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Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology.

ABSTRACT: Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

SUBMITTER: Mullins N

PROVIDER: S-EPMC8192451 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology.

Mullins Niamh N Forstner Andreas J AJ O'Connell Kevin S KS Coombes Brandon B Coleman Jonathan R I JRI Qiao Zhen Z Als Thomas D TD Bigdeli Tim B TB Børte Sigrid S Bryois Julien J Charney Alexander W AW Drange Ole Kristian OK Gandal Michael J MJ Hagenaars Saskia P SP Ikeda Masashi M Kamitaki Nolan N Kim Minsoo M Krebs Kristi K Panagiotaropoulou Georgia G Schilder Brian M BM Sloofman Laura G LG Steinberg Stacy S Trubetskoy Vassily V Winsvold Bendik S BS Won Hong-Hee HH Abramova Liliya L Adorjan Kristina K Agerbo Esben E Al Eissa Mariam M Albani Diego D Alliey-Rodriguez Ney N Anjorin Adebayo A Antilla Verneri V Antoniou Anastasia A Awasthi Swapnil S Baek Ji Hyun JH Bækvad-Hansen Marie M Bass Nicholas N Bauer Michael M Beins Eva C EC Bergen Sarah E SE Birner Armin A Bøcker Pedersen Carsten C Bøen Erlend E Boks Marco P MP Bosch Rosa R Brum Murielle M Brumpton Ben M BM Brunkhorst-Kanaan Nathalie N Budde Monika M Bybjerg-Grauholm Jonas J Byerley William W Cairns Murray M Casas Miquel M Cervantes Pablo P Clarke Toni-Kim TK Cruceanu Cristiana C Cuellar-Barboza Alfredo A Cunningham Julie J Curtis David D Czerski Piotr M PM Dale Anders M AM Dalkner Nina N David Friederike S FS Degenhardt Franziska F Djurovic Srdjan S Dobbyn Amanda L AL Douzenis Athanassios A Elvsåshagen Torbjørn T Escott-Price Valentina V Ferrier I Nicol IN Fiorentino Alessia A Foroud Tatiana M TM Forty Liz L Frank Josef J Frei Oleksandr O Freimer Nelson B NB Frisén Louise L Gade Katrin K Garnham Julie J Gelernter Joel J Giørtz Pedersen Marianne M Gizer Ian R IR Gordon Scott D SD Gordon-Smith Katherine K Greenwood Tiffany A TA Grove Jakob J Guzman-Parra José J Ha Kyooseob K Haraldsson Magnus M Hautzinger Martin M Heilbronner Urs U Hellgren Dennis D Herms Stefan S Hoffmann Per P Holmans Peter A PA Huckins Laura L Jamain Stéphane S Johnson Jessica S JS Kalman Janos L JL Kamatani Yoichiro Y Kennedy James L JL Kittel-Schneider Sarah S Knowles James A JA Kogevinas Manolis M Koromina Maria M Kranz Thorsten M TM Kranzler Henry R HR Kubo Michiaki M Kupka Ralph R Kushner Steven A SA Lavebratt Catharina C Lawrence Jacob J Leber Markus M Lee Heon-Jeong HJ Lee Phil H PH Levy Shawn E SE Lewis Catrin C Liao Calwing C Lucae Susanne S Lundberg Martin M MacIntyre Donald J DJ Magnusson Sigurdur H SH Maier Wolfgang W Maihofer Adam A Malaspina Dolores D Maratou Eirini E Martinsson Lina L Mattheisen Manuel M McCarroll Steven A SA McGregor Nathaniel W NW McGuffin Peter P McKay James D JD Medeiros Helena H Medland Sarah E SE Millischer Vincent V Montgomery Grant W GW Moran Jennifer L JL Morris Derek W DW Mühleisen Thomas W TW O'Brien Niamh N O'Donovan Claire C Olde Loohuis Loes M LM Oruc Lilijana L Papiol Sergi S Pardiñas Antonio F AF Perry Amy A Pfennig Andrea A Porichi Evgenia E Potash James B JB Quested Digby D Raj Towfique T Rapaport Mark H MH DePaulo J Raymond JR Regeer Eline J EJ Rice John P JP Rivas Fabio F Rivera Margarita M Roth Julian J Roussos Panos P Ruderfer Douglas M DM Sánchez-Mora Cristina C Schulte Eva C EC Senner Fanny F Sharp Sally S Shilling Paul D PD Sigurdsson Engilbert E Sirignano Lea L Slaney Claire C Smeland Olav B OB Smith Daniel J DJ Sobell Janet L JL Søholm Hansen Christine C Soler Artigas Maria M Spijker Anne T AT Stein Dan J DJ Strauss John S JS Świątkowska Beata B Terao Chikashi C Thorgeirsson Thorgeir E TE Toma Claudio C Tooney Paul P Tsermpini Evangelia-Eirini EE Vawter Marquis P MP Vedder Helmut H Walters James T R JTR Witt Stephanie H SH Xi Simon S Xu Wei W Yang Jessica Mei Kay JMK Young Allan H AH Young Hannah H Zandi Peter P PP Zhou Hang H Zillich Lea L Adolfsson Rolf R Agartz Ingrid I Alda Martin M Alfredsson Lars L Babadjanova Gulja G Backlund Lena L Baune Bernhard T BT Bellivier Frank F Bengesser Susanne S Berrettini Wade H WH Blackwood Douglas H R DHR Boehnke Michael M Børglum Anders D AD Breen Gerome G Carr Vaughan J VJ Catts Stanley S Corvin Aiden A Craddock Nicholas N Dannlowski Udo U Dikeos Dimitris D Esko Tõnu T Etain Bruno B Ferentinos Panagiotis P Frye Mark M Fullerton Janice M JM Gawlik Micha M Gershon Elliot S ES Goes Fernando S FS Green Melissa J MJ Grigoroiu-Serbanescu Maria M Hauser Joanna J Henskens Frans F Hillert Jan J Hong Kyung Sue KS Hougaard David M DM Hultman Christina M CM Hveem Kristian K Iwata Nakao N Jablensky Assen V AV Jones Ian I Jones Lisa A LA Kahn René S RS Kelsoe John R JR Kirov George G Landén Mikael M Leboyer Marion M Lewis Cathryn M CM Li Qingqin S QS Lissowska Jolanta J Lochner Christine C Loughland Carmel C Martin Nicholas G NG Mathews Carol A CA Mayoral Fermin F McElroy Susan L SL McIntosh Andrew M AM McMahon Francis J FJ Melle Ingrid I Michie Patricia P Milani Lili L Mitchell Philip B PB Morken Gunnar G Mors Ole O Mortensen Preben Bo PB Mowry Bryan B Müller-Myhsok Bertram B Myers Richard M RM Neale Benjamin M BM Nievergelt Caroline M CM Nordentoft Merete M Nöthen Markus M MM O'Donovan Michael C MC Oedegaard Ketil J KJ Olsson Tomas T Owen Michael J MJ Paciga Sara A SA Pantelis Chris C Pato Carlos C Pato Michele T MT Patrinos George P GP Perlis Roy H RH Posthuma Danielle D Ramos-Quiroga Josep Antoni JA Reif Andreas A Reininghaus Eva Z EZ Ribasés Marta M Rietschel Marcella M Ripke Stephan S Rouleau Guy A GA Saito Takeo T Schall Ulrich U Schalling Martin M Schofield Peter R PR Schulze Thomas G TG Scott Laura J LJ Scott Rodney J RJ Serretti Alessandro A Shannon Weickert Cynthia C Smoller Jordan W JW Stefansson Hreinn H Stefansson Kari K Stordal Eystein E Streit Fabian F Sullivan Patrick F PF Turecki Gustavo G Vaaler Arne E AE Vieta Eduard E Vincent John B JB Waldman Irwin D ID Weickert Thomas W TW Werge Thomas T Wray Naomi R NR Zwart John-Anker JA Biernacka Joanna M JM Nurnberger John I JI Cichon Sven S Edenberg Howard J HJ Stahl Eli A EA McQuillin Andrew A Di Florio Arianna A Ophoff Roel A RA Andreassen Ole A OA

Nature genetics 20210517 6

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in ge ...[more]

PMID: 34002096

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Project description:ImportancePredicting the onset of bipolar disorder (BD) could facilitate preventive treatments. Among risk measures, bipolar at-risk (BAR) criteria have shown promise in predicting onset of bipolar disorder in the first year in clinical cohorts; however, it is not known whether BAR criteria are associated with the onset of BD in the longer term.ObjectiveTo assess the association of BAR criteria with onset of BD over 10 to 13 years follow-up.Design, setting, and participantsThis prospective cohort study, completed between May 1, 2020, and November 7, 2022, included consenting people seeking help for nonpsychotic major mental health difficulties, including mood, personality, and substance use disorders, who were originally recruited at ages 15 to 25 years from a tertiary youth mental health setting in metropolitan Melbourne, Victoria, Australia, from May 1, 2008, to September 30, 2010.ExposureMeeting BAR criteria at baseline. Criteria included subthreshold mania, cyclothymic features, subthreshold depression, and family history of BD. A matched clinical comparison group was recruited from the same help-seeking population.Main outcomes and measuresThe primary outcome was expert consensus diagnosis of BD I or II based on the Mini International Neuropsychiatric Interview, self-reported information collected through online assessments, and linked data on mental health service utilization in Victoria over 10 to 13 years of follow-up.ResultsAmong 69 eligible participants, follow-up data were available for 60 (88.2%). The mean (SD) age at the end of follow-up was 32.9 (2.8) years, and 49 (81.7%) were women. A total of 28 participants met BAR criteria, and 32 were in the comparison group. In the BAR group, 8 patients (28.6%) developed BD over a mean (SD) of 11.1 (0.7) years of follow-up, and no patients in the comparison group developed BD. The risk of developing BD was higher in the BAR group than in the non-BAR group (χ21 = 70.0; P < .001). The proportions of transitions to BD were equal in the first and second halves of the follow-up period.Conclusions and relevanceIn this cohort study of participants seeking care for mental health difficulties, patients meeting the BAR criteria were significantly more likely to transition to BD over a decade after ascertainment compared with patients not meeting the BAR criteria. The findings suggest that those meeting BAR criteria may benefit from longer-term monitoring and support. Evaluation of predictive properties in longer-term studies using a risk measure will help with implementation of BAR criteria in clinical settings.

Project description:BackgroundMood 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.MethodsTo 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).ResultsSeventy-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.ConclusionsThe 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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Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology.

Publications

Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology.

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