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Cited by 199Genetic Associations and EpidemiologyBipolar Disorder and TreatmentTreatment of Major Depression

The Genetics of the Mood Disorder Spectrum: Genome-wide Association Analyses of More Than 185,000 Cases and 439,000 Controls

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Coleman, Jonathan R.I., Gaspar, Héléna A., Bryois, Julien, Byrne, Enda M., Forstner, Andreas J., Holmans, Peter A., de Leeuw, Christiaan A., Mattheisen, Manuel +776 more·2020·Biological Psychiatry
DOI 10.1016/j.biopsych.2019.10.015PMC PMC8136147

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Abstract

BACKGROUND: Mood disorders (including major depressive disorder and bipolar disorder) affect 10% to 20% of the population. They range from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Multiple approaches have shown considerable sharing of risk factors across mood disorders despite their diagnostic distinction. METHODS: To clarify the shared molecular genetic basis of major depressive disorder and bipolar disorder and to highlight disorder-specific associations, we meta-analyzed data from the latest Psychiatric Genomics Consortium genome-wide association studies of major depression (including data from 23andMe) and bipolar disorder, and an additional major depressive disorder cohort from UK Biobank (total: 185,285 cases, 439,741 controls; nonoverlapping N = 609,424). RESULTS: Seventy-three loci reached genome-wide significance in the meta-analysis, including 15 that are novel for mood disorders. More loci from the Psychiatric Genomics Consortium analysis of major depression than from that for bipolar disorder reached genome-wide significance. Genetic correlations revealed that type 2 bipolar disorder correlates strongly with recurrent and single-episode major depressive disorder. Systems biology analyses highlight both similarities and differences between the mood disorders, particularly in the mouse brain cell types implicated by the expression patterns of associated genes. The mood disorders also differ in their genetic correlation with educational attainment-the relationship is positive in bipolar disorder but negative in major depressive disorder. CONCLUSIONS: The mood disorders share several genetic associations, and genetic studies of major depressive disorder and bipolar disorder can be combined effectively to enable the discovery of variants not identified by studying either disorder alone. However, we demonstrate several differences between these disorders. Analyzing subtypes of major depressive disorder and bipolar disorder provides evidence for a genetic mood disorders spectrum.

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  • The major haplotype outside Africa was found significantly associated with greater susceptibility to major depression and other related psychiatric disorders and with higher values for self-reported helping behavior.

    “The major haplotype outside Africa was found significantly associated with greater susceptibility to major depression and other related psychiatric disorders [55,56] as well as with higher values for self-reported helping behavior [57].”

    From Human genetic adaptation related to cellular zinc homeostasis (2023) · cites this paper as [55]

    The Participants and Discussion sections describe genetic analyses of major depression and bipolar disorder, but do not identify a major haplotype outside Africa or link it to increased psychiatric-disorder susceptibility. Searches for “haplotype” and “outside Africa” found no passage establishing that association. The helping-behavior clause is attached to a different citation in the citing sentence. (LLM, conf=0.76)

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Research works printed but not linked: 5

  1. [12]National Collaborating Centre for Mental Health (UK) (2018): Bipolar Disorder: The NICE Guideline on the Assessment and Management of Bipolar Disorder in Adults, Children and Young People in Primary and Secondary Care. Leicester (UK): British Psychological Society. 29718639
  2. [21]Gilly A, Tachmazidou I, Zeggini E (2015): Meta-analysis of summary statistics from quantitative trait association studies with unknown sample overlap. GENETIC EPIDEMIOLOGY. (Vol. 39), WILEY-BLACKWELL 111 RIVER ST, HOBOKEN 07030–5774, NJ USA, pp 552– 553.
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  4. [31]Purves KL, Coleman JRI, Rayner C, Hettema JM, Deckert J, McIntosh AM, (2017, 10 16): The Common Genetic Architecture of Anxiety Disorders. bioRxiv. bioRxiv.
  5. [63]National Institute for Healthcare and Excellence (2009): Depression in adults: recognition and management: Clinical guideline [CG90].. Retrieved from https://www.nice.org.uk/guidance/cg90. 31990491

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Authors
Coleman, J. R. I., Gaspar, H. A., Bryois, J., Byrne, E. M., Forstner, A. J., Holmans, P. A., de Leeuw, C. A., Mattheisen, M., McQuillin, A., Whitehead Pavlides, J. M., Pers, T. H., Ripke, S., Stahl, E. A., Steinberg, S., Trubetskoy, V., Trzaskowski, M., Wang, Y., Abbott, L., Abdellaoui, A., Adams, M. J., Adolfsson, A. N., Agerbo, E., Akil, H., Albani, D., Alliey-Rodriguez, N., Als, T. D., Andlauer, T. F. M., Anjorin, A., Antilla, V., Van der Auwera, S., Awasthi, S., Bacanu, S.-A., Badner, J. A., Bækvad-Hansen, M., Barchas, J. D., Bass, N., Bauer, M., Beekman, A. T. F., Belliveau, R., Bergen, S. E., Bigdeli, T. B., Binder, E. B., Bøen, E., Boks, M., Boocock, J., Budde, M., Bunney, W., Burmeister, M., Buttenschøn, H. N., Bybjerg-Grauholm, J., Byerley, W., Cai, N., Casas, M., Castelao, E., Cerrato, F., Cervantes, P., Chambert, K., Charney, A. W., Chen, D., Christensen, J. H., Churchhouse, C., St Clair, D., Clarke, T.-K., Colodro-Conde, L., Coryell, W., Couvy-Duchesne, B., Craig, D. W., Crawford, G. E., Cruceanu, C., Czerski, P. M., Dale, A. M., Davies, G., Deary, I. J., Degenhardt, F., Del-Favero, J., DePaulo, J. R., Derks, E. M., Direk, N., Djurovic, S., Dobbyn, A. L., Dolan, C. V., Dumont, A., Dunn, E. C., Eley, T. C., Elvsåshagen, T., Escott-Price, V., Fan, C. C., Finucane, H. K., Fischer, S. B., Flickinger, M., Foo, J. C., Foroud, T. M., Forty, L., Frank, J., Fraser, C., Freimer, N. B., Frisén, L., Gade, K., Gage, D., Garnham, J., Giambartolomei, C., Goes, F. S., Goldstein, J., Gordon, S. D., Gordon-Smith, K., Green, E. K., Green, M. J., Greenwood, T. A., Grove, J., Guan, W., Hall, L. S., Hamshere, M. L., Hansen, C. S., Hansen, T. F., Hautzinger, M., Heilbronner, U., van Hemert, A. M., Herms, S., Hickie, I. B., Hipolito, M., Hoffmann, P., Holland, D., Homuth, G., Horn, C., Hottenga, J.-J., Huckins, L., Ising, M., Jamain, S., Jansen, R., Johnson, J. S., de Jong, S., Jorgenson, E., Juréus, A., Kandaswamy, R., Karlsson, R., Kennedy, J. L., Hassan Kiadeh, F. F., Kittel-Schneider, S., Knowles, J. A., Kogevinas, M., Kohane, I. S., Koller, A. C., Kraft, J., Kretzschmar, W. W., Krogh, J., Kupka, R., Kutalik, Z., Lavebratt, C., Lawrence, J., Lawson, W. B., Leber, M., Lee, P. H., Levy, S. E., Li, J. Z., Li, Y., Lind, P. A., Liu, C., Olde Loohuis, L. M., Maaser, A., MacIntyre, D. J., MacKinnon, D. F., Mahon, P. B., Maier, W., Maier, R. M., Marchini, J., Martinsson, L., Mbarek, H., McCarroll, S., McGrath, P., McGuffin, P., McInnis, M. G., McKay, J. D., Medeiros, H., Medland, S. E., Mehta, D., Meng, F., Middeldorp, C. M., Mihailov, E., Milaneschi, Y., Milani, L., Mirza, S. S., Mondimore, F. M., Montgomery, G. W., Morris, D. W., Mostafavi, S., Mühleisen, T. W., Mullins, N., Nauck, M., Ng, B., Nguyen, H., Nievergelt, C. M., Nivard, M. G., Nwulia, E. A., Nyholt, D. R., O'Donovan, C., O'Reilly, P. F., Ori, A. P. S., Oruc, L., Ösby, U., Oskarsson, H., Painter, J. N., Parra, J. G., Pedersen, C. B., Pedersen, M. G., Perry, A., Peterson, R. E., Pettersson, E., Peyrot, W. J., Pfennig, A., Pistis, G., Purcell, S. M., Quiroz, J. A., Qvist, P., Regeer, E. J., Reif, A., Reinbold, C. S., Rice, J. P., Riley, B. P., Rivas, F., Rivera, M., Roussos, P., Ruderfer, D. M., Ryu, E., Sánchez-Mora, C., Schatzberg, A. F., Scheftner, W. A., Schoevers, R., Schork, N. J., Schulte, E. C., Shehktman, T., Shen, L., Shi, J., Shilling, P. D., Shyn, S. I., Sigurdsson, E., Slaney, C., Smeland, O. B., Smit, J. H., Smith, D. J., Sobell, J. L., Spijker, A. T., Steffens, M., Strauss, J. S., Streit, F., Strohmaier, J., Szelinger, S., Tansey, K. E., Teismann, H., Teumer, A., Thompson, R. C., Thompson, W., Thomson, P. A., Thorgeirsson, T. E., Traylor, M., Treutlein, J., Uitterlinden, A. G., Umbricht, D., Vedder, H., Viktorin, A., Visscher, P. M., Wang, W., Watson, S. J., Webb, B. T., Weickert, C. S., Weickert, T. W., Weinsheimer, S. M., Wellmann, J., Willemsen, G., Witt, S. H., Wu, Y., Xi, H. S., Xu, W., Yang, J., Young, A. H., Zandi, P., Zhang, P., Zhang, F., Zollner, S., Adolfsson, R., Agartz, I., Alda, M., Arolt, V., Backlund, L., Baune, B. T., Bellivier, F., Berger, K., Berrettini, W. H., Biernacka, J. M., Blackwood, D. H. R., Boehnke, M., Boomsma, D. I., Corvin, A., Craddock, N., Daly, M. J., Dannlowski, U., Domenici, E., Domschke, K., Esko, T., Etain, B., Frye, M., Fullerton, J. M., Gershon, E. S., de Geus, E. J. C., Gill, M., Goes, F., Grabe, H. J., Grigoroiu-Serbanescu, M., Hamilton, S. P., Hauser, J., Hayward, C., Heath, A. C., Hougaard, D. M., Hultman, C. M., Jones, I., Jones, L. A., Kahn, R. S., Kendler, K. S., Kirov, G., Kloiber, S., Landén, M., Leboyer, M., Lewis, G., Li, Q. S., Lissowska, J., Lucae, S., Madden, P. A. F., Magnusson, P. K., Martin, N. G., Mayoral, F., McElroy, S. L., McIntosh, A. M., McMahon, F. J., Melle, I., Metspalu, A., Mitchell, P. B., Morken, G., Mors, O., Mortensen, P. B., Müller-Myhsok, B., Myers, R. M., Neale, B. M., Nimgaonkar, V., Nordentoft, M., Nöthen, M. M., O'Donovan, M. C., Oedegaard, K. J., Owen, M. J., Paciga, S. A., Pato, C., Pato, M. T., Pedersen, N. L., Penninx, B. W. J. H., Perlis, R. H., Porteous, D. J., Posthuma, D., Potash, J. B., Preisig, M., Ramos-Quiroga, J. A., Ribasés, M., Rietschel, M., Rouleau, G. A., Schaefer, C., Schalling, M., Schofield, P. R., Schulze, T. G., Serretti, A., Smoller, J. W., Stefansson, H., Stefansson, K., Stordal, E., Tiemeier, H., Turecki, G., Uher, R., Vaaler, A. E., Vieta, E., Vincent, J. B., Völzke, H., Weissman, M. M., Werge, T., Andreassen, O. A., Børglum, A. D., Cichon, S., Edenberg, H. J., Di Florio, A., Kelsoe, J., Levinson, D. F., Lewis, C. M., Nurnberger, J. I., Ophoff, R. A., Scott, L. J., Sklar, P., Sullivan, P. F., Wray, N. R., Byrne, E. M., Forstner, A. J., Holmans, P. A., de Leeuw, C. A., Mattheisen, M., McQuillin, A., Whitehead Pavlides, J. M., Pers, T. H., Ripke, S., Stahl, E. A., Steinberg, S., Trubetskoy, V., Trzaskowski, M., Wang, Y., Abbott, L., Abdellaoui, A., Adams, M. J., Adolfsson, A. N., Agerbo, E., Akil, H., Albani, D., Alliey-Rodriguez, N., Als, T. D., Andlauer, T. F. M., Anjorin, A., Antilla, V., Van der Auwera, S., Awasthi, S., Bacanu, S.-A., Badner, J. A., Bækvad-Hansen, M., Barchas, J. D., Bass, N., Bauer, M., Beekman, A. T. F., Belliveau, R., Bergen, S. E., Bigdeli, T. B., Binder, E. B., Bøen, E., Boks, M., Boocock, J., Budde, M., Bunney, W., Burmeister, M., Buttenschøn, H. N., Bybjerg-Grauholm, J., Byerley, W., Cai, N., Casas, M., Castelao, E., Cerrato, F., Cervantes, P., Chambert, K., Charney, A. W., Chen, D., Christensen, J. H., Churchhouse, C., St Clair, D., Clarke, T.-K., Colodro-Conde, L., Coryell, W., Couvy-Duchesne, B., Craig, D. W., Crawford, G. E., Cruceanu, C., Czerski, P. M., Dale, A. M., Davies, G., Deary, I. J., Degenhardt, F., Del-Favero, J., DePaulo, J. R., Derks, E. M., Direk, N., Djurovic, S., Dobbyn, A. L., Dolan, C. V., Dumont, A., Dunn, E. C., Eley, T. C., Elvsåshagen, T., Escott-Price, V., Fan, C. C., Finucane, H. K., Fischer, S. B., Flickinger, M., Foo, J. C., Foroud, T. M., Forty, L., Frank, J., Fraser, C., Freimer, N. B., Frisén, L., Gade, K., Gage, D., Garnham, J., Giambartolomei, C., Goes, F. S., Goldstein, J., Gordon, S. D., Gordon-Smith, K., Green, E. K., Green, M. J., Greenwood, T. A., Grove, J., Guan, W., Hall, L. S., Hamshere, M. L., Hansen, C. S., Hansen, T. F., Hautzinger, M., Heilbronner, U., van Hemert, A. M., Herms, S., Hickie, I. B., Hipolito, M., Hoffmann, P., Holland, D., Homuth, G., Horn, C., Hottenga, J.-J., Huckins, L., Ising, M., Jamain, S., Jansen, R., Johnson, J. S., de Jong, S., Jorgenson, E., Juréus, A., Kandaswamy, R., Karlsson, R., Kennedy, J. L., Hassan Kiadeh, F. F., Kittel-Schneider, S., Knowles, J. A., Kogevinas, M., Kohane, I. S., Koller, A. C., Kraft, J., Kretzschmar, W. W., Krogh, J., Kupka, R., Kutalik, Z., Lavebratt, C., Lawrence, J., Lawson, W. B., Leber, M., Lee, P. H., Levy, S. E., Li, J. Z., Li, Y., Lind, P. A., Liu, C., Olde Loohuis, L. M., Maaser, A., MacIntyre, D. J., MacKinnon, D. F., Mahon, P. B., Maier, W., Maier, R. M., Marchini, J., Martinsson, L., Mbarek, H., McCarroll, S., McGrath, P., McGuffin, P., McInnis, M. G., McKay, J. D., Medeiros, H., Medland, S. E., Mehta, D., Meng, F., Middeldorp, C. M., Mihailov, E., Milaneschi, Y., Milani, L., Mirza, S. S., Mondimore, F. M., Montgomery, G. W., Morris, D. W., Mostafavi, S., Mühleisen, T. W., Mullins, N., Nauck, M., Ng, B., Nguyen, H., Nievergelt, C. M., Nivard, M. G., Nwulia, E. A., Nyholt, D. R., O'Donovan, C., O'Reilly, P. F., Ori, A. P. S., Oruc, L., Ösby, U., Oskarsson, H., Painter, J. N., Parra, J. G., Pedersen, C. B., Pedersen, M. G., Perry, A., Peterson, R. E., Pettersson, E., Peyrot, W. J., Pfennig, A., Pistis, G., Purcell, S. M., Quiroz, J. A., Qvist, P., Regeer, E. J., Reif, A., Reinbold, C. S., Rice, J. P., Riley, B. P., Rivas, F., Rivera, M., Roussos, P., Ruderfer, D. M., Ryu, E., Sánchez-Mora, C., Schatzberg, A. F., Scheftner, W. A., Schoevers, R., Schork, N. J., Schulte, E. C., Shehktman, T., Shen, L., Shi, J., Shilling, P. D., Shyn, S. I., Sigurdsson, E., Slaney, C., Smeland, O. B., Smit, J. H., Smith, D. J., Sobell, J. L., Spijker, A. T., Steffens, M., Strauss, J. S., Streit, F., Strohmaier, J., Szelinger, S., Tansey, K. E., Teismann, H., Teumer, A., Thompson, R. C., Thompson, W., Thomson, P. A., Thorgeirsson, T. E., Traylor, M., Treutlein, J., Uitterlinden, A. G., Umbricht, D., Vedder, H., Viktorin, A., Visscher, P. M., Wang, W., Watson, S. J., Webb, B. T., Weickert, C. S., Weickert, T. W., Weinsheimer, S. M., Wellmann, J., Willemsen, G., Witt, S. H., Wu, Y., Xi, H. S., Xu, W., Yang, J., Young, A. H., Zandi, P., Zhang, P., Zhang, F., Zollner, S., Adolfsson, R., Agartz, I., Alda, M., Arolt, V., Backlund, L., Baune, B. T., Bellivier, F., Berger, K., Berrettini, W. H., Biernacka, J. M., Blackwood, D. H. R., Boehnke, M., Boomsma, D. I., Corvin, A., Craddock, N., Daly, M. J., Dannlowski, U., Domenici, E., Domschke, K., Esko, T., Etain, B., Frye, M., Fullerton, J. M., Gershon, E. S., de Geus, E. J. C., Gill, M., Goes, F., Grabe, H. J., Grigoroiu-Serbanescu, M., Hamilton, S. P., Hauser, J., Hayward, C., Heath, A. C., Hougaard, D. M., Hultman, C. M., Jones, I., Jones, L. A., Kahn, R. S., Kendler, K. S., Kirov, G., Kloiber, S., Landén, M., Leboyer, M., Lewis, G., Li, Q. S., Lissowska, J., Lucae, S., Madden, P. A. F., Magnusson, P. K., Martin, N. G., Mayoral, F., McElroy, S. L., McIntosh, A. M., McMahon, F. J., Melle, I., Metspalu, A., Mitchell, P. B., Morken, G., Mors, O., Mortensen, P. B., Müller-Myhsok, B., Myers, R. M., Neale, B. M., Nimgaonkar, V., Nordentoft, M., Nöthen, M. M., O'Donovan, M. C., Oedegaard, K. J., Owen, M. J., Paciga, S. A., Pato, C., Pato, M. T., Pedersen, N. L., Penninx, B. W. J. H., Perlis, R. H., Porteous, D. J., Posthuma, D., Potash, J. B., Preisig, M., Ramos-Quiroga, J. A., Ribasés, M., Rietschel, M., Rouleau, G. A., Schaefer, C., Schalling, M., Schofield, P. R., Schulze, T. G., Serretti, A., Smoller, J. W., Stefansson, H., Stefansson, K., Stordal, E., Tiemeier, H., Turecki, G., Uher, R., Vaaler, A. E., Vieta, E., Vincent, J. B., Völzke, H., Weissman, M. M., Werge, T., Andreassen, O. A., Børglum, A. D., Cichon, S., Edenberg, H. J., Di Florio, A., Kelsoe, J., Levinson, D. F., Lewis, C. M., Nurnberger, J. I., Ophoff, R. A., Scott, L. J., Sklar, P., Sullivan, P. F., Wray, N. R., & Breen, G.
Affiliations
  • King's College London (GB)
  • Karolinska Institutet (SE)
Corresponding author
Breen, Gerome
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2020-07
Volume
88
Issue
2
Pages
169-184
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2019.10.015
PMC
PMC8136147
OpenAlex
W2984805909
Cited by
199
References
70
Citations by year
2026: 14 · 2025: 30 · 2024: 27 · 2023: 28 · 2022: 35 · 2021: 42 · 2020: 21 · 2019: 1 · 2018: 1
FWCI
3.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Biological Psychiatry (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Research Portal (King's College London) (publishedVersion, cc-by-nc-nd)
  • Pure Amsterdam UMC (publishedVersion, other-oa)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
  • VU Research Portal (publishedVersion, other-oa)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
  • PubMed Central (acceptedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion)
  • Worcester Research and Publications (University of Worcester) (submittedVersion)
  • ScholarWorks @ UTRGV (The University of Texas Rio Grande Valley) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
  • Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
  • Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Research Portal (King's College London) (submittedVersion, cc-by-nc-nd)
  • SUNY Digital Repository Support (State University of New York System) (submittedVersion, cc-by-nc-nd)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Funders
  • National Health and Medical Research Council
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek
  • Vetenskapsrådet
  • National Institute on Drug Abuse
  • Maudsley Charity
  • National Institutes of Health
  • National Institute for Health Research
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Keywords
mood disorders, major depressive disorder, bipolar disorder, genetic susceptibility loci, genetic overlap, genetic correlation, educational attainment, systems biology, Psychiatric Genomics Consortium
MeSH terms
Animals, Bipolar Disorder, Major Depressive Disorder, Risk Factors, Mood Disorders, Mice, Genome-Wide Association Study

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