Characterization of Age and Polarity at Onset in Bipolar Disorder
Authors: Kalman Janos L. , Olde Loohuis Loes M. , Vreeker Annabel , McQuillin Andrew , Stahl Eli A. , Ruderfer Douglas , Grigoroiu-Serbanescu Maria , Panagiotaropoulou Georgia , Ripke Stephan , Bigdeli Tim B , Stein Frederike , Meller Tina , Meinert Susanne , Pelin Helena , Streit Fabian , Papiol Sergi , Adams Mark J , Adolfsson Rolf , Adorjan Kristina , Agartz Ingrid , Aminoff Sofie R. , Anderson-Schmidt Heike , Andreassen Ole A. , Ardau Raffaella , Aubry Jean-Michel , Balaban Ceylan , Bass Nicholas , Baune Bernhard T , Bellivier Frank , Benabarre Antonio , Bengesser Susanne , Berrettini Wade H , Boks Marco P. , Bromet Evelyn J , Brosch Katharina , Budde Monika , Byerley William , Cervantes Pablo , Chillotti Catina , Cichon Sven , Clark Scott R , Comes Ashley L. , Corvin Aiden , Coryell William , Craddock Nick , Craig David W. , Croarkin Paul E. , Cruceanu Cristiana , Czerski Piotr M. , Dalkner Nina , Dannlowski Udo , Degenhardt Franziska , DePaulo J. Raymond , Djurovic Srdjan , Edenberg Howard J. , Eissa Mariam Al , Elvsåshagen Torbjørn , Etain Bruno , Fanous Ayman H , Fellendorf Frederike , Fiorentino Alessia , Forstner Andreas J , Frye Mark A. , Fullerton Janice M. , Gade Katrin , Garnham Julie , George Kirov , Gershon Elliot , Gill Michael , Goes Fernando S. , Gordon-Smith Katherine , Grof Paul , Guzman-Parra Jose , Hahn Tim , Hake Maria , Hasler Roland , Heilbronner Urs , Jamain Stephane , Jimenez Esther , Jones Ian , Jones Lisa , Jonsson Lina , Kahn Rene S , Kelsoe John R. , Kennedy James L. , Kircher Tilo , Kittel-Schneider Sarah , Klöhn-Saghatolislam Farah , Knowles James A , Kranz Thorsten Manfred , Lagerberg Trine Vik , Landen Mikael , Lawson William B , Leboyer Marion , Li Qingqin S , Maj Mario , Malaspina Dolores , Manchia Mirko , Mayoral Fermin , McElroy Susan L , McInnis Melvin G , McIntosh Andrew M , Medeiros Helena , Melle Ingrid , Milanova Vihra , Mitchell Philip B. , Monteleone Palmiero , Monteleone Alessio Maria , Nöthen Markus M , Novak Tomas , Nurnberger John J , O’Brien Niamh , O’Connell Kevin S. , O’Donovan Claire , O’Donovan Michael C , Opel Nils , Ortiz Abigail , Owen Michael J , Pålsson Erik , Pato Carlos , Pato Michele T , Pawlak Joanna , Pfarr Julia-Katharina , Pisanu Claudia , Potash James B. , Rapaport Mark H , Reich-Erkelenz Daniela , Reif Andreas , Reininghaus Eva , Repple Jonathan , Richard-Lepouriel Helène , Rietschel Marcella , Ringwald Kai , Roberts Gloria , Rouleau Guy , Schaupp Sabrina , Scheftner William A , Schmitt Simon , Schofield Peter R. , Schubert K Oliver , Schulte Eva C. , Schweizer Barbara , Senner Fanny , Severino Giovanni , Sharp Sally , Slaney Claire , Smeland Olav B. , Sobell Janet L , Squassina Alessio , Stopkova Pavla , Strauss John , Tortorella Alfonso , Turecki Gustavo , Twarowska-Hauser Joanna , Veldic Marin , Vieta Eduard , Vincent John B. , Xu Wei , Zai Clement C. , Zandi Peter P. , Del Zompo Maria ,   Psychiatric Genomics Consortium (PGC) BD Working Group,   International Consortium on Lithium Genetics (ConLiGen),   Colombia-US Cross Disorder Collaboration in Psychiatric Genetics, Florio Arianna Di , Smoller Jordan W. , Biernacka Joanna M. , McMahon Francis J. , Alda Martin , Muller-Myhsok Bertram , Koutsouleris Nikolaos , Falkai Peter , Freimer Nelson B. , Andlauer Till F.M. , Schulze Thomas G , Ophoff Roel A. 
Published: April 2021

Background

Studying the phenotypic and genetic characteristics of age and polarity at onset (AAO, PAO) in bipolar disorder (BD) 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 BD disease characteristics.

Methods

Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (N=12977) and PAO (N=6773) were conducted in BD patients of 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 an increased risk of psychotic symptoms, suicidality, and fewer episodes. A depressive onset correlated with lifetime suicidality and a manic onset with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in SNV-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased polygenic scores for autism spectrum disorder (β=-0.34 years, SE=0.08), major depression (β=-0.34 years, SE=0.08), schizophrenia (β=-0.39 years, SE=0.08), and educational attainment (β=-0.31 years, SE=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 BD 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.

RELEVANCE STATEMENT

In the largest study to systematically characterize age at onset (N=12977) and polarity at onset (N=6773) in bipolar disorder, we describe an association between illness onset characteristics and indicators of severity, confirming their clinical relevance. Our study shows that that early illness onset is associated with genetic liability for a broad range of psychiatric disorders. However, we also highlight systematic differences in age at onset across cohorts, continents, and phenotype definitions. This heterogeneity results in reduced heritability and affects genetic analyses, underscoring the need for the development of standardized phenotype definitions.