, The Netherlands Organization for the Health Research and Development (ZonMw), the Ministry of Education, Culture and Science, and the Ministry for Health, Welfare and Sports. SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. This work was also funded by the German Research Foundation (DFG: GR 1912/5-1). The University of Greifswald is a member of the Caché Campus program of the InterSystems GmbH. The QIMR samples are made available through the generous and willing participation of twins and their families registered at the Australian Twin Registry and through grant funding awarded from many grant funding bodies including the Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496675, 496739, 552485, 552498, 613608), the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254), the US National Institutes of Health (NIH grants AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854, DA019951) and the Center for Inherited Disease Research, Baltimore. We thank Dixie Statham (sample collection); Leanne Wallace, Anthony Caracella and staff of the Molecular Epidemiology Laboratory (DNA processing); David Smyth, Harry Beeby and Daniel Park (IT support). Statistical analyses were partly conducted at the Genetic Cluster Computer (http://www.geneticcluster.org), which is financially supported by the Netherlands Scientific Organization (NWO 480-05-003). EMB (1053639), SEM, GM and NRW (613602, 1078901) are supported by the National Health and Medical Research Council Fellowship Scheme. The CoLaus|PsyCoLaus study was and is supported by research grants from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (grants 3200B0–105993, 3200B0-118308, 33CSCO-122661, 33CS30-139468 and 33CS30-148401). Participating centers of TRAILS include various departments of the University Medical Center and University of Groningen, the Erasmus University Medical Center Rotterdam, the University of Utrecht, the Radboud Medical Center Nijmegen and the Parnassia Bavo group, all in the Netherlands. TRAILS has been financially supported by various grants from the Netherlands Organization for Scientific Research NWO (Medical Research Council program grant GB-MW 940-38-011; ZonMW Brainpower grant 100-001-004; ZonMw Risk Behavior and Dependence grants 60-60600-97-118; ZonMw Culture and Health grant 261-98-710; Social Sciences Council medium-sized investment grants GB-MaGW 480-01-006 and GB-MaGW 480-07-001; Social Sciences Council project grants GB-MaGW 452-04-314 and GB-MaGW 452-06-004; NWO large-sized investment grant 175.010.2003.005; NWO Longitudinal Survey and Panel Funding 481-08-013), the Dutch Ministry of Justice (WODC), the European Science Foundation (EuroSTRESS project FP-006), Biobanking and Biomolecular Resources Research Infrastructure BBMRI-NL (CP 32), the participating universities, and Accare Center for Child and Adolescent Psychiatry. Statistical analyses were carried out on the Genetic Cluster Computer (http://www. geneticcluster.org), which is financially supported by the Netherlands Scientific Organization (NWO 480-05-003) along with a supplement from the Dutch Brain Foundation. Funding for the NESDA/NTR studies was obtained from the Netherlands Organization for Scientific Research (Geestkracht program grant 10-000-1002; 904-61-090, 985-10-002, 904-61-193, 480-04-004, 400-05-717, 912-100-20; Spinozapremie 56-464-14192); the Center for Medical Systems Biology (CSMB, NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL), VU University’s Institutes for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam, European Research Council (ERC, 230374),National Institutes of Health (NIH, R01D0042157-01 A, MH081802, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. Computing was supported by BiG Grid, the Dutch e-Science Grid, which is financially supported by NWO. Funding Information: ACKNOWLEDGMENTS This overall project was supported by NIH grant R01MH87646 to JMH. TO was supported by a research fellowship from the Japan Society for the Promotion of Science (no. 21-8373). Samples and associated phenotype data for the MGS study were collected under the following grants: NIMH Schizophrenia Genetics Initiative U01s: MH046276 (CR Cloninger), MH46289 (C Kaufmann), and MH46318 (MT Tsuang); and MGS Part 1 (MGS1) and Part 2 (MGS2) R01s: MH67257 (NG Buccola), MH59588 (BJ Mowry), MH59571 (PV Gejman), MH59565(R Freedman), MH59587 (F Amin), MH60870 (WF Byerley), MH59566 (DW Black), MH59586 (JM Silverman), MH61675 (DF Levinson) and MH60879 (CR Cloninger). Analyses in the Rotterdam Study were supported by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), The Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Ageing (NCHA) project No. 050-060-810. The work of HT is supported by Vidi (grant 017.106.370). The Rotterdam Study is funded by Erasmus Medical Center, Rotterdam, The Netherlands Organization for the Health Research and Development (ZonMw), the Ministry of Education, Culture and Science, and the Ministry for Health, Welfare and Sports. SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. This work was also funded by the German Research Foundation (DFG: GR 1912/5-1). The University of Greifswald is a member of the Caché Campus program of the InterSystems GmbH. The QIMR samples are made available through the generous and willing participation of twins and their families registered at the Australian Twin Registry and through grant funding awarded from many grant funding bodies including the Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496675, 496739, 552485, 552498, 613608), the FP-5 GenomEUtwin Project (QLG2-CT- 2002-01254), the US National Institutes of Health (NIH grants AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854, DA019951) and the Center for Inherited Disease Research, Baltimore. We thank Dixie Statham (sample collection); Leanne Wallace, Anthony Caracella and staff of the Molecular Epidemiology Laboratory (DNA processing); David Smyth, Harry Beeby and Daniel Park (IT support). Statistical analyses were partly conducted at the Genetic Cluster Computer (http://www.geneticcluster.org), which is financially supported by the Netherlands Scientific Organization (NWO 480-05-003). EMB (1053639), SEM, GM and NRW (613602, 1078901) are supported by the National Health and Medical Research Council Fellowship Scheme. The CoLaus|PsyCoLaus study was and is supported by research grants from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (grants 3200B0-105993, 3200B0-118308, 33CSCO-122661, 33CS30-139468 and 33CS30-148401). Participating centers of TRAILS include various departments of the University Medical Center and University of Groningen, the Erasmus University Medical Center Rotterdam, the University of Utrecht, the Radboud Medical Center Nijmegen and the Parnassia Bavo group, all in the Netherlands. TRAILS has been financially supported by various grants from the Netherlands Organization for Scientific Research NWO (Medical Research Council program grant GB-MW 940-38- 011; ZonMW Brainpower grant 100-001-004; ZonMw Risk Behavior and Dependence grants 60-60600-97-118; ZonMw Culture and Health grant 261-98-710; Social Sciences Council medium-sized investment grants GB-MaGW 480-01-006 and GBMaGW 480-07-001; Social Sciences Council project grants GB-MaGW 452-04-314 and GB-MaGW 452-06-004; NWO large-sized investment grant 175.010.2003.005; NWO Longitudinal Survey and Panel Funding 481-08-013), the Dutch Ministry of Justice (WODC), the European Science Foundation (EuroSTRESS project FP-006), Biobanking and Biomolecular Resources Research Infrastructure BBMRI-NL (CP 32), the participating universities, and Accare Center for Child and Adolescent Psychiatry. Statistical analyses were carried out on the Genetic Cluster Computer (http://www. geneticcluster.org), which is financially supported by the Netherlands Scientific Organization (NWO 480-05-003) along with a supplement from the Dutch Brain Foundation. Funding for the NESDA/NTR studies was obtained from the Netherlands Organization for Scientific Research (Geestkracht program grant 10-000-1002; 904-61- 090, 985-10- 002, 904-61-193, 480-04-004, 400-05-717, 912-100-20; Spinozapremie 56-464-14192); the Center for Medical Systems Biology (CSMB, NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL), VU University's Institutes for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam, European Research Council (ERC, 230374),National Institutes of Health (NIH, R01D0042157-01 A, MH081802, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. Computing was supported by BiG Grid, the Dutch e- Science Grid, which is financially supported by NWO. Publisher Copyright: © 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
PY - 2016/10/1
Y1 - 2016/10/1
N2 - 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.
AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=84954550234&partnerID=8YFLogxK
U2 - 10.1038/mp.2015.197
DO - 10.1038/mp.2015.197
M3 - Article
C2 - 26754954
AN - SCOPUS:84954550234
SN - 1359-4184
VL - 21
SP - 1391
EP - 1399
JO - Molecular psychiatry
JF - Molecular psychiatry
IS - 10
ER -