Investigating polygenic burden in age at disease onset in bipolar disorder. Findings from an international multicentric study

TY - JOUR

T1 - Investigating polygenic burden in age at disease onset in bipolar disorder. Findings from an international multicentric study

AU - Kalman, Janos L

AU - Papiol, Sergi

AU - Forstner, Andreas J

AU - Heilbronner, Urs

AU - Degenhardt, Franziska

AU - Strohmaier, Jana

AU - Adli, Mazda

AU - Adorjan, Kristina

AU - Akula, Nirmala

AU - Alda, Martin

AU - Anderson-Schmidt, Heike

AU - Andlauer, Till Fm

AU - Anghelescu, Ion-George

AU - Ardau, Raffaella

AU - Arias, Bárbara

AU - Arolt, Volker

AU - Aubry, Jean-Michel

AU - Backlund, Lena

AU - Bartholdi, Kim

AU - Bauer, Michael

AU - Baune, Bernhard T

AU - Becker, Thomas

AU - Bellivier, Frank

AU - Benabarre, Antonio

AU - Bengesser, Susanne

AU - Bhattacharjee, Abesh Kumar

AU - Biernacka, Joanna M

AU - Birner, Armin

AU - Brichant-Petitjean, Clara

AU - Budde, Monika

AU - Cervantes, Pablo

AU - Chillotti, Caterina

AU - Cichon, Sven

AU - Clark, Scott R

AU - Colom, Francesc

AU - Comes, Ashley L

AU - Cruceanu, Cristiana

AU - Czerski, Piotr M

AU - Dannlowski, Udo

AU - Dayer, Alexandre

AU - Del Zompo, Maria

AU - DePaulo, Jay Raymond

AU - Dietrich, Detlef E

AU - Étain, Bruno

AU - Ethofer, Thomas

AU - Falkai, Peter

AU - Fallgatter, Andreas

AU - Figge, Christian

AU - Flatau, Laura

AU - Folkerts, Here

AU - Frisen, Louise

AU - Frye, Mark A

AU - Fullerton, Janice M

AU - Gade, Katrin

AU - Gard, Sébastien

AU - Garnham, Julie S

AU - Goes, Fernando S

AU - Grigoroiu-Serbanescu, Maria

AU - Gryaznova, Anna

AU - Hake, Maria

AU - Hauser, Joanna

AU - Herms, Stefan

AU - Hoffmann, Per

AU - Hou, Liping

AU - Jäger, Markus

AU - Jamain, Stephane

AU - Jiménez, Esther

AU - Juckel, Georg

AU - Kahn, Jean-Pierre

AU - Kassem, Layla

AU - Kelsoe, John

AU - Kittel-Schneider, Sarah

AU - Kliwicki, Sebastian

AU - Klohn-Sagatholislam, Farah

AU - Koller, Manfred

AU - König, Barbara

AU - Konrad, Carsten

AU - Lackner, Nina

AU - Laje, Gonzalo

AU - Landén, Mikael

AU - Lang, Fabian U

AU - Lavebratt, Catharina

AU - Leboyer, Marion

AU - Leckband, Susan G

AU - Maj, Mario

AU - Manchia, Mirko

AU - Martinsson, Lina

AU - McCarthy, Michael J

AU - McElroy, Susan L

AU - McMahon, Francis J

AU - Mitchell, Philip B

AU - Mitjans, Marina

AU - Mondimore, Francis M

AU - Monteleone, Palmiero

AU - Nieratschker, Vanessa

AU - Nievergelt, Caroline M

AU - Novák, Tomas

AU - Ösby, Urban

AU - Pfennig, Andrea

AU - Potash, James B

AU - Reich-Erkelenz, Daniela

AU - Reif, Andreas

AU - Reimer, Jens

AU - Reininghaus, Eva

AU - Reitt, Markus

AU - Ripke, Stephan

AU - Rouleau, Guy A

AU - Rybakowski, Janusz K

AU - Schalling, Martin

AU - Scherk, Harald

AU - Schmauß, Max

AU - Schofield, Peter R

AU - Schubert, K Oliver

AU - Schulte, Eva C

AU - Schulz, Sybille

AU - Senner, Fanny

AU - Severino, Giovanni

AU - Shekhtman, Tatyana

AU - Shilling, Paul D

AU - Simhandl, Christian

AU - Slaney, Claire M

AU - Spitzer, Carsten

AU - Squassina, Alessio

AU - Stamm, Thomas

AU - Stegmaier, Sophia

AU - Stierl, Sebastian

AU - Stopkova, Pavla

AU - Thiel, Andreas

AU - Tighe, Sarah K

AU - Tortorella, Alfonso

AU - Turecki, Gustavo

AU - Vieta, Eduard

AU - Veeh, Julia

AU - von Hagen, Martin

AU - Wigand, Moritz E

AU - Wiltfang, Jens

AU - Witt, Stephanie

AU - Wright, Adam

AU - Zandi, Peter P

AU - Zimmermann, Jörg

AU - Nöthen, Markus

AU - Rietschel, Marcella

AU - Schulze, Thomas G

N1 - © 2018 The Authors. Bipolar Disorders Published by John Wiley & Sons Ltd.

PY - 2019/2

Y1 - 2019/2

N2 - OBJECTIVES: Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients.METHODS: A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models.RESULTS: BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment.CONCLUSIONS: The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.

AB - OBJECTIVES: Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients.METHODS: A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models.RESULTS: BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment.CONCLUSIONS: The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.

KW - Adolescent

KW - Adult

KW - Age Factors

KW - Bipolar Disorder/genetics

KW - Child

KW - Female

KW - Humans

KW - Male

KW - Middle Aged

KW - Multifactorial Inheritance

KW - Phenotype

KW - Schizophrenia/genetics

U2 - 10.1111/bdi.12659

DO - 10.1111/bdi.12659

M3 - SCORING: Journal article

C2 - 29956436

VL - 21

SP - 68

EP - 75

JO - BIPOLAR DISORD

JF - BIPOLAR DISORD

SN - 1398-5647

IS - 1

ER -