Identifying genetic differences between bipolar disorder and major depression through multiple genome-wide association analyses

Georgia Panagiotaropoulou; Kajsa Lotta Georgii Hellberg; Jonathan R.I. Coleman; Darsol Seok; Janos Kalman; Philip B. Mitchell; Peter R. Schofield; Andreas J. Forstner; Major Depressive Disorder and Bipolar Disorder Working Groups of the Psychiatric Genomics Consortium; Michael Bauer; Laura J. Scott; Carlos N. Pato; Michele T. Pato; Qingqin S. Li; George Kirov; Mikael Landén; Lina Jonsson; Bertram Müller-Myhsok; Jordan W. Smoller; Elisabeth B. Binder; Tanja M. Brückl; Darina Czamara; Sandra Van Der Auwera; Hans J. Grabe; Georg Homuth; Carsten O. Schmidt; James B. Potash; J. Raymond Depaulo; Fernando S. Goes; Dean F. MacKinnon; Francis M. Mondimore; Myrna M. Weissman; Jianxin Shi; Mark A. Frye; Joanna M. Biernacka; Andreas Reif; Stephanie H. Witt; René R. Kahn; Marco M. Boks; Michael J. Owen; Katherine Gordon-Smith; Brittany L. Mitchell; Nicholas G. Martin; Sarah E. Medland; Lisa Jones; James A. Knowles; Douglas F. Levinson; Michael C. O'Donovan; Cathryn M. Lewis; Gerome Breen; Thomas Werge

doi:10.1192/bjp.2024.125

Identifying genetic differences between bipolar disorder and major depression through multiple genome-wide association analyses

Georgia Panagiotaropoulou^*, Kajsa Lotta Georgii Hellberg, Jonathan R.I. Coleman, Darsol Seok, Janos Kalman, Philip B. Mitchell, Peter R. Schofield, Andreas J. Forstner, Major Depressive Disorder and Bipolar Disorder Working Groups of the Psychiatric Genomics Consortium, Michael Bauer, Laura J. Scott, Carlos N. Pato, Michele T. Pato, Qingqin S. Li, George Kirov, Mikael Landén, Lina Jonsson, Bertram Müller-Myhsok, Jordan W. Smoller, Elisabeth B. BinderTanja M. Brückl, Darina Czamara, Sandra Van Der Auwera, Hans J. Grabe, Georg Homuth, Carsten O. Schmidt, James B. Potash, J. Raymond Depaulo, Fernando S. Goes, Dean F. MacKinnon, Francis M. Mondimore, Myrna M. Weissman, Jianxin Shi, Mark A. Frye, Joanna M. Biernacka, Andreas Reif, Stephanie H. Witt, René R. Kahn, Marco M. Boks, Michael J. Owen, Katherine Gordon-Smith, Brittany L. Mitchell, Nicholas G. Martin, Sarah E. Medland, Lisa Jones, James A. Knowles, Douglas F. Levinson, Michael C. O'Donovan, Cathryn M. Lewis, Gerome Breen, Thomas Werge

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Background Accurate diagnosis of bipolar disorder (BPD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A depressive episode often precedes the first manic episode, making it difficult to distinguish BPD from unipolar major depressive disorder (MDD). Aims We use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores (PRS) that may aid early differential diagnosis. Method Based on individual genotypes from case-control cohorts of BPD and MDD shared through the Psychiatric Genomics Consortium, we compile case-case-control cohorts, applying a careful quality control procedure. In a resulting cohort of 51 149 individuals (15 532 BPD patients, 12 920 MDD patients and 22 697 controls), we perform a variety of GWAS and PRS analyses. Results Although our GWAS is not well powered to identify genome-wide significant loci, we find significant chip heritability and demonstrate the ability of the resulting PRS to distinguish BPD from MDD, including BPD cases with depressive onset (BPD-D). We replicate our PRS findings in an independent Danish cohort (iPSYCH 2015, N = 25 966). We observe strong genetic correlation between our case-case GWAS and that of case-control BPD. Conclusions We find that MDD and BPD, including BPD-D are genetically distinct. Our findings support that controls, MDD and BPD patients primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BPD and, importantly, BPD-D from MDD.

Original language	English
Pages (from-to)	79-90
Number of pages	12
Journal	British Journal of Psychiatry
Volume	226
Issue number	2
Early online date	14 Jan 2025
DOIs	https://doi.org/10.1192/bjp.2024.125
Publication status	Published - 1 Feb 2025

Keywords

Bipolar disorder
early differential diagnosis
genome-wide association analysis
major depressive disorder
polygenic risk scoring

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10.1192/bjp.2024.125

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Panagiotaropoulou, G., Hellberg, K. L. G., Coleman, J. R. I., Seok, D., Kalman, J., Mitchell, P. B., Schofield, P. R., Forstner, A. J., Major Depressive Disorder and Bipolar Disorder Working Groups of the Psychiatric Genomics Consortium, Bauer, M., Scott, L. J., Pato, C. N., Pato, M. T., Li, Q. S., Kirov, G., Landén, M., Jonsson, L., Müller-Myhsok, B., Smoller, J. W., ... Werge, T. (2025). Identifying genetic differences between bipolar disorder and major depression through multiple genome-wide association analyses. British Journal of Psychiatry, 226(2), 79-90. https://doi.org/10.1192/bjp.2024.125

@article{8e1b18a5f4154c1fb94eaccea8a9ba0f,

title = "Identifying genetic differences between bipolar disorder and major depression through multiple genome-wide association analyses",

abstract = "Background Accurate diagnosis of bipolar disorder (BPD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A depressive episode often precedes the first manic episode, making it difficult to distinguish BPD from unipolar major depressive disorder (MDD). Aims We use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores (PRS) that may aid early differential diagnosis. Method Based on individual genotypes from case-control cohorts of BPD and MDD shared through the Psychiatric Genomics Consortium, we compile case-case-control cohorts, applying a careful quality control procedure. In a resulting cohort of 51 149 individuals (15 532 BPD patients, 12 920 MDD patients and 22 697 controls), we perform a variety of GWAS and PRS analyses. Results Although our GWAS is not well powered to identify genome-wide significant loci, we find significant chip heritability and demonstrate the ability of the resulting PRS to distinguish BPD from MDD, including BPD cases with depressive onset (BPD-D). We replicate our PRS findings in an independent Danish cohort (iPSYCH 2015, N = 25 966). We observe strong genetic correlation between our case-case GWAS and that of case-control BPD. Conclusions We find that MDD and BPD, including BPD-D are genetically distinct. Our findings support that controls, MDD and BPD patients primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BPD and, importantly, BPD-D from MDD.",

keywords = "Bipolar disorder, early differential diagnosis, genome-wide association analysis, major depressive disorder, polygenic risk scoring",

author = "Georgia Panagiotaropoulou and Hellberg, {Kajsa Lotta Georgii} and Coleman, {Jonathan R.I.} and Darsol Seok and Janos Kalman and Mitchell, {Philip B.} and Schofield, {Peter R.} and Forstner, {Andreas J.} and {Major Depressive Disorder and Bipolar Disorder Working Groups of the Psychiatric Genomics Consortium} and Michael Bauer and Scott, {Laura J.} and Pato, {Carlos N.} and Pato, {Michele T.} and Li, {Qingqin S.} and George Kirov and Mikael Land{\'e}n and Lina Jonsson and Bertram M{\"u}ller-Myhsok and Smoller, {Jordan W.} and Binder, {Elisabeth B.} and Br{\"u}ckl, {Tanja M.} and Darina Czamara and {Van Der Auwera}, Sandra and Grabe, {Hans J.} and Georg Homuth and Schmidt, {Carsten O.} and Potash, {James B.} and {Raymond Depaulo}, J. and Goes, {Fernando S.} and MacKinnon, {Dean F.} and Mondimore, {Francis M.} and Weissman, {Myrna M.} and Jianxin Shi and Frye, {Mark A.} and Biernacka, {Joanna M.} and Andreas Reif and Witt, {Stephanie H.} and Kahn, {Ren{\'e} R.} and Boks, {Marco M.} and Owen, {Michael J.} and Katherine Gordon-Smith and Mitchell, {Brittany L.} and Martin, {Nicholas G.} and Medland, {Sarah E.} and Lisa Jones and Knowles, {James A.} and Levinson, {Douglas F.} and O'Donovan, {Michael C.} and Lewis, {Cathryn M.} and Gerome Breen and Thomas Werge",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s).",

year = "2025",

month = feb,

day = "1",

doi = "10.1192/bjp.2024.125",

language = "English",

volume = "226",

pages = "79--90",

journal = "British Journal of Psychiatry",

issn = "0007-1250",

publisher = "Cambridge University Press",

number = "2",

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Panagiotaropoulou, G, Hellberg, KLG, Coleman, JRI, Seok, D, Kalman, J, Mitchell, PB, Schofield, PR, Forstner, AJ, Major Depressive Disorder and Bipolar Disorder Working Groups of the Psychiatric Genomics Consortium, Bauer, M, Scott, LJ, Pato, CN, Pato, MT, Li, QS, Kirov, G, Landén, M, Jonsson, L, Müller-Myhsok, B, Smoller, JW, Binder, EB, Brückl, TM, Czamara, D, Van Der Auwera, S, Grabe, HJ, Homuth, G, Schmidt, CO, Potash, JB, Raymond Depaulo, J, Goes, FS, MacKinnon, DF, Mondimore, FM, Weissman, MM, Shi, J, Frye, MA, Biernacka, JM, Reif, A, Witt, SH, Kahn, RR, Boks, MM, Owen, MJ, Gordon-Smith, K, Mitchell, BL, Martin, NG, Medland, SE, Jones, L, Knowles, JA, Levinson, DF, O'Donovan, MC, Lewis, CM , Breen, G & Werge, T 2025, 'Identifying genetic differences between bipolar disorder and major depression through multiple genome-wide association analyses', British Journal of Psychiatry, vol. 226, no. 2, pp. 79-90. https://doi.org/10.1192/bjp.2024.125

TY - JOUR

T1 - Identifying genetic differences between bipolar disorder and major depression through multiple genome-wide association analyses

AU - Panagiotaropoulou, Georgia

AU - Hellberg, Kajsa Lotta Georgii

AU - Coleman, Jonathan R.I.

AU - Seok, Darsol

AU - Kalman, Janos

AU - Mitchell, Philip B.

AU - Schofield, Peter R.

AU - Forstner, Andreas J.

AU - Major Depressive Disorder and Bipolar Disorder Working Groups of the Psychiatric Genomics Consortium

AU - Bauer, Michael

AU - Scott, Laura J.

AU - Pato, Carlos N.

AU - Pato, Michele T.

AU - Li, Qingqin S.

AU - Kirov, George

AU - Landén, Mikael

AU - Jonsson, Lina

AU - Müller-Myhsok, Bertram

AU - Smoller, Jordan W.

AU - Binder, Elisabeth B.

AU - Brückl, Tanja M.

AU - Czamara, Darina

AU - Van Der Auwera, Sandra

AU - Grabe, Hans J.

AU - Homuth, Georg

AU - Schmidt, Carsten O.

AU - Potash, James B.

AU - Raymond Depaulo, J.

AU - Goes, Fernando S.

AU - MacKinnon, Dean F.

AU - Mondimore, Francis M.

AU - Weissman, Myrna M.

AU - Shi, Jianxin

AU - Frye, Mark A.

AU - Biernacka, Joanna M.

AU - Reif, Andreas

AU - Witt, Stephanie H.

AU - Kahn, René R.

AU - Boks, Marco M.

AU - Owen, Michael J.

AU - Gordon-Smith, Katherine

AU - Mitchell, Brittany L.

AU - Martin, Nicholas G.

AU - Medland, Sarah E.

AU - Jones, Lisa

AU - Knowles, James A.

AU - Levinson, Douglas F.

AU - O'Donovan, Michael C.

AU - Lewis, Cathryn M.

AU - Breen, Gerome

AU - Werge, Thomas

PY - 2025/2/1

Y1 - 2025/2/1

N2 - Background Accurate diagnosis of bipolar disorder (BPD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A depressive episode often precedes the first manic episode, making it difficult to distinguish BPD from unipolar major depressive disorder (MDD). Aims We use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores (PRS) that may aid early differential diagnosis. Method Based on individual genotypes from case-control cohorts of BPD and MDD shared through the Psychiatric Genomics Consortium, we compile case-case-control cohorts, applying a careful quality control procedure. In a resulting cohort of 51 149 individuals (15 532 BPD patients, 12 920 MDD patients and 22 697 controls), we perform a variety of GWAS and PRS analyses. Results Although our GWAS is not well powered to identify genome-wide significant loci, we find significant chip heritability and demonstrate the ability of the resulting PRS to distinguish BPD from MDD, including BPD cases with depressive onset (BPD-D). We replicate our PRS findings in an independent Danish cohort (iPSYCH 2015, N = 25 966). We observe strong genetic correlation between our case-case GWAS and that of case-control BPD. Conclusions We find that MDD and BPD, including BPD-D are genetically distinct. Our findings support that controls, MDD and BPD patients primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BPD and, importantly, BPD-D from MDD.

AB - Background Accurate diagnosis of bipolar disorder (BPD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A depressive episode often precedes the first manic episode, making it difficult to distinguish BPD from unipolar major depressive disorder (MDD). Aims We use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores (PRS) that may aid early differential diagnosis. Method Based on individual genotypes from case-control cohorts of BPD and MDD shared through the Psychiatric Genomics Consortium, we compile case-case-control cohorts, applying a careful quality control procedure. In a resulting cohort of 51 149 individuals (15 532 BPD patients, 12 920 MDD patients and 22 697 controls), we perform a variety of GWAS and PRS analyses. Results Although our GWAS is not well powered to identify genome-wide significant loci, we find significant chip heritability and demonstrate the ability of the resulting PRS to distinguish BPD from MDD, including BPD cases with depressive onset (BPD-D). We replicate our PRS findings in an independent Danish cohort (iPSYCH 2015, N = 25 966). We observe strong genetic correlation between our case-case GWAS and that of case-control BPD. Conclusions We find that MDD and BPD, including BPD-D are genetically distinct. Our findings support that controls, MDD and BPD patients primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BPD and, importantly, BPD-D from MDD.

KW - Bipolar disorder

KW - early differential diagnosis

KW - genome-wide association analysis

KW - major depressive disorder

KW - polygenic risk scoring

UR - http://www.scopus.com/inward/record.url?scp=85216756230&partnerID=8YFLogxK

U2 - 10.1192/bjp.2024.125

DO - 10.1192/bjp.2024.125

M3 - Article

C2 - 39806801

AN - SCOPUS:85216756230

SN - 0007-1250

VL - 226

SP - 79

EP - 90

JO - British Journal of Psychiatry

JF - British Journal of Psychiatry

IS - 2

ER -

Identifying genetic differences between bipolar disorder and major depression through multiple genome-wide association analyses

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