Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
40666370
TITLE
Immune, Developmental, and Synaptic Pathways Define Bipolar Disorder Clinical Heterogeneity.
ABSTRACT
IMPORTANCE NlmCategory: UNASSIGNED
The clinical heterogeneity of bipolar disorder (BD) is a major obstacle to improving diagnosis, predicting patient outcomes, and developing personalized treatments. A genetic approach is needed to deconstruct the disorder and uncover its fundamental biology. Previous genetic studies focusing on broad diagnostic categories have been limited in their ability to parse this complexity.
OBJECTIVE NlmCategory: UNASSIGNED
The clinical heterogeneity of bipolar disorder (BD) is a major obstacle to improving diagnosis, predicting patient outcomes, and developing personalized treatments. A genetic approach is needed to deconstruct the disorder and uncover its fundamental biology. Previous genetic studies focusing on broad diagnostic categories have been limited in their ability to parse this complexity. To test the hypothesis that clinically distinct subphenotypes of BD are associated with different underlying common variant genetic architectures.
DESIGN SETTING AND PARTICIPANTS NlmCategory: UNASSIGNED
The clinical heterogeneity of bipolar disorder (BD) is a major obstacle to improving diagnosis, predicting patient outcomes, and developing personalized treatments. A genetic approach is needed to deconstruct the disorder and uncover its fundamental biology. Previous genetic studies focusing on broad diagnostic categories have been limited in their ability to parse this complexity. To test the hypothesis that clinically distinct subphenotypes of BD are associated with different underlying common variant genetic architectures. This multicenter study included a primary genome-wide association study (GWAS) of up to 23,819 bipolar disorder (BD) cases and 163,839 controls. These results were integrated via multi-trait analysis of GWAS (MTAG) with external summary statistics for BD (59,287 cases; 781,022 controls) and schizophrenia (SCZ; 53,386 cases; 77,258 controls). Sample overlap was statistically accounted for.
MAIN OUTCOMES AND MEASURES NlmCategory: UNASSIGNED
The clinical heterogeneity of bipolar disorder (BD) is a major obstacle to improving diagnosis, predicting patient outcomes, and developing personalized treatments. A genetic approach is needed to deconstruct the disorder and uncover its fundamental biology. Previous genetic studies focusing on broad diagnostic categories have been limited in their ability to parse this complexity. To test the hypothesis that clinically distinct subphenotypes of BD are associated with different underlying common variant genetic architectures. This multicenter study included a primary genome-wide association study (GWAS) of up to 23,819 bipolar disorder (BD) cases and 163,839 controls. These results were integrated via multi-trait analysis of GWAS (MTAG) with external summary statistics for BD (59,287 cases; 781,022 controls) and schizophrenia (SCZ; 53,386 cases; 77,258 controls). Sample overlap was statistically accounted for. The primary outcomes were the genetic dimensions underlying BD heterogeneity, differentiated by single nucleotide polymorphism (SNP)-heritability (h ), genetic correlations, genomic loci ( ≤5×10 ), and functional, cell-type, and gene-expression pathway analyses.
RESULTS NlmCategory: UNASSIGNED
The clinical heterogeneity of bipolar disorder (BD) is a major obstacle to improving diagnosis, predicting patient outcomes, and developing personalized treatments. A genetic approach is needed to deconstruct the disorder and uncover its fundamental biology. Previous genetic studies focusing on broad diagnostic categories have been limited in their ability to parse this complexity. To test the hypothesis that clinically distinct subphenotypes of BD are associated with different underlying common variant genetic architectures. This multicenter study included a primary genome-wide association study (GWAS) of up to 23,819 bipolar disorder (BD) cases and 163,839 controls. These results were integrated via multi-trait analysis of GWAS (MTAG) with external summary statistics for BD (59,287 cases; 781,022 controls) and schizophrenia (SCZ; 53,386 cases; 77,258 controls). Sample overlap was statistically accounted for. The primary outcomes were the genetic dimensions underlying BD heterogeneity, differentiated by single nucleotide polymorphism (SNP)-heritability (h ), genetic correlations, genomic loci ( ≤5×10 ), and functional, cell-type, and gene-expression pathway analyses. We identified four genetically-informed dimensions of BD: Severe Illness, Core Mania, Externalizing/Impulsive Comorbidity, and Internalizing/Affective Comorbidity. The analyses yielded up to 181 subphenotype-associated loci, 53 of which are novel. The Severe Illness Dimension was characterized by a unique neuro-immune signature (a protective association with , =2.50×10 ) evident only when leveraging SCZ genetic data. The Internalizing/Affective dimension was associated with neurodevelopmental genes (e.g., ). Notably, the rapid-cycling subphenotype showed a unique signature of strong negative selection, a finding not observed in other subphenotypes.
CONCLUSIONS AND RELEVANCE NlmCategory: UNASSIGNED
The clinical heterogeneity of bipolar disorder (BD) is a major obstacle to improving diagnosis, predicting patient outcomes, and developing personalized treatments. A genetic approach is needed to deconstruct the disorder and uncover its fundamental biology. Previous genetic studies focusing on broad diagnostic categories have been limited in their ability to parse this complexity. To test the hypothesis that clinically distinct subphenotypes of BD are associated with different underlying common variant genetic architectures. This multicenter study included a primary genome-wide association study (GWAS) of up to 23,819 bipolar disorder (BD) cases and 163,839 controls. These results were integrated via multi-trait analysis of GWAS (MTAG) with external summary statistics for BD (59,287 cases; 781,022 controls) and schizophrenia (SCZ; 53,386 cases; 77,258 controls). Sample overlap was statistically accounted for. The primary outcomes were the genetic dimensions underlying BD heterogeneity, differentiated by single nucleotide polymorphism (SNP)-heritability (h ), genetic correlations, genomic loci ( ≤5×10 ), and functional, cell-type, and gene-expression pathway analyses. We identified four genetically-informed dimensions of BD: Severe Illness, Core Mania, Externalizing/Impulsive Comorbidity, and Internalizing/Affective Comorbidity. The analyses yielded up to 181 subphenotype-associated loci, 53 of which are novel. The Severe Illness Dimension was characterized by a unique neuro-immune signature (a protective association with , =2.50×10 ) evident only when leveraging SCZ genetic data. The Internalizing/Affective dimension was associated with neurodevelopmental genes (e.g., ). Notably, the rapid-cycling subphenotype showed a unique signature of strong negative selection, a finding not observed in other subphenotypes. The clinical heterogeneity of bipolar disorder appears to be defined by a complex and multi-layered genetic architecture. The presented findings provide an empirical framework that may advance psychiatric nosology beyond its current diagnostic boundaries. These results may also inform future research to identify targets for personalized interventions. The delineation of these genetically-informed dimensions offers specific, biologically-grounded hypotheses for subsequent therapeutic discovery. Establishing such a framework is an essential step toward refining diagnostic criteria and developing more effective, personalized treatments. This work lays the foundation for a transition from a uniform treatment model to the paradigm of precision psychiatry.
KEY POINTS NlmCategory: UNASSIGNED
The clinical heterogeneity of bipolar disorder (BD) is a major obstacle to improving diagnosis, predicting patient outcomes, and developing personalized treatments. A genetic approach is needed to deconstruct the disorder and uncover its fundamental biology. Previous genetic studies focusing on broad diagnostic categories have been limited in their ability to parse this complexity. To test the hypothesis that clinically distinct subphenotypes of BD are associated with different underlying common variant genetic architectures. This multicenter study included a primary genome-wide association study (GWAS) of up to 23,819 bipolar disorder (BD) cases and 163,839 controls. These results were integrated via multi-trait analysis of GWAS (MTAG) with external summary statistics for BD (59,287 cases; 781,022 controls) and schizophrenia (SCZ; 53,386 cases; 77,258 controls). Sample overlap was statistically accounted for. The primary outcomes were the genetic dimensions underlying BD heterogeneity, differentiated by single nucleotide polymorphism (SNP)-heritability (h ), genetic correlations, genomic loci ( ≤5×10 ), and functional, cell-type, and gene-expression pathway analyses. We identified four genetically-informed dimensions of BD: Severe Illness, Core Mania, Externalizing/Impulsive Comorbidity, and Internalizing/Affective Comorbidity. The analyses yielded up to 181 subphenotype-associated loci, 53 of which are novel. The Severe Illness Dimension was characterized by a unique neuro-immune signature (a protective association with , =2.50×10 ) evident only when leveraging SCZ genetic data. The Internalizing/Affective dimension was associated with neurodevelopmental genes (e.g., ). Notably, the rapid-cycling subphenotype showed a unique signature of strong negative selection, a finding not observed in other subphenotypes. The clinical heterogeneity of bipolar disorder appears to be defined by a complex and multi-layered genetic architecture. The presented findings provide an empirical framework that may advance psychiatric nosology beyond its current diagnostic boundaries. These results may also inform future research to identify targets for personalized interventions. The delineation of these genetically-informed dimensions offers specific, biologically-grounded hypotheses for subsequent therapeutic discovery. Establishing such a framework is an essential step toward refining diagnostic criteria and developing more effective, personalized treatments. This work lays the foundation for a transition from a uniform treatment model to the paradigm of precision psychiatry. What are the distinct genetic architectures underlying the clinical heterogeneity of bipolar disorder? In this genetic study of 23,819 bipolar disorder (BD) cases and 163,839 controls, clinical heterogeneity mapped onto four genetically-informed dimensions. A severe illness dimension was defined by a neuro-immune signature ( ) shared with schizophrenia. An affective comorbidity dimension was distinguished by neurodevelopmental pathways involving axonal guidance ( ). Notably, the rapid-cycling phenotype showed evidence of purifying selection, suggesting influence by rare, highly penetrant alleles. These findings provide a data-driven biological framework for bipolar disorder, guiding future research toward patient stratification and targeted therapeutics.
DATE PUBLISHED
2025 Jun 27
HISTORY
PUBSTATUS PUBSTATUSDATE
medline 2025/07/16 06:26
pubmed 2025/07/16 06:25
entrez 2025/07/16 05:29
pmc-release 2025/07/15
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
van der Veen T van der Veen Tracey T
Tesfaye M Tesfaye Markos M
Yang JMK Yang Jessica Mei Kay JMK
Boltz T Boltz Toni T
David FS David Friederike S FS
Crinion S Crinion Shane S
Koromina M Koromina Maria M
Andlauer TFM Andlauer Till F M TFM
Bigdeli TB Bigdeli Tim B TB
Coombes BJ Coombes Brandon J BJ
Greenwood TA Greenwood Tiffany A TA
Panagiotaropoulou G Panagiotaropoulou Georgia G
Parker N Parker Nadine N
Sung H Sung Heejong H
Bass N Bass Nicholas N
Coleman JRI Coleman Jonathan R I JRI
Guzman-Parra J Guzman-Parra José J
Kalman JL Kalman Janos L JL
McGrouther CC McGrouther Caroline C CC
Mitchell BL Mitchell Brittany L BL
Rangan AV Rangan Aaditya V AV
Scott K Scott Katie K
Shadrin A Shadrin Alexey A
Smith DJ Smith Daniel J DJ
Vreeker A Vreeker Annabel A
Adorjan K Adorjan Kristina K
Albani D Albani Diego D
Alemany S Alemany Silvia S
Alliey-Rodriguez N Alliey-Rodriguez Ney N
Antoniou A Antoniou Anastasia A
Bauer M Bauer Michael M
Beins EC Beins Eva C EC
Boks MP Boks Marco P MP
Bosch R Bosch Rosa R
Brumpton BM Brumpton Ben M BM
Brunkhorst-Kanaan N Brunkhorst-Kanaan Nathalie N
Budde M Budde Monika M
Byerley W Byerley William W
Cabana-Domínguez J Cabana-Domínguez Judit J
Cairns MJ Cairns Murray J MJ
Carpiniello B Carpiniello Bernardo B
Casas M Casas Miquel M
Cervantes P Cervantes Pablo P
Chatzinakos C Chatzinakos Chris C
Clarke TK Clarke Toni-Kim TK
Claus I Claus Isabelle I
Cruceanu C Cruceanu Cristiana C
Cuellar-Barboza A Cuellar-Barboza Alfredo A
Czerski PM Czerski Piotr M PM
Dafnas K Dafnas Konstantinos K
Dale AM Dale Anders M AM
Dalkner N Dalkner Nina N
DePaulo JR DePaulo J Raymond JR
Degenhardt F Degenhardt Franziska F
Djurovic S Djurovic Srdjan S
Escott-Price V Escott-Price Valentina V
Fanous AH Fanous Ayman H AH
Fellendorf FT Fellendorf Frederike T FT
Ferrier IN Ferrier I Nicol IN
Forty L Forty Liz L
Frank J Frank Josef J
Frei O Frei Oleksandr O
Freimer NB Freimer Nelson B NB
Garnham J Garnham Julie J
Gizer IR Gizer Ian R IR
Gordon SD Gordon Scott D SD
Gordon-Smith K Gordon-Smith Katherine K
Hahn T Hahn Tim T
Marian L Marian L L
Harder A Harder Arvid A
Hautzinger M Hautzinger Martin M
Heilbronner U Heilbronner Urs U
Hellgren D Hellgren Dennis D
Herms S Herms Stefan S
Hickie IB Hickie Ian B IB
Hoffmann P Hoffmann Per P
Holmans PA Holmans Peter A PA
Jamain S Jamain Stéphane S
Jonsson L Jonsson Lina L
Kennedy JL Kennedy James L JL
Kittel-Schneider S Kittel-Schneider Sarah S
Knowles JA Knowles James A JA
Koch E Koch Elise E
Kogevinas M Kogevinas Manolis M
Kranz TM Kranz Thorsten M TM
Kushner SA Kushner Steven A SA
Lavebratt C Lavebratt Catharina C
Lawrence J Lawrence Jacob J
Leber M Leber Markus M
Lind PA Lind Penelope A PA
Lucae S Lucae Susanne S
Lundberg M Lundberg Martin M
MacIntyre DJ MacIntyre Donald J DJ
Maier W Maier Wolfgang W
Maihofer AX Maihofer Adam X AX
Malaspina D Malaspina Dolores D
Manchia M Manchia Mirko M
Maratou E Maratou Eirini E
Martinsson L Martinsson Lina L
McInnis MG McInnis Melvin G MG
McKay JD McKay James D JD
Medeiros H Medeiros Helena H
Meyer-Lindenberg A Meyer-Lindenberg Andreas A
Millischer V Millischer Vincent V
Morris DW Morris Derek W DW
Moutsatsou P Moutsatsou Paraskevi P
Mühleisen TW Mühleisen Thomas W TW
'Donovan CO 'Donovan Claire O CO
Olsen CM Olsen Catherine M CM
Papiol S Papiol Sergi S
Pardiñas AF Pardiñas Antonio F AF
Perry A Perry Amy A
Pfennig A Pfennig Andrea A
Pisanu C Pisanu Claudia C
Potash JB Potash James B JB
Quested D Quested Digby D
Rapaport MH Rapaport Mark H MH
Regeer EJ Regeer Eline J EJ
Rice JP Rice John P JP
Rivera M Rivera Margarita M
Schulte EC Schulte Eva C EC
Senner F Senner Fanny F
Shilling PD Shilling Paul D PD
Sindermann L Sindermann Lisa L
Sirignano L Sirignano Lea L
Siskind D Siskind Dan D
Slaney C Slaney Claire C
Smeland OB Smeland Olav B OB
Sobell JL Sobell Janet L JL
Artigas MS Artigas Maria Soler MS
Stein DJ Stein Dan J DJ
Stein F Stein Frederike F
Swiatkowska B Swiatkowska Beata B
Thorp JG Thorp Jackson G JG
Toma C Toma Claudio C
Tondo L Tondo Leonardo L
Tooney PA Tooney Paul A PA
Vawter MP Vawter Marquis P MP
Vedder H Vedder Helmut H
Walters JTR Walters James T R JTR
Witt SH Witt Stephanie H SH
Young AH Young Allan H AH
Zandi PP Zandi Peter P PP
Zillich L Zillich Lea L
Estonian Biobank research team
Genomic Psychiatry Cohort (GPC) Investigators
HUNT All-In Psychiatry
Adolfsson R Adolfsson Rolf R
Alfredsson L Alfredsson Lars L
Backlund L Backlund Lena L
Baune BT Baune Bernhard T BT
Bellivier F Bellivier Frank F
Bengesser S Bengesser Susanne S
Berrettini WH Berrettini Wade H WH
Biernacka JM Biernacka Joanna M JM
Blackwood D Blackwood Douglas D
Boehnke M Boehnke Michael M
Breen G Breen Gerome G
Carr VJ Carr Vaughan J VJ
Catts S Catts Stanley S
Cichon S Cichon Sven S
Corvin A Corvin Aiden A
Craddock N Craddock Nicholas N
Dannlowski U Dannlowski Udo U
Dikeos D Dikeos Dimitris D
Esko T Esko Tõnu T
Etain B Etain Bruno B
Ferentinos P Ferentinos Panagiotis P
Frye M Frye Mark M
Fullerton JM Fullerton Janice M JM
Gawlik M Gawlik Micha M
Gershon ES Gershon Elliot S ES
Goes FS Goes Fernando S FS
Green MJ Green Melissa J MJ
Hauser J Hauser Joanna J
Henskens FA Henskens Frans A FA
Hjerling-Leffler J Hjerling-Leffler Jens J
Jones I Jones Ian I
Jones LA Jones Lisa A LA
Kahn RS Kahn René S RS
Kelsoe JR Kelsoe John R JR
Kircher T Kircher Tilo T
Kirov G Kirov George G
Kobayashi N Kobayashi Nene N
Landén M Landén Mikael M
Leboyer M Leboyer Marion M
Lenger M Lenger Melanie M
Li QS Li Qingqin S QS
Lissowska J Lissowska Jolanta J
Loughland C Loughland Carmel C
Luykx JJ Luykx Jurjen J JJ
Martin NG Martin Nicholas G NG
Mathews CA Mathews Carol A CA
Mayoral F Mayoral Fermin F
McElroy SL McElroy Susan L SL
McIntosh AM McIntosh Andrew M AM
Medland SE Medland Sarah E SE
Melle I Melle Ingrid I
Mitchell PB Mitchell Philip B PB
Morken G Morken Gunnar G
Myers RM Myers Richard M RM
Möser C Möser Chiara C
Müller-Myhsok B Müller-Myhsok Bertram B
Neale BM Neale Benjamin M BM
Nievergelt CM Nievergelt Caroline M CM
Nurnberger JI Nurnberger John I JI
Nöthen MM Nöthen Markus M MM
O'Donovan MC O'Donovan Michael C MC
Oedegaard KJ Oedegaard Ketil J KJ
Olsson T Olsson Tomas T
Owen MJ Owen Michael J MJ
Paciga SA Paciga Sara A SA
Pantelis C Pantelis Christos C
Pato CN Pato Carlos N CN
Pato MT Pato Michele T MT
Patrinos GP Patrinos George P GP
Pawlak JM Pawlak Joanna M JM
Perlis R Perlis Roy R
Ramos-Quiroga JA Ramos-Quiroga Josep Antoni JA
Reif A Reif Andreas A
Reininghaus EZ Reininghaus Eva Z EZ
Ribasés M Ribasés Marta M
Rietschel M Rietschel Marcella M
Ripke S Ripke Stephan S
Rouleau GA Rouleau Guy A GA
Schall U Schall Ulrich U
Schalling M Schalling Martin M
Schofield PR Schofield Peter R PR
Schulze TG Schulze Thomas G TG
Scott LJ Scott Laura J LJ
Scott RJ Scott Rodney J RJ
Serretti A Serretti Alessandro A
Smoller JW Smoller Jordan W JW
Squassina A Squassina Alessio A
Stahl EA Stahl Eli A EA
Stordal E Stordal Eystein E
Streit F Streit Fabian F
Sullivan PF Sullivan Patrick F PF
Turecki G Turecki Gustavo G
Vaaler AE Vaaler Arne E AE
Vieta E Vieta Eduard E
Vincent JB Vincent John B JB
Waldman ID Waldman Irwin D ID
Weickert CS Weickert Cynthia S CS
Weickert TW Weickert Thomas W TW
Whiteman DC Whiteman David C DC
Alda M Alda Martin M
Ophoff RA Ophoff Roel A RA
O'Connell KS O'Connell Kevin S KS
Mullins N Mullins Niamh N
Forstner AJ Forstner Andreas J AJ
Grigoroiu-Serbanescu M Grigoroiu-Serbanescu Maria M
Edenberg HJ Edenberg Howard J HJ
McMahon FJ McMahon Francis J FJ
Andreassen OA Andreassen Ole A OA
Di Florio A Di Florio Arianna A
McQuillin A McQuillin Andrew A
Bipolar Disorder Working Group of the Psychiatric Genomics Consortium
INVESTIGATORS
JOURNAL
VOLUME:
ISSUE:
TITLE: medRxiv : the preprint server for health sciences
ISOABBREVIATION: medRxiv
YEAR: 2025
MONTH: Jun
DAY: 27
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN:
ISSNTYPE:
MEDLINE JOURNAL
MEDLINETA: medRxiv
COUNTRY: United States
ISSNLINKING:
NLMUNIQUEID: 101767986
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Preprint
COMMENTS AND CORRECTIONS
GRANTS
GENERAL NOTE
KEYWORDS
MESH HEADINGS
SUPPLEMENTARY MESH
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