Abstract
Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E–06), PCDH7 (P = 2.0E–06), and IPO13 (P = 2.5E–06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg = 0.46 between self- and teacher-assessment to rg = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range ∣ rg∣ : 0.19–1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg = ~−0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range ∣ rg∣ : 0.46–0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.
| Original language | English |
|---|---|
| Article number | 413 |
| Journal | Translational psychiatry |
| Volume | 11 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2021 |
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Genetic association study of childhood aggression across raters, instruments, and age. / Ip, Hill F.; van der Laan, Camiel M.; Krapohl, Eva M.L.; Brikell, Isabell; Sánchez-Mora, Cristina; Nolte, Ilja M.; St Pourcain, Beate; Bolhuis, Koen; Palviainen, Teemu; Zafarmand, Hadi; Colodro-Conde, Lucía; Gordon, Scott; Zayats, Tetyana; Aliev, Fazil; Jiang, Chang; Wang, Carol A.; Saunders, Gretchen; Karhunen, Ville; Hammerschlag, Anke R.; Adkins, Daniel E.; Border, Richard; Peterson, Roseann E.; Prinz, Joseph A.; Thiering, Elisabeth; Seppälä, Ilkka; Vilor-Tejedor, Natàlia; Ahluwalia, Tarunveer S.; Day, Felix R.; Hottenga, Jouke Jan; Allegrini, Andrea G.; Rimfeld, Kaili; Chen, Qi; Lu, Yi; Martin, Joanna; Soler Artigas, María; Rovira, Paula; Bosch, Rosa; Español, Gemma; Ramos Quiroga, Josep Antoni; Neumann, Alexander; Ensink, Judith; Grasby, Katrina; Morosoli, José J.; Tong, Xiaoran; Marrington, Shelby; Middeldorp, Christel; Scott, James G.; Vinkhuyzen, Anna; Shabalin, Andrey A.; Corley, Robin; Evans, Luke M.; Sugden, Karen; Alemany, Silvia; Sass, Lærke; Vinding, Rebecca; Ruth, Kate; Tyrrell, Jess; Davies, Gareth E.; Ehli, Erik A.; Hagenbeek, Fiona A.; De Zeeuw, Eveline; Van Beijsterveldt, Toos C.E.M.; Larsson, Henrik; Snieder, Harold; Verhulst, Frank C.; Amin, Najaf; Whipp, Alyce M.; Korhonen, Tellervo; Vuoksimaa, Eero; Rose, Richard J.; Uitterlinden, André G.; Heath, Andrew C.; Madden, Pamela; Haavik, Jan; Harris, Jennifer R.; Helgeland, Øyvind; Johansson, Stefan; Knudsen, Gun Peggy S.; Njolstad, Pal Rasmus; Lu, Qing; Rodriguez, Alina; Henders, Anjali K.; Mamun, Abdullah; Najman, Jackob M.; Brown, Sandy; Hopfer, Christian; Krauter, Kenneth; Reynolds, Chandra; Smolen, Andrew; Stallings, Michael; Wadsworth, Sally; Wall, Tamara L.; Silberg, Judy L.; Miller, Allison; Keltikangas-Järvinen, Liisa; Hakulinen, Christian; Pulkki-Råback, Laura; Havdahl, Alexandra; Magnus, Per; Raitakari, Olli T.; Perry, John R.B.; Llop, Sabrina; Lopez-Espinosa, Maria Jose; Bønnelykke, Klaus; Bisgaard, Hans; Sunyer, Jordi; Lehtimäki, Terho; Arseneault, Louise; Standl, Marie; Heinrich, Joachim; Boden, Joseph; Pearson, John; Horwood, L. John; Kennedy, Martin; Poulton, Richie; Eaves, Lindon J.; Maes, Hermine H.; Hewitt, John; Copeland, William E.; Costello, Elizabeth J.; Williams, Gail M.; Wray, Naomi; Järvelin, Marjo Riitta; McGue, Matt; Iacono, William; Caspi, Avshalom; Moffitt, Terrie E.; Whitehouse, Andrew; Pennell, Craig E.; Klump, Kelly L.; Burt, S. Alexandra; Dick, Danielle M.; Reichborn-Kjennerud, Ted; Martin, Nicholas G.; Medland, Sarah E.; Vrijkotte, Tanja; Kaprio, Jaakko; Tiemeier, Henning; Davey Smith, George; Hartman, Catharina A.; Oldehinkel, Albertine J.; Casas, Miquel; Ribasés, Marta; Lichtenstein, Paul; Lundström, Sebastian; Plomin, Robert; Bartels, Meike; Nivard, Michel G.; Boomsma, Dorret I.
In: Translational psychiatry, Vol. 11, No. 1, 413, 12.2021.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Genetic association study of childhood aggression across raters, instruments, and age
AU - Ip, Hill F.
AU - van der Laan, Camiel M.
AU - Krapohl, Eva M.L.
AU - Brikell, Isabell
AU - Sánchez-Mora, Cristina
AU - Nolte, Ilja M.
AU - St Pourcain, Beate
AU - Bolhuis, Koen
AU - Palviainen, Teemu
AU - Zafarmand, Hadi
AU - Colodro-Conde, Lucía
AU - Gordon, Scott
AU - Zayats, Tetyana
AU - Aliev, Fazil
AU - Jiang, Chang
AU - Wang, Carol A.
AU - Saunders, Gretchen
AU - Karhunen, Ville
AU - Hammerschlag, Anke R.
AU - Adkins, Daniel E.
AU - Border, Richard
AU - Peterson, Roseann E.
AU - Prinz, Joseph A.
AU - Thiering, Elisabeth
AU - Seppälä, Ilkka
AU - Vilor-Tejedor, Natàlia
AU - Ahluwalia, Tarunveer S.
AU - Day, Felix R.
AU - Hottenga, Jouke Jan
AU - Allegrini, Andrea G.
AU - Rimfeld, Kaili
AU - Chen, Qi
AU - Lu, Yi
AU - Martin, Joanna
AU - Soler Artigas, María
AU - Rovira, Paula
AU - Bosch, Rosa
AU - Español, Gemma
AU - Ramos Quiroga, Josep Antoni
AU - Neumann, Alexander
AU - Ensink, Judith
AU - Grasby, Katrina
AU - Morosoli, José J.
AU - Tong, Xiaoran
AU - Marrington, Shelby
AU - Middeldorp, Christel
AU - Scott, James G.
AU - Vinkhuyzen, Anna
AU - Shabalin, Andrey A.
AU - Corley, Robin
AU - Evans, Luke M.
AU - Sugden, Karen
AU - Alemany, Silvia
AU - Sass, Lærke
AU - Vinding, Rebecca
AU - Ruth, Kate
AU - Tyrrell, Jess
AU - Davies, Gareth E.
AU - Ehli, Erik A.
AU - Hagenbeek, Fiona A.
AU - De Zeeuw, Eveline
AU - Van Beijsterveldt, Toos C.E.M.
AU - Larsson, Henrik
AU - Snieder, Harold
AU - Verhulst, Frank C.
AU - Amin, Najaf
AU - Whipp, Alyce M.
AU - Korhonen, Tellervo
AU - Vuoksimaa, Eero
AU - Rose, Richard J.
AU - Uitterlinden, André G.
AU - Heath, Andrew C.
AU - Madden, Pamela
AU - Haavik, Jan
AU - Harris, Jennifer R.
AU - Helgeland, Øyvind
AU - Johansson, Stefan
AU - Knudsen, Gun Peggy S.
AU - Njolstad, Pal Rasmus
AU - Lu, Qing
AU - Rodriguez, Alina
AU - Henders, Anjali K.
AU - Mamun, Abdullah
AU - Najman, Jackob M.
AU - Brown, Sandy
AU - Hopfer, Christian
AU - Krauter, Kenneth
AU - Reynolds, Chandra
AU - Smolen, Andrew
AU - Stallings, Michael
AU - Wadsworth, Sally
AU - Wall, Tamara L.
AU - Silberg, Judy L.
AU - Miller, Allison
AU - Keltikangas-Järvinen, Liisa
AU - Hakulinen, Christian
AU - Pulkki-Råback, Laura
AU - Havdahl, Alexandra
AU - Magnus, Per
AU - Raitakari, Olli T.
AU - Perry, John R.B.
AU - Llop, Sabrina
AU - Lopez-Espinosa, Maria Jose
AU - Bønnelykke, Klaus
AU - Bisgaard, Hans
AU - Sunyer, Jordi
AU - Lehtimäki, Terho
AU - Arseneault, Louise
AU - Standl, Marie
AU - Heinrich, Joachim
AU - Boden, Joseph
AU - Pearson, John
AU - Horwood, L. John
AU - Kennedy, Martin
AU - Poulton, Richie
AU - Eaves, Lindon J.
AU - Maes, Hermine H.
AU - Hewitt, John
AU - Copeland, William E.
AU - Costello, Elizabeth J.
AU - Williams, Gail M.
AU - Wray, Naomi
AU - Järvelin, Marjo Riitta
AU - McGue, Matt
AU - Iacono, William
AU - Caspi, Avshalom
AU - Moffitt, Terrie E.
AU - Whitehouse, Andrew
AU - Pennell, Craig E.
AU - Klump, Kelly L.
AU - Burt, S. Alexandra
AU - Dick, Danielle M.
AU - Reichborn-Kjennerud, Ted
AU - Martin, Nicholas G.
AU - Medland, Sarah E.
AU - Vrijkotte, Tanja
AU - Kaprio, Jaakko
AU - Tiemeier, Henning
AU - Davey Smith, George
AU - Hartman, Catharina A.
AU - Oldehinkel, Albertine J.
AU - Casas, Miquel
AU - Ribasés, Marta
AU - Lichtenstein, Paul
AU - Lundström, Sebastian
AU - Plomin, Robert
AU - Bartels, Meike
AU - Nivard, Michel G.
AU - Boomsma, Dorret I.
N1 - Funding Information: MC has received travel grants and research support from Eli Lilly and Co., Janssen-Cilag, Shire, and Lundbeck and served as consultant for Eli Lilly and Co., Janssen-Cilag, Shire, and Lundbeck. JARQ was on the speakers’ bureau and/or acted as consultant Eli Lilly, Janssen-Cilag, Novartis, Shire, Lundbeck, Almirall, Braingaze, Sincrolab, Medicine, Exeltis, and Rubió in the last 5 years. He also received travel awards (air tickets + hotel) for taking part in psychiatric meetings from Janssen-Cilag, Rubió, Shire, Medice, and Eli-Lilly. The Department of Psychiatry chaired by him received unrestricted educational and research support from the following companies in the last 5 years: Eli-Lilly, Lundbeck, Janssen-Cilag, Actelion, Shire, Ferrer, Oryzon, Roche, Psious, and Rubió. Funding Information: We very warmly thank all participants, their parents, and teachers for making this study possible. The project was supported by the “Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies” project (ACTION). ACTION received funding from the European Union Seventh Framework Program (FP7/2007-2013) under grant agreement no 602768. Cohort-specific acknowledgements and funding information may be found in the Supplementary text. Publisher Copyright: © 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E–06), PCDH7 (P = 2.0E–06), and IPO13 (P = 2.5E–06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg = 0.46 between self- and teacher-assessment to rg = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range ∣ rg∣ : 0.19–1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg = ~−0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range ∣ rg∣ : 0.46–0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.
AB - Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E–06), PCDH7 (P = 2.0E–06), and IPO13 (P = 2.5E–06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg = 0.46 between self- and teacher-assessment to rg = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range ∣ rg∣ : 0.19–1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg = ~−0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range ∣ rg∣ : 0.46–0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.
UR - http://www.scopus.com/inward/record.url?scp=85111704583&partnerID=8YFLogxK
U2 - 10.1038/s41398-021-01480-x
DO - 10.1038/s41398-021-01480-x
M3 - Article
C2 - 34330890
AN - SCOPUS:85111704583
VL - 11
JO - Translational Psychiatry
JF - Translational Psychiatry
SN - 2158-3188
IS - 1
M1 - 413
ER -