Genetic association study of childhood aggression across raters, instruments, and age

Hill F. Ip; Camiel M. van der Laan; Eva M.L. Krapohl; Isabell Brikell; Cristina Sánchez-Mora; Ilja M. Nolte; Beate St Pourcain; Koen Bolhuis; Teemu Palviainen; Hadi Zafarmand; Lucía Colodro-Conde; Scott Gordon; Tetyana Zayats; Fazil Aliev; Chang Jiang; Carol A. Wang; Gretchen Saunders; Ville Karhunen; Anke R. Hammerschlag; Daniel E. Adkins; Richard Border; Roseann E. Peterson; Joseph A. Prinz; Elisabeth Thiering; Ilkka Seppälä; Natàlia Vilor-Tejedor; Tarunveer S. Ahluwalia; Felix R. Day; Jouke Jan Hottenga; Andrea G. Allegrini; Kaili Rimfeld; Qi Chen; Yi Lu; Joanna Martin; María Soler Artigas; Paula Rovira; Rosa Bosch; Gemma Español; Josep Antoni Ramos Quiroga; Alexander Neumann; Judith Ensink; Katrina Grasby; José J. Morosoli; Xiaoran Tong; Shelby Marrington; Christel Middeldorp; James G. Scott; Anna Vinkhuyzen; Andrey A. Shabalin; Robin Corley; Luke M. Evans; Karen Sugden; Silvia Alemany; Lærke Sass; Rebecca Vinding; Kate Ruth; Jess Tyrrell; Gareth E. Davies; Erik A. Ehli; Fiona A. Hagenbeek; Eveline De Zeeuw; Toos C.E.M. Van Beijsterveldt; Henrik Larsson; Harold Snieder; Frank C. Verhulst; Najaf Amin; Alyce M. Whipp; Tellervo Korhonen; Eero Vuoksimaa; Richard J. Rose; André G. Uitterlinden; Andrew C. Heath; Pamela Madden; Jan Haavik; Jennifer R. Harris; Øyvind Helgeland; Stefan Johansson; Gun Peggy S. Knudsen; Pal Rasmus Njolstad; Qing Lu; Alina Rodriguez; Anjali K. Henders; Abdullah Mamun; Jackob M. Najman; Sandy Brown; Christian Hopfer; Kenneth Krauter; Chandra Reynolds; Andrew Smolen; Michael Stallings; Sally Wadsworth; Tamara L. Wall; Judy L. Silberg; Allison Miller; Liisa Keltikangas-Järvinen; Christian Hakulinen; Laura Pulkki-Råback; Alexandra Havdahl; Per Magnus; Olli T. Raitakari; John R.B. Perry; Sabrina Llop; Maria Jose Lopez-Espinosa; Klaus Bønnelykke; Hans Bisgaard; Jordi Sunyer; Terho Lehtimäki; Louise Arseneault; Marie Standl; Joachim Heinrich; Joseph Boden; John Pearson; L. John Horwood; Martin Kennedy; Richie Poulton; Lindon J. Eaves; Hermine H. Maes; John Hewitt; William E. Copeland; Elizabeth J. Costello; Gail M. Williams; Naomi Wray; Marjo Riitta Järvelin; Matt McGue; William Iacono; Avshalom Caspi; Terrie E. Moffitt; Andrew Whitehouse; Craig E. Pennell; Kelly L. Klump; S. Alexandra Burt; Danielle M. Dick; Ted Reichborn-Kjennerud; Nicholas G. Martin; Sarah E. Medland; Tanja Vrijkotte; Jaakko Kaprio; Henning Tiemeier; George Davey Smith; Catharina A. Hartman; Albertine J. Oldehinkel; Miquel Casas; Marta Ribasés; Paul Lichtenstein; Sebastian Lundström; Robert Plomin; Meike Bartels; Michel G. Nivard; Dorret I. Boomsma

doi:10.1038/s41398-021-01480-x

Genetic association study of childhood aggression across raters, instruments, and age

Hill F. Ip, Camiel M. van der Laan, Eva M.L. Krapohl, Isabell Brikell, Cristina Sánchez-Mora, Ilja M. Nolte, Beate St Pourcain, Koen Bolhuis, Teemu Palviainen, Hadi Zafarmand, Lucía Colodro-Conde, Scott Gordon, Tetyana Zayats, Fazil Aliev, Chang Jiang, Carol A. Wang, Gretchen Saunders, Ville Karhunen, Anke R. Hammerschlag, Daniel E. AdkinsRichard Border, Roseann E. Peterson, Joseph A. Prinz, Elisabeth Thiering, Ilkka Seppälä, Natàlia Vilor-Tejedor, Tarunveer S. Ahluwalia, Felix R. Day, Jouke Jan Hottenga, Andrea G. Allegrini, Kaili Rimfeld, Qi Chen, Yi Lu, Joanna Martin, María Soler Artigas, Paula Rovira, Rosa Bosch, Gemma Español, Josep Antoni Ramos Quiroga, Alexander Neumann, Judith Ensink, Katrina Grasby, José J. Morosoli, Xiaoran Tong, Shelby Marrington, Christel Middeldorp, James G. Scott, Anna Vinkhuyzen, Andrey A. Shabalin, Robin Corley, Luke M. Evans, Karen Sugden, Silvia Alemany, Lærke Sass, Rebecca Vinding, Kate Ruth, Jess Tyrrell, Gareth E. Davies, Erik A. Ehli, Fiona A. Hagenbeek, Eveline De Zeeuw, Toos C.E.M. Van Beijsterveldt, Henrik Larsson, Harold Snieder, Frank C. Verhulst, Najaf Amin, Alyce M. Whipp, Tellervo Korhonen, Eero Vuoksimaa, Richard J. Rose, André G. Uitterlinden, Andrew C. Heath, Pamela Madden, Jan Haavik, Jennifer R. Harris, Øyvind Helgeland, Stefan Johansson, Gun Peggy S. Knudsen, Pal Rasmus Njolstad, Qing Lu, Alina Rodriguez, Anjali K. Henders, Abdullah Mamun, Jackob M. Najman, Sandy Brown, Christian Hopfer, Kenneth Krauter, Chandra Reynolds, Andrew Smolen, Michael Stallings, Sally Wadsworth, Tamara L. Wall, Judy L. Silberg, Allison Miller, Liisa Keltikangas-Järvinen, Christian Hakulinen, Laura Pulkki-Råback, Alexandra Havdahl, Per Magnus, Olli T. Raitakari, John R.B. Perry, Sabrina Llop, Maria Jose Lopez-Espinosa, Klaus Bønnelykke, Hans Bisgaard, Jordi Sunyer, Terho Lehtimäki, Louise Arseneault, Marie Standl, Joachim Heinrich, Joseph Boden, John Pearson, L. John Horwood, Martin Kennedy, Richie Poulton, Lindon J. Eaves, Hermine H. Maes, John Hewitt, William E. Copeland, Elizabeth J. Costello, Gail M. Williams, Naomi Wray, Marjo Riitta Järvelin, Matt McGue, William Iacono, Avshalom Caspi, Terrie E. Moffitt, Andrew Whitehouse, Craig E. Pennell, Kelly L. Klump, S. Alexandra Burt, Danielle M. Dick, Ted Reichborn-Kjennerud, Nicholas G. Martin, Sarah E. Medland, Tanja Vrijkotte, Jaakko Kaprio, Henning Tiemeier, George Davey Smith, Catharina A. Hartman, Albertine J. Oldehinkel, Miquel Casas, Marta Ribasés, Paul Lichtenstein, Sebastian Lundström, Robert Plomin, Meike Bartels, Michel G. Nivard, Dorret I. Boomsma

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

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 (AGG_overall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGG_overall. 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 (r_g) among rater-specific assessment of AGG ranged from r_g = 0.46 between self- and teacher-assessment to r_g = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong r_gs 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 ∣ r_g∣ : 0.19–1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (r_g = ~−0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range ∣ r_g∣ : 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	https://doi.org/10.1038/s41398-021-01480-x
State	Published - Dec 2021

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10.1038/s41398-021-01480-x

Cite this

Ip, H. F., van der Laan, C. M., Krapohl, E. M. L., Brikell, I., Sánchez-Mora, C., Nolte, I. M., St Pourcain, B., Bolhuis, K., Palviainen, T., Zafarmand, H., Colodro-Conde, L., Gordon, S., Zayats, T., Aliev, F., Jiang, C., Wang, C. A., Saunders, G., Karhunen, V., Hammerschlag, A. R., ... Boomsma, D. I. (2021). Genetic association study of childhood aggression across raters, instruments, and age. Translational psychiatry, 11(1), [413]. https://doi.org/10.1038/s41398-021-01480-x

@article{6ae2245133e94e8581dacad46037d0cb,

title = "Genetic association study of childhood aggression across raters, instruments, and age",

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.",

author = "Ip, {Hill F.} and {van der Laan}, {Camiel M.} and Krapohl, {Eva M.L.} and Isabell Brikell and Cristina S{\'a}nchez-Mora and Nolte, {Ilja M.} and {St Pourcain}, Beate and Koen Bolhuis and Teemu Palviainen and Hadi Zafarmand and Luc{\'i}a Colodro-Conde and Scott Gordon and Tetyana Zayats and Fazil Aliev and Chang Jiang and Wang, {Carol A.} and Gretchen Saunders and Ville Karhunen and Hammerschlag, {Anke R.} and Adkins, {Daniel E.} and Richard Border and Peterson, {Roseann E.} and Prinz, {Joseph A.} and Elisabeth Thiering and Ilkka Sepp{\"a}l{\"a} and Nat{\`a}lia Vilor-Tejedor and Ahluwalia, {Tarunveer S.} and Day, {Felix R.} and Hottenga, {Jouke Jan} and Allegrini, {Andrea G.} and Kaili Rimfeld and Qi Chen and Yi Lu and Joanna Martin and {Soler Artigas}, Mar{\'i}a and Paula Rovira and Rosa Bosch and Gemma Espa{\~n}ol and {Ramos Quiroga}, {Josep Antoni} and Alexander Neumann and Judith Ensink and Katrina Grasby and Morosoli, {Jos{\'e} J.} and Xiaoran Tong and Shelby Marrington and Christel Middeldorp and Scott, {James G.} and Anna Vinkhuyzen and Shabalin, {Andrey A.} and Robin Corley and Evans, {Luke M.} and Karen Sugden and Silvia Alemany and L{\ae}rke Sass and Rebecca Vinding and Kate Ruth and Jess Tyrrell and Davies, {Gareth E.} and Ehli, {Erik A.} and Hagenbeek, {Fiona A.} and {De Zeeuw}, Eveline and {Van Beijsterveldt}, {Toos C.E.M.} and Henrik Larsson and Harold Snieder and Verhulst, {Frank C.} and Najaf Amin and Whipp, {Alyce M.} and Tellervo Korhonen and Eero Vuoksimaa and Rose, {Richard J.} and Uitterlinden, {Andr{\'e} G.} and Heath, {Andrew C.} and Pamela Madden and Jan Haavik and Harris, {Jennifer R.} and {\O}yvind Helgeland and Stefan Johansson and Knudsen, {Gun Peggy S.} and Njolstad, {Pal Rasmus} and Qing Lu and Alina Rodriguez and Henders, {Anjali K.} and Abdullah Mamun and Najman, {Jackob M.} and Sandy Brown and Christian Hopfer and Kenneth Krauter and Chandra Reynolds and Andrew Smolen and Michael Stallings and Sally Wadsworth and Wall, {Tamara L.} and Silberg, {Judy L.} and Allison Miller and Liisa Keltikangas-J{\"a}rvinen and Christian Hakulinen and Laura Pulkki-R{\aa}back and Alexandra Havdahl and Per Magnus and Raitakari, {Olli T.} and Perry, {John R.B.} and Sabrina Llop and Lopez-Espinosa, {Maria Jose} and Klaus B{\o}nnelykke and Hans Bisgaard and Jordi Sunyer and Terho Lehtim{\"a}ki and Louise Arseneault and Marie Standl and Joachim Heinrich and Joseph Boden and John Pearson and Horwood, {L. John} and Martin Kennedy and Richie Poulton and Eaves, {Lindon J.} and Maes, {Hermine H.} and John Hewitt and Copeland, {William E.} and Costello, {Elizabeth J.} and Williams, {Gail M.} and Naomi Wray and J{\"a}rvelin, {Marjo Riitta} and Matt McGue and William Iacono and Avshalom Caspi and Moffitt, {Terrie E.} and Andrew Whitehouse and Pennell, {Craig E.} and Klump, {Kelly L.} and Burt, {S. Alexandra} and Dick, {Danielle M.} and Ted Reichborn-Kjennerud and Martin, {Nicholas G.} and Medland, {Sarah E.} and Tanja Vrijkotte and Jaakko Kaprio and Henning Tiemeier and {Davey Smith}, George and Hartman, {Catharina A.} and Oldehinkel, {Albertine J.} and Miquel Casas and Marta Ribas{\'e}s and Paul Lichtenstein and Sebastian Lundstr{\"o}m and Robert Plomin and Meike Bartels and Nivard, {Michel G.} and Boomsma, {Dorret I.}",

note = "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{\textquoteright} bureau and/or acted as consultant Eli Lilly, Janssen-Cilag, Novartis, Shire, Lundbeck, Almirall, Braingaze, Sincrolab, Medicine, Exeltis, and Rubi{\'o} in the last 5 years. He also received travel awards (air tickets + hotel) for taking part in psychiatric meetings from Janssen-Cilag, Rubi{\'o}, 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 Rubi{\'o}. 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: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1038/s41398-021-01480-x",

language = "English",

volume = "11",

journal = "Translational Psychiatry",

issn = "2158-3188",

number = "1",

}

Ip, HF, van der Laan, CM, Krapohl, EML, Brikell, I, Sánchez-Mora, C, Nolte, IM, St Pourcain, B, Bolhuis, K, Palviainen, T, Zafarmand, H, Colodro-Conde, L, Gordon, S, Zayats, T, Aliev, F, Jiang, C, Wang, CA, Saunders, G, Karhunen, V, Hammerschlag, AR, Adkins, DE, Border, R, Peterson, RE, Prinz, JA, Thiering, E, Seppälä, I, Vilor-Tejedor, N, Ahluwalia, TS, Day, FR, Hottenga, JJ, Allegrini, AG, Rimfeld, K, Chen, Q, Lu, Y, Martin, J, Soler Artigas, M, Rovira, P, Bosch, R, Español, G, Ramos Quiroga, JA, Neumann, A, Ensink, J, Grasby, K, Morosoli, JJ, Tong, X, Marrington, S, Middeldorp, C, Scott, JG, Vinkhuyzen, A, Shabalin, AA, Corley, R, Evans, LM, Sugden, K, Alemany, S, Sass, L, Vinding, R, Ruth, K, Tyrrell, J, Davies, GE, Ehli, EA, Hagenbeek, FA, De Zeeuw, E, Van Beijsterveldt, TCEM, Larsson, H, Snieder, H, Verhulst, FC, Amin, N, Whipp, AM, Korhonen, T, Vuoksimaa, E, Rose, RJ, Uitterlinden, AG, Heath, AC , Madden, P, Haavik, J, Harris, JR, Helgeland, Ø, Johansson, S, Knudsen, GPS, Njolstad, PR, Lu, Q, Rodriguez, A, Henders, AK, Mamun, A, Najman, JM, Brown, S, Hopfer, C, Krauter, K, Reynolds, C, Smolen, A, Stallings, M, Wadsworth, S, Wall, TL, Silberg, JL, Miller, A, Keltikangas-Järvinen, L, Hakulinen, C, Pulkki-Råback, L, Havdahl, A, Magnus, P, Raitakari, OT, Perry, JRB, Llop, S, Lopez-Espinosa, MJ, Bønnelykke, K, Bisgaard, H, Sunyer, J, Lehtimäki, T, Arseneault, L, Standl, M, Heinrich, J, Boden, J, Pearson, J, Horwood, LJ, Kennedy, M, Poulton, R, Eaves, LJ, Maes, HH, Hewitt, J, Copeland, WE, Costello, EJ, Williams, GM, Wray, N, Järvelin, MR, McGue, M, Iacono, W, Caspi, A, Moffitt, TE, Whitehouse, A, Pennell, CE, Klump, KL, Burt, SA, Dick, DM, Reichborn-Kjennerud, T, Martin, NG, Medland, SE, Vrijkotte, T, Kaprio, J, Tiemeier, H, Davey Smith, G, Hartman, CA, Oldehinkel, AJ, Casas, M, Ribasés, M, Lichtenstein, P, Lundström, S, Plomin, R, Bartels, M, Nivard, MG & Boomsma, DI 2021, 'Genetic association study of childhood aggression across raters, instruments, and age', Translational psychiatry, vol. 11, no. 1, 413. https://doi.org/10.1038/s41398-021-01480-x

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 -

Genetic association study of childhood aggression across raters, instruments, and age

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