Meta-analysis of Genome-wide Association Studies for Neuroticism, and the Polygenic Association With Major Depressive Disorder

M.H.M. de Moor; S.M. van den Berg; C.J.H. Verweij; R.F. Krueger; M. Luciano; A. Arias-Vasquez; L.K. Matteson; J. Derringer; T. Esko; N. Amin; S.D. Gordon; N.K. Hansell; A.B. Hart; I. Seppälä; J.E. Huffman; B. Konte; J. Lahti; M.Y. Lee; M. Miller; T. Nutile; T. Tanaka; A. Teumer; A. Viktorin; J. Wedenoja; G.R. Abecasis; D.E. Adkins; A. Agrawal; J. Allik; K. Appel; T.B. Bigdeli; F. Busonero; H. Campbell; P.T. Costa; G. Davey Smith; G. Davies; H. de Wit; J. Ding; B.E. Engelhardt; J.G. Eriksson; I.O. Fedko; L. Ferrucci; B. Franke; I. Giegling; R. Grucza; A.M. Hartmann; A.C. Heath; K. Heinonen; A.K. Henders; G. Homuth; J.J. Hottenga; W.G. Iacono; J. Janzing; M Jokela; R. Karlsson; J.P. Kemp; M.G. Kirkpatrick; A. Latvala; T. Lehtimäki; D.C. Liewald; P.A.F. Madden; C. Magri; P.K.E. Magnusson; J. Marten; A. Maschio; S.E. Medland; E. Mihailov; Y. Milaneschi; G.W. Montgomery; M. Nauck; K.G. Ouwens; A. Palotie; E. Pettersson; O. Polasek; Y. Qian; L. Pulkki-Råback; O.T. Raitakari; A. Realo; R.J. Rose; D. Ruggiero; C.O. Schmidt; W.S. Slutske; R. Sorice; J.M. Starr; B. St Pourcain; A.R. Sutin; N.J. Timpson; H. Trochet; S. Vermeulen; E. Vuoksimaa; E. Widén; J. Wouda; M.J. Wright; L. Zgaga; D. Porteous; A. Minelli; A.A. Palmer; D. Rujescu; M. Ciullo; C. Hayward; I. Rudan; A. Metspalu; J. Kaprio; I.J. Deary; K. Räikkönen; J.F. Wilson; L. Keltikangas-Järvinen; L.J. Bierut; J.M. Hettema; H.J. Grabe; C.M. van Duijn; D.M. Evans; D. Schlessinger; N.L. Pedersen; A. Terracciano; M. McGue; B.W.J.H. Penninx; N.G. Martin; D.I. Boomsma

doi:10.1001/jamapsychiatry.2015.0554

Meta-analysis of Genome-wide Association Studies for Neuroticism, and the Polygenic Association With Major Depressive Disorder

M.H.M. de Moor, S.M. van den Berg, C.J.H. Verweij, R.F. Krueger, M. Luciano, A. Arias-Vasquez, L.K. Matteson, J. Derringer, T. Esko, N. Amin, S.D. Gordon, N.K. Hansell, A.B. Hart, I. Seppälä, J.E. Huffman, B. Konte, J. Lahti, M.Y. Lee, M. Miller, T. NutileT. Tanaka, A. Teumer, A. Viktorin, J. Wedenoja, G.R. Abecasis, D.E. Adkins, A. Agrawal, J. Allik, K. Appel, T.B. Bigdeli, F. Busonero, H. Campbell, P.T. Costa, G. Davey Smith, G. Davies, H. de Wit, J. Ding, B.E. Engelhardt, J.G. Eriksson, I.O. Fedko, L. Ferrucci, B. Franke, I. Giegling, R. Grucza, A.M. Hartmann, A.C. Heath, K. Heinonen, A.K. Henders, G. Homuth, J.J. Hottenga, W.G. Iacono, J. Janzing, M Jokela, R. Karlsson, J.P. Kemp, M.G. Kirkpatrick, A. Latvala, T. Lehtimäki, D.C. Liewald, P.A.F. Madden, C. Magri, P.K.E. Magnusson, J. Marten, A. Maschio, S.E. Medland, E. Mihailov, Y. Milaneschi, G.W. Montgomery, M. Nauck, K.G. Ouwens, A. Palotie, E. Pettersson, O. Polasek, Y. Qian, L. Pulkki-Råback, O.T. Raitakari, A. Realo, R.J. Rose, D. Ruggiero, C.O. Schmidt, W.S. Slutske, R. Sorice, J.M. Starr, B. St Pourcain, A.R. Sutin, N.J. Timpson, H. Trochet, S. Vermeulen, E. Vuoksimaa, E. Widén, J. Wouda, M.J. Wright, L. Zgaga, D. Porteous, A. Minelli, A.A. Palmer, D. Rujescu, M. Ciullo, C. Hayward, I. Rudan, A. Metspalu, J. Kaprio, I.J. Deary, K. Räikkönen, J.F. Wilson, L. Keltikangas-Järvinen, L.J. Bierut, J.M. Hettema, H.J. Grabe, C.M. van Duijn, D.M. Evans, D. Schlessinger, N.L. Pedersen, A. Terracciano, M. McGue, B.W.J.H. Penninx, N.G. Martin, D.I. Boomsma

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

IMPORTANCE Neuroticism is a pervasive risk factor for psychiatric conditions. It genetically overlaps with major depressive disorder (MDD) and is therefore an important phenotype for psychiatric genetics. The Genetics of Personality Consortium has created a resource for genome-wide association analyses of personality traits in more than 63 000 participants (including MDD cases). OBJECTIVES To identify genetic variants associated with neuroticism by performing a meta-analysis of genome-wide association results based on 1000 Genomes imputation; to evaluate whether common genetic variants as assessed by single-nucleotide polymorphisms (SNPs) explain variation in neuroticism by estimating SNP-based heritability; and to examine whether SNPs that predict neuroticism also predict MDD. DESIGN, SETTING, AND PARTICIPANTS Genome-wide association meta-analysis of 30 cohorts with genome-wide genotype, personality, and MDD data from the Genetics of Personality Consortium. The study included 63 661 participants from 29 discovery cohorts and 9786 participants from a replication cohort. Participants came from Europe, the United States, or Australia. Analyses were conducted between 2012 and 2014. MAIN OUTCOMES AND MEASURES Neuroticism scores harmonized across all 29 discovery cohorts by item response theory analysis, and clinical MDD case-control status in 2 of the cohorts. RESULTS A genome-wide significant SNP was found on 3p14 in MAGI1 (rs35855737; P = 9.26 × 10^-9 in the discovery meta-analysis). This association was not replicated (P = .32), but the SNP was still genome-wide significant in the meta-analysis of all 30 cohorts (P = 2.38 × 10^-8). Common genetic variants explain 15%of the variance in neuroticism. Polygenic scores based on the meta-analysis of neuroticism in 27 cohorts significantly predicted neuroticism (1.09 × 10^-12 < P <.05) and MDD (4.02 × 10^-9 < P < .05) in the 2 other cohorts. CONCLUSIONS AND RELEVANCE This study identifies a novel locus for neuroticism. The variant is located in a known gene that has been associated with bipolar disorder and schizophrenia in previous studies. In addition, the study shows that neuroticism is influenced by many genetic variants of small effect that are either common or tagged by common variants. These genetic variants also influence MDD. Future studies should confirm the role of the MAGI1 locus for neuroticism and further investigate the association of MAGI1 and the polygenic association to a range of other psychiatric disorders that are phenotypically correlated with neuroticism.

Original language	English
Pages (from-to)	642-650
Number of pages	9
Journal	JAMA Psychiatry
Volume	72
Issue number	7
DOIs	https://doi.org/10.1001/jamapsychiatry.2015.0554
Publication status	Published - 2015

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de Moor, M. H. M., van den Berg, S. M., Verweij, C. J. H., Krueger, R. F., Luciano, M., Arias-Vasquez, A., Matteson, L. K., Derringer, J., Esko, T., Amin, N., Gordon, S. D., Hansell, N. K., Hart, A. B., Seppälä, I., Huffman, J. E., Konte, B., Lahti, J., Lee, M. Y., Miller, M., ... Boomsma, D. I. (2015). Meta-analysis of Genome-wide Association Studies for Neuroticism, and the Polygenic Association With Major Depressive Disorder. JAMA Psychiatry, 72(7), 642-650. https://doi.org/10.1001/jamapsychiatry.2015.0554

@article{79db039666a2439597593fe591426745,

title = "Meta-analysis of Genome-wide Association Studies for Neuroticism, and the Polygenic Association With Major Depressive Disorder",

abstract = "IMPORTANCE Neuroticism is a pervasive risk factor for psychiatric conditions. It genetically overlaps with major depressive disorder (MDD) and is therefore an important phenotype for psychiatric genetics. The Genetics of Personality Consortium has created a resource for genome-wide association analyses of personality traits in more than 63 000 participants (including MDD cases). OBJECTIVES To identify genetic variants associated with neuroticism by performing a meta-analysis of genome-wide association results based on 1000 Genomes imputation; to evaluate whether common genetic variants as assessed by single-nucleotide polymorphisms (SNPs) explain variation in neuroticism by estimating SNP-based heritability; and to examine whether SNPs that predict neuroticism also predict MDD. DESIGN, SETTING, AND PARTICIPANTS Genome-wide association meta-analysis of 30 cohorts with genome-wide genotype, personality, and MDD data from the Genetics of Personality Consortium. The study included 63 661 participants from 29 discovery cohorts and 9786 participants from a replication cohort. Participants came from Europe, the United States, or Australia. Analyses were conducted between 2012 and 2014. MAIN OUTCOMES AND MEASURES Neuroticism scores harmonized across all 29 discovery cohorts by item response theory analysis, and clinical MDD case-control status in 2 of the cohorts. RESULTS A genome-wide significant SNP was found on 3p14 in MAGI1 (rs35855737; P = 9.26 × 10-9 in the discovery meta-analysis). This association was not replicated (P = .32), but the SNP was still genome-wide significant in the meta-analysis of all 30 cohorts (P = 2.38 × 10-8). Common genetic variants explain 15%of the variance in neuroticism. Polygenic scores based on the meta-analysis of neuroticism in 27 cohorts significantly predicted neuroticism (1.09 × 10-12 < P <.05) and MDD (4.02 × 10-9 < P < .05) in the 2 other cohorts. CONCLUSIONS AND RELEVANCE This study identifies a novel locus for neuroticism. The variant is located in a known gene that has been associated with bipolar disorder and schizophrenia in previous studies. In addition, the study shows that neuroticism is influenced by many genetic variants of small effect that are either common or tagged by common variants. These genetic variants also influence MDD. Future studies should confirm the role of the MAGI1 locus for neuroticism and further investigate the association of MAGI1 and the polygenic association to a range of other psychiatric disorders that are phenotypically correlated with neuroticism.",

author = "{de Moor}, M.H.M. and {van den Berg}, S.M. and C.J.H. Verweij and R.F. Krueger and M. Luciano and A. Arias-Vasquez and L.K. Matteson and J. Derringer and T. Esko and N. Amin and S.D. Gordon and N.K. Hansell and A.B. Hart and I. Sepp{\"a}l{\"a} and J.E. Huffman and B. Konte and J. Lahti and M.Y. Lee and M. Miller and T. Nutile and T. Tanaka and A. Teumer and A. Viktorin and J. Wedenoja and G.R. Abecasis and D.E. Adkins and A. Agrawal and J. Allik and K. Appel and T.B. Bigdeli and F. Busonero and H. Campbell and P.T. Costa and {Davey Smith}, G. and G. Davies and {de Wit}, H. and J. Ding and B.E. Engelhardt and J.G. Eriksson and I.O. Fedko and L. Ferrucci and B. Franke and I. Giegling and R. Grucza and A.M. Hartmann and A.C. Heath and K. Heinonen and A.K. Henders and G. Homuth and J.J. Hottenga and W.G. Iacono and J. Janzing and M Jokela and R. Karlsson and J.P. Kemp and M.G. Kirkpatrick and A. Latvala and T. Lehtim{\"a}ki and D.C. Liewald and P.A.F. Madden and C. Magri and P.K.E. Magnusson and J. Marten and A. Maschio and S.E. Medland and E. Mihailov and Y. Milaneschi and G.W. Montgomery and M. Nauck and K.G. Ouwens and A. Palotie and E. Pettersson and O. Polasek and Y. Qian and L. Pulkki-R{\aa}back and O.T. Raitakari and A. Realo and R.J. Rose and D. Ruggiero and C.O. Schmidt and W.S. Slutske and R. Sorice and J.M. Starr and {St Pourcain}, B. and A.R. Sutin and N.J. Timpson and H. Trochet and S. Vermeulen and E. Vuoksimaa and E. Wid{\'e}n and J. Wouda and M.J. Wright and L. Zgaga and D. Porteous and A. Minelli and A.A. Palmer and D. Rujescu and M. Ciullo and C. Hayward and I. Rudan and A. Metspalu and J. Kaprio and I.J. Deary and K. R{\"a}ikk{\"o}nen and J.F. Wilson and L. Keltikangas-J{\"a}rvinen and L.J. Bierut and J.M. Hettema and H.J. Grabe and {van Duijn}, C.M. and D.M. Evans and D. Schlessinger and N.L. Pedersen and A. Terracciano and M. McGue and B.W.J.H. Penninx and N.G. Martin and D.I. Boomsma",

year = "2015",

doi = "10.1001/jamapsychiatry.2015.0554",

language = "English",

volume = "72",

pages = "642--650",

journal = "JAMA Psychiatry",

issn = "2168-622X",

publisher = "American Medical Association",

number = "7",

}

de Moor, MHM, van den Berg, SM, Verweij, CJH, Krueger, RF, Luciano, M, Arias-Vasquez, A, Matteson, LK, Derringer, J, Esko, T, Amin, N, Gordon, SD, Hansell, NK, Hart, AB, Seppälä, I, Huffman, JE, Konte, B, Lahti, J, Lee, MY, Miller, M, Nutile, T, Tanaka, T, Teumer, A, Viktorin, A, Wedenoja, J, Abecasis, GR, Adkins, DE, Agrawal, A, Allik, J, Appel, K, Bigdeli, TB, Busonero, F, Campbell, H, Costa, PT, Davey Smith, G, Davies, G, de Wit, H, Ding, J, Engelhardt, BE, Eriksson, JG, Fedko, IO, Ferrucci, L, Franke, B, Giegling, I, Grucza, R, Hartmann, AM, Heath, AC, Heinonen, K, Henders, AK, Homuth, G, Hottenga, JJ, Iacono, WG, Janzing, J, Jokela, M, Karlsson, R, Kemp, JP, Kirkpatrick, MG, Latvala, A, Lehtimäki, T, Liewald, DC, Madden, PAF, Magri, C, Magnusson, PKE, Marten, J, Maschio, A, Medland, SE, Mihailov, E, Milaneschi, Y, Montgomery, GW, Nauck, M, Ouwens, KG, Palotie, A, Pettersson, E, Polasek, O, Qian, Y, Pulkki-Råback, L, Raitakari, OT, Realo, A, Rose, RJ, Ruggiero, D, Schmidt, CO, Slutske, WS, Sorice, R, Starr, JM, St Pourcain, B, Sutin, AR, Timpson, NJ, Trochet, H, Vermeulen, S, Vuoksimaa, E, Widén, E, Wouda, J, Wright, MJ, Zgaga, L, Porteous, D, Minelli, A, Palmer, AA, Rujescu, D, Ciullo, M, Hayward, C, Rudan, I, Metspalu, A, Kaprio, J, Deary, IJ, Räikkönen, K, Wilson, JF, Keltikangas-Järvinen, L, Bierut, LJ, Hettema, JM, Grabe, HJ, van Duijn, CM, Evans, DM, Schlessinger, D, Pedersen, NL, Terracciano, A, McGue, M, Penninx, BWJH, Martin, NG & Boomsma, DI 2015, 'Meta-analysis of Genome-wide Association Studies for Neuroticism, and the Polygenic Association With Major Depressive Disorder', JAMA Psychiatry, vol. 72, no. 7, pp. 642-650. https://doi.org/10.1001/jamapsychiatry.2015.0554

TY - JOUR

T1 - Meta-analysis of Genome-wide Association Studies for Neuroticism, and the Polygenic Association With Major Depressive Disorder

AU - de Moor, M.H.M.

AU - van den Berg, S.M.

AU - Verweij, C.J.H.

AU - Krueger, R.F.

AU - Luciano, M.

AU - Arias-Vasquez, A.

AU - Matteson, L.K.

AU - Derringer, J.

AU - Esko, T.

AU - Amin, N.

AU - Gordon, S.D.

AU - Hansell, N.K.

AU - Hart, A.B.

AU - Seppälä, I.

AU - Huffman, J.E.

AU - Konte, B.

AU - Lahti, J.

AU - Lee, M.Y.

AU - Miller, M.

AU - Nutile, T.

AU - Tanaka, T.

AU - Teumer, A.

AU - Viktorin, A.

AU - Wedenoja, J.

AU - Abecasis, G.R.

AU - Adkins, D.E.

AU - Agrawal, A.

AU - Allik, J.

AU - Appel, K.

AU - Bigdeli, T.B.

AU - Busonero, F.

AU - Campbell, H.

AU - Costa, P.T.

AU - Davey Smith, G.

AU - Davies, G.

AU - de Wit, H.

AU - Ding, J.

AU - Engelhardt, B.E.

AU - Eriksson, J.G.

AU - Fedko, I.O.

AU - Ferrucci, L.

AU - Franke, B.

AU - Giegling, I.

AU - Grucza, R.

AU - Hartmann, A.M.

AU - Heath, A.C.

AU - Heinonen, K.

AU - Henders, A.K.

AU - Homuth, G.

AU - Hottenga, J.J.

AU - Iacono, W.G.

AU - Janzing, J.

AU - Jokela, M

AU - Karlsson, R.

AU - Kemp, J.P.

AU - Kirkpatrick, M.G.

AU - Latvala, A.

AU - Lehtimäki, T.

AU - Liewald, D.C.

AU - Madden, P.A.F.

AU - Magri, C.

AU - Magnusson, P.K.E.

AU - Marten, J.

AU - Maschio, A.

AU - Medland, S.E.

AU - Mihailov, E.

AU - Milaneschi, Y.

AU - Montgomery, G.W.

AU - Nauck, M.

AU - Ouwens, K.G.

AU - Palotie, A.

AU - Pettersson, E.

AU - Polasek, O.

AU - Qian, Y.

AU - Pulkki-Råback, L.

AU - Raitakari, O.T.

AU - Realo, A.

AU - Rose, R.J.

AU - Ruggiero, D.

AU - Schmidt, C.O.

AU - Slutske, W.S.

AU - Sorice, R.

AU - Starr, J.M.

AU - St Pourcain, B.

AU - Sutin, A.R.

AU - Timpson, N.J.

AU - Trochet, H.

AU - Vermeulen, S.

AU - Vuoksimaa, E.

AU - Widén, E.

AU - Wouda, J.

AU - Wright, M.J.

AU - Zgaga, L.

AU - Porteous, D.

AU - Minelli, A.

AU - Palmer, A.A.

AU - Rujescu, D.

AU - Ciullo, M.

AU - Hayward, C.

AU - Rudan, I.

AU - Metspalu, A.

AU - Kaprio, J.

AU - Deary, I.J.

AU - Räikkönen, K.

AU - Wilson, J.F.

AU - Keltikangas-Järvinen, L.

AU - Bierut, L.J.

AU - Hettema, J.M.

AU - Grabe, H.J.

AU - van Duijn, C.M.

AU - Evans, D.M.

AU - Schlessinger, D.

AU - Pedersen, N.L.

AU - Terracciano, A.

AU - McGue, M.

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

AU - Martin, N.G.

AU - Boomsma, D.I.

PY - 2015

Y1 - 2015

N2 - IMPORTANCE Neuroticism is a pervasive risk factor for psychiatric conditions. It genetically overlaps with major depressive disorder (MDD) and is therefore an important phenotype for psychiatric genetics. The Genetics of Personality Consortium has created a resource for genome-wide association analyses of personality traits in more than 63 000 participants (including MDD cases). OBJECTIVES To identify genetic variants associated with neuroticism by performing a meta-analysis of genome-wide association results based on 1000 Genomes imputation; to evaluate whether common genetic variants as assessed by single-nucleotide polymorphisms (SNPs) explain variation in neuroticism by estimating SNP-based heritability; and to examine whether SNPs that predict neuroticism also predict MDD. DESIGN, SETTING, AND PARTICIPANTS Genome-wide association meta-analysis of 30 cohorts with genome-wide genotype, personality, and MDD data from the Genetics of Personality Consortium. The study included 63 661 participants from 29 discovery cohorts and 9786 participants from a replication cohort. Participants came from Europe, the United States, or Australia. Analyses were conducted between 2012 and 2014. MAIN OUTCOMES AND MEASURES Neuroticism scores harmonized across all 29 discovery cohorts by item response theory analysis, and clinical MDD case-control status in 2 of the cohorts. RESULTS A genome-wide significant SNP was found on 3p14 in MAGI1 (rs35855737; P = 9.26 × 10-9 in the discovery meta-analysis). This association was not replicated (P = .32), but the SNP was still genome-wide significant in the meta-analysis of all 30 cohorts (P = 2.38 × 10-8). Common genetic variants explain 15%of the variance in neuroticism. Polygenic scores based on the meta-analysis of neuroticism in 27 cohorts significantly predicted neuroticism (1.09 × 10-12 < P <.05) and MDD (4.02 × 10-9 < P < .05) in the 2 other cohorts. CONCLUSIONS AND RELEVANCE This study identifies a novel locus for neuroticism. The variant is located in a known gene that has been associated with bipolar disorder and schizophrenia in previous studies. In addition, the study shows that neuroticism is influenced by many genetic variants of small effect that are either common or tagged by common variants. These genetic variants also influence MDD. Future studies should confirm the role of the MAGI1 locus for neuroticism and further investigate the association of MAGI1 and the polygenic association to a range of other psychiatric disorders that are phenotypically correlated with neuroticism.

AB - IMPORTANCE Neuroticism is a pervasive risk factor for psychiatric conditions. It genetically overlaps with major depressive disorder (MDD) and is therefore an important phenotype for psychiatric genetics. The Genetics of Personality Consortium has created a resource for genome-wide association analyses of personality traits in more than 63 000 participants (including MDD cases). OBJECTIVES To identify genetic variants associated with neuroticism by performing a meta-analysis of genome-wide association results based on 1000 Genomes imputation; to evaluate whether common genetic variants as assessed by single-nucleotide polymorphisms (SNPs) explain variation in neuroticism by estimating SNP-based heritability; and to examine whether SNPs that predict neuroticism also predict MDD. DESIGN, SETTING, AND PARTICIPANTS Genome-wide association meta-analysis of 30 cohorts with genome-wide genotype, personality, and MDD data from the Genetics of Personality Consortium. The study included 63 661 participants from 29 discovery cohorts and 9786 participants from a replication cohort. Participants came from Europe, the United States, or Australia. Analyses were conducted between 2012 and 2014. MAIN OUTCOMES AND MEASURES Neuroticism scores harmonized across all 29 discovery cohorts by item response theory analysis, and clinical MDD case-control status in 2 of the cohorts. RESULTS A genome-wide significant SNP was found on 3p14 in MAGI1 (rs35855737; P = 9.26 × 10-9 in the discovery meta-analysis). This association was not replicated (P = .32), but the SNP was still genome-wide significant in the meta-analysis of all 30 cohorts (P = 2.38 × 10-8). Common genetic variants explain 15%of the variance in neuroticism. Polygenic scores based on the meta-analysis of neuroticism in 27 cohorts significantly predicted neuroticism (1.09 × 10-12 < P <.05) and MDD (4.02 × 10-9 < P < .05) in the 2 other cohorts. CONCLUSIONS AND RELEVANCE This study identifies a novel locus for neuroticism. The variant is located in a known gene that has been associated with bipolar disorder and schizophrenia in previous studies. In addition, the study shows that neuroticism is influenced by many genetic variants of small effect that are either common or tagged by common variants. These genetic variants also influence MDD. Future studies should confirm the role of the MAGI1 locus for neuroticism and further investigate the association of MAGI1 and the polygenic association to a range of other psychiatric disorders that are phenotypically correlated with neuroticism.

U2 - 10.1001/jamapsychiatry.2015.0554

DO - 10.1001/jamapsychiatry.2015.0554

M3 - Article

SN - 2168-622X

VL - 72

SP - 642

EP - 650

JO - JAMA Psychiatry

JF - JAMA Psychiatry

IS - 7

ER -

Meta-analysis of Genome-wide Association Studies for Neuroticism, and the Polygenic Association With Major Depressive Disorder

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