Dataset Information

Characterisation of age and polarity at onset in bipolar disorder.

ABSTRACT:

Background

Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.

Aims

To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.

Method

Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.

Results

Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = -0.34 years, s.e. = 0.08), major depression (β = -0.34 years, s.e. = 0.08), schizophrenia (β = -0.39 years, s.e. = 0.08), and educational attainment (β = -0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.

Conclusions

AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.

SUBMITTER: Kalman JL

PROVIDER: S-EPMC8636611 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Publications

Characterisation of age and polarity at onset in bipolar disorder.

Kalman Janos L JL Olde Loohuis Loes M LM Vreeker Annabel A McQuillin Andrew A Stahl Eli A EA Ruderfer Douglas D Grigoroiu-Serbanescu Maria M Panagiotaropoulou Georgia G Ripke Stephan S Bigdeli Tim B TB Stein Frederike F Meller Tina T Meinert Susanne S Pelin Helena H Streit Fabian F Papiol Sergi S Adams Mark J MJ Adolfsson Rolf R Adorjan Kristina K Agartz Ingrid I Aminoff Sofie R SR Anderson-Schmidt Heike H Andreassen Ole A OA Ardau Raffaella R Aubry Jean-Michel JM Balaban Ceylan C Bass Nicholas N Baune Bernhard T BT Bellivier Frank F Benabarre Antoni A Bengesser Susanne S Berrettini Wade H WH Boks Marco P MP Bromet Evelyn J EJ Brosch Katharina K Budde Monika M Byerley William W Cervantes Pablo P Chillotti Catina C Cichon Sven S Clark Scott R SR Comes Ashley L AL Corvin Aiden A Coryell William W Craddock Nick N Craig David W DW Croarkin Paul E PE Cruceanu Cristiana C Czerski Piotr M PM Dalkner Nina N Dannlowski Udo U Degenhardt Franziska F Del Zompo Maria M DePaulo J Raymond JR Djurovic Srdjan S Edenberg Howard J HJ Eissa Mariam Al MA Elvsåshagen Torbjørn T Etain Bruno B Fanous Ayman H AH Fellendorf Frederike F Fiorentino Alessia A Forstner Andreas J AJ Frye Mark A MA Fullerton Janice M JM Gade Katrin K Garnham Julie J Gershon Elliot E Gill Michael M Goes Fernando S FS Gordon-Smith Katherine K Grof Paul P Guzman-Parra Jose J Hahn Tim T Hasler Roland R Heilbronner Maria M Heilbronner Urs U Jamain Stephane S Jimenez Esther E Jones Ian I Jones Lisa L Jonsson Lina L Kahn Rene S RS Kelsoe John R JR Kennedy James L JL Kircher Tilo T Kirov George G Kittel-Schneider Sarah S Klöhn-Saghatolislam Farah F Knowles James A JA Kranz Thorsten M TM Lagerberg Trine Vik TV Landen Mikael M Lawson William B WB Leboyer Marion M Li Qingqin S QS Maj Mario M Malaspina Dolores D Manchia Mirko M Mayoral Fermin F McElroy Susan L SL McInnis Melvin G MG McIntosh Andrew M AM Medeiros Helena H Melle Ingrid I Milanova Vihra V Mitchell Philip B PB Monteleone Palmiero P Monteleone Alessio Maria AM Nöthen Markus M MM Novak Tomas T Nurnberger John I JI O'Brien Niamh N O'Connell Kevin S KS O'Donovan Claire C O'Donovan Michael C MC Opel Nils N Ortiz Abigail A Owen Michael J MJ Pålsson Erik E Pato Carlos C Pato Michele T MT Pawlak Joanna J Pfarr Julia-Katharina JK Pisanu Claudia C Potash James B JB Rapaport Mark H MH Reich-Erkelenz Daniela D Reif Andreas A Reininghaus Eva E Repple Jonathan J Richard-Lepouriel Hélène H Rietschel Marcella M Ringwald Kai K Roberts Gloria G Rouleau Guy G Schaupp Sabrina S Scheftner William A WA Schmitt Simon S Schofield Peter R PR Schubert K Oliver KO Schulte Eva C EC Schweizer Barbara B Senner Fanny F Severino Giovanni G Sharp Sally S Slaney Claire C Smeland Olav B OB Sobell Janet L JL Squassina Alessio A Stopkova Pavla P Strauss John J Tortorella Alfonso A Turecki Gustavo G Twarowska-Hauser Joanna J Veldic Marin M Vieta Eduard E Vincent John B JB Xu Wei W Zai Clement C CC Zandi Peter P PP Di Florio Arianna A Smoller Jordan W JW Biernacka Joanna M JM McMahon Francis J FJ Alda Martin M Müller-Myhsok Bertram B Koutsouleris Nikolaos N Falkai Peter P Freimer Nelson B NB Andlauer Till F M TFM Schulze Thomas G TG Ophoff Roel A RA

The British journal of psychiatry : the journal of mental science 20211201 6

<h4>Background</h4>Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.<h4>Aims</h4>To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.<h4>Method</h4>Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were ...[more]

PMID: 35048876

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Project description:ObjectiveIn this study, we performed a candidate genetic risk score (GRS) analysis of early-onset bipolar disorder (BD).MethodsTreatment of Early Age Mania (TEAM) study enrollment and sample collection took place from 2003 to 2008. Mayo Clinic Bipolar Biobank samples were collected from 2009 to 2013. Genotyping and analyses for the present study took place from 2013 to 2014. The diagnosis of BD was based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria. Eight single-nucleotide polymorphisms (SNPs), previously reported in genome-wide association studies to be associated with BD, were chosen for GRS analysis in early-onset bipolar disease. These SNPs map to 3 genes: CACNA1C (calcium channel, voltage-dependent, L type, alpha 1C subunit), ANK3 (ankyrin-3, node of Ranvier [ankyrin G]), and ODZ4 (teneurin transmembrane protein 4 [formerly "odz, odd Oz/10-m homolog 4 {Drosophila}, ODZ4"]). The 8 candidate SNPs were genotyped in patients from the TEAM study (n = 69); adult patients with BD (n = 732), including a subset with early-onset illness (n = 192); and healthy controls (n = 776). GRS analyses were performed to compare early-onset cases with controls. In addition, associations of early-onset BD with individual SNPs and haplotypes were explored.ResultsGRS analysis revealed associations of the risk score with early-onset BD (P = .01). Gene-level haplotype analysis comparing TEAM patients with controls suggested association of early-onset BD with a CACNA1C haplotype (global test, P = .01). At the level of individual SNPs, comparison of TEAM cases with healthy controls provided nominally significant evidence for association of SNP rs10848632 in CACNA1C with early-onset BD (P = .017), which did not remain significant after correction for multiple comparisons.ConclusionsThese preliminary analyses suggest that previously identified BD risk loci, especially CACNA1C, have a role in early-onset BD, possibly with stronger effects than for late-onset BD.

Dataset Information

Characterisation of age and polarity at onset in bipolar disorder.

Background

Aims

Method

Results

Conclusions

Publications

Characterisation of age and polarity at onset in bipolar disorder.

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