1. Characterisation of age and polarity at onset in bipolar disorder.
- Author
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Kalman JL, Olde Loohuis LM, Vreeker A, McQuillin A, Stahl EA, Ruderfer D, Grigoroiu-Serbanescu M, Panagiotaropoulou G, Ripke S, Bigdeli TB, Stein F, Meller T, Meinert S, Pelin H, Streit F, Papiol S, Adams MJ, Adolfsson R, Adorjan K, Agartz I, Aminoff SR, Anderson-Schmidt H, Andreassen OA, Ardau R, Aubry JM, Balaban C, Bass N, Baune BT, Bellivier F, Benabarre A, Bengesser S, Berrettini WH, Boks MP, Bromet EJ, Brosch K, Budde M, Byerley W, Cervantes P, Chillotti C, Cichon S, Clark SR, Comes AL, Corvin A, Coryell W, Craddock N, Craig DW, Croarkin PE, Cruceanu C, Czerski PM, Dalkner N, Dannlowski U, Degenhardt F, Del Zompo M, DePaulo JR, Djurovic S, Edenberg HJ, Eissa MA, Elvsåshagen T, Etain B, Fanous AH, Fellendorf F, Fiorentino A, Forstner AJ, Frye MA, Fullerton JM, Gade K, Garnham J, Gershon E, Gill M, Goes FS, Gordon-Smith K, Grof P, Guzman-Parra J, Hahn T, Hasler R, Heilbronner M, Heilbronner U, Jamain S, Jimenez E, Jones I, Jones L, Jonsson L, Kahn RS, Kelsoe JR, Kennedy JL, Kircher T, Kirov G, Kittel-Schneider S, Klöhn-Saghatolislam F, Knowles JA, Kranz TM, Lagerberg TV, Landen M, Lawson WB, Leboyer M, Li QS, Maj M, Malaspina D, Manchia M, Mayoral F, McElroy SL, McInnis MG, McIntosh AM, Medeiros H, Melle I, Milanova V, Mitchell PB, Monteleone P, Monteleone AM, Nöthen MM, Novak T, Nurnberger JI, O'Brien N, O'Connell KS, O'Donovan C, O'Donovan MC, Opel N, Ortiz A, Owen MJ, Pålsson E, Pato C, Pato MT, Pawlak J, Pfarr JK, Pisanu C, Potash JB, Rapaport MH, Reich-Erkelenz D, Reif A, Reininghaus E, Repple J, Richard-Lepouriel H, Rietschel M, Ringwald K, Roberts G, Rouleau G, Schaupp S, Scheftner WA, Schmitt S, Schofield PR, Schubert KO, Schulte EC, Schweizer B, Senner F, Severino G, Sharp S, Slaney C, Smeland OB, Sobell JL, Squassina A, Stopkova P, Strauss J, Tortorella A, Turecki G, Twarowska-Hauser J, Veldic M, Vieta E, Vincent JB, Xu W, Zai CC, Zandi PP, Di Florio A, Smoller JW, Biernacka JM, McMahon FJ, Alda M, Müller-Myhsok B, Koutsouleris N, Falkai P, Freimer NB, Andlauer TFM, Schulze TG, and Ophoff RA
- Subjects
- Age of Onset, Genome-Wide Association Study, Humans, Multifactorial Inheritance, Autism Spectrum Disorder, Bipolar Disorder diagnosis, Bipolar Disorder epidemiology, Bipolar Disorder genetics, Depressive Disorder, Major genetics
- 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.
- Published
- 2021
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