High Loading of Polygenic Risk for ADHD in Children With Comorbid Aggression

Marian L Hamshere; Kate Langley; Joanna Martin; Sharifah Shameem Agha; Evangelia Stergiakouli; Richard J L Anney; Jan Buitelaar; Stephen V Faraone; Klaus-Peter Lesch; Benjamin M Neale; Barbara Franke; Edmund Sonuga-Barke; Philip Asherson; Andrew Merwood; Jonna Kuntsi; Sarah E Medland; Stephan Ripke; Hans-Christoph Steinhausen; Christine Freitag; Andreas Reif; Tobias J Renner; Marcel Romanos; Jasmin Romanos; Andreas Warnke; Jobst Meyer; Haukur Palmason; Alejandro Arias Vasquez; Nanda Lambregts-Rommelse; Herbert Roeyers; Joseph Biederman; Alysa E Doyle; Hakon Hakonarson; Aribert Rothenberger; Tobias Banaschewski; Robert D Oades; James J McGough; Lindsey Kent; Nigel Williams; Michael J Owen; Peter Holmans; Michael C O'Donovan; Anita Thapar

doi:10.1176/appi.ajp.2013.12081129

High Loading of Polygenic Risk for ADHD in Children With Comorbid Aggression

Marian L Hamshere, Kate Langley, Joanna Martin, Sharifah Shameem Agha, Evangelia Stergiakouli, Richard J L Anney, Jan Buitelaar, Stephen V Faraone, Klaus-Peter Lesch, Benjamin M Neale, Barbara Franke, Edmund Sonuga-Barke, Philip Asherson, Andrew Merwood, Jonna Kuntsi, Sarah E Medland, Stephan Ripke, Hans-Christoph Steinhausen, Christine Freitag, Andreas ReifTobias J Renner, Marcel Romanos, Jasmin Romanos, Andreas Warnke, Jobst Meyer, Haukur Palmason, Alejandro Arias Vasquez, Nanda Lambregts-Rommelse, Herbert Roeyers, Joseph Biederman, Alysa E Doyle, Hakon Hakonarson, Aribert Rothenberger, Tobias Banaschewski, Robert D Oades, James J McGough, Lindsey Kent, Nigel Williams, Michael J Owen, Peter Holmans, Michael C O'Donovan, Anita Thapar

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

113 Citations (Scopus)

Abstract

Objective: Although attention deficit hyperactivity disorder (ADHD) is highly heritable, genome-wide association studies (GWAS) have not yet identified any common genetic variants that contribute to risk. There is evidence that aggression or conduct disorder in children with ADHD indexes higher genetic loading and clinical severity. The authors examine whether common genetic variants considered en masse as polygenic scores for ADHD are especially enriched in children with comorbid conduct disorder.

Method: Polygenic scores derived from an ADHD GWAS meta-analysis were calculated in an independent ADHD sample (452 case subjects, 5,081 comparison subjects). Multivariate logistic regression analyses were employed to compare polygenic scores in the ADHD and comparison groups and test for higher scores in ADHD case subjects with comorbid conduct disorder relative to comparison subjects and relative to those without comorbid conduct disorder. Association with symptom scores was tested using linear regression.

Results: Polygenic risk for ADHD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group. Polygenic score was significantly higher in ADHD case subjects with conduct disorder relative to ADHD case subjects without conduct disorder. ADHD polygenic score showed significant association with comorbid conduct disorder symptoms. This relationship was explained by the aggression items.

Conclusions: Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression. The findings suggest that the previously published ADHD GWAS meta-analysis contains weak but true associations with common variants, support for which falls below genome-wide significance levels. The findings also highlight the fact that aggression in ADHD indexes genetic as well as clinical severity.

Original language	English
Journal	The American Journal of Psychiatry
DOIs	https://doi.org/10.1176/appi.ajp.2013.12081129
Publication status	E-pub ahead of print - 2013

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Hamshere, M. L., Langley, K., Martin, J., Agha, S. S., Stergiakouli, E., Anney, R. J. L., Buitelaar, J., Faraone, S. V., Lesch, K.-P., Neale, B. M., Franke, B., Sonuga-Barke, E., Asherson, P., Merwood, A., Kuntsi, J., Medland, S. E., Ripke, S., Steinhausen, H.-C., Freitag, C., ... Thapar, A. (2013). High Loading of Polygenic Risk for ADHD in Children With Comorbid Aggression. The American Journal of Psychiatry. Advance online publication. https://doi.org/10.1176/appi.ajp.2013.12081129

@article{e235d09c6a6a47b8a5808efefd990c5c,

title = "High Loading of Polygenic Risk for ADHD in Children With Comorbid Aggression",

abstract = "Objective: Although attention deficit hyperactivity disorder (ADHD) is highly heritable, genome-wide association studies (GWAS) have not yet identified any common genetic variants that contribute to risk. There is evidence that aggression or conduct disorder in children with ADHD indexes higher genetic loading and clinical severity. The authors examine whether common genetic variants considered en masse as polygenic scores for ADHD are especially enriched in children with comorbid conduct disorder.Method: Polygenic scores derived from an ADHD GWAS meta-analysis were calculated in an independent ADHD sample (452 case subjects, 5,081 comparison subjects). Multivariate logistic regression analyses were employed to compare polygenic scores in the ADHD and comparison groups and test for higher scores in ADHD case subjects with comorbid conduct disorder relative to comparison subjects and relative to those without comorbid conduct disorder. Association with symptom scores was tested using linear regression.Results: Polygenic risk for ADHD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group. Polygenic score was significantly higher in ADHD case subjects with conduct disorder relative to ADHD case subjects without conduct disorder. ADHD polygenic score showed significant association with comorbid conduct disorder symptoms. This relationship was explained by the aggression items.Conclusions: Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression. The findings suggest that the previously published ADHD GWAS meta-analysis contains weak but true associations with common variants, support for which falls below genome-wide significance levels. The findings also highlight the fact that aggression in ADHD indexes genetic as well as clinical severity.",

author = "Hamshere, {Marian L} and Kate Langley and Joanna Martin and Agha, {Sharifah Shameem} and Evangelia Stergiakouli and Anney, {Richard J L} and Jan Buitelaar and Faraone, {Stephen V} and Klaus-Peter Lesch and Neale, {Benjamin M} and Barbara Franke and Edmund Sonuga-Barke and Philip Asherson and Andrew Merwood and Jonna Kuntsi and Medland, {Sarah E} and Stephan Ripke and Hans-Christoph Steinhausen and Christine Freitag and Andreas Reif and Renner, {Tobias J} and Marcel Romanos and Jasmin Romanos and Andreas Warnke and Jobst Meyer and Haukur Palmason and Vasquez, {Alejandro Arias} and Nanda Lambregts-Rommelse and Herbert Roeyers and Joseph Biederman and Doyle, {Alysa E} and Hakon Hakonarson and Aribert Rothenberger and Tobias Banaschewski and Oades, {Robert D} and McGough, {James J} and Lindsey Kent and Nigel Williams and Owen, {Michael J} and Peter Holmans and O'Donovan, {Michael C} and Anita Thapar",

year = "2013",

doi = "10.1176/appi.ajp.2013.12081129",

language = "English",

journal = "The American Journal of Psychiatry",

issn = "0002-953X",

publisher = "American Psychiatric Publishing Inc.",

}

Hamshere, ML, Langley, K, Martin, J, Agha, SS, Stergiakouli, E, Anney, RJL, Buitelaar, J, Faraone, SV, Lesch, K-P, Neale, BM, Franke, B, Sonuga-Barke, E , Asherson, P , Merwood, A , Kuntsi, J, Medland, SE, Ripke, S, Steinhausen, H-C, Freitag, C, Reif, A, Renner, TJ, Romanos, M, Romanos, J, Warnke, A, Meyer, J, Palmason, H, Vasquez, AA, Lambregts-Rommelse, N, Roeyers, H, Biederman, J, Doyle, AE, Hakonarson, H, Rothenberger, A, Banaschewski, T, Oades, RD, McGough, JJ, Kent, L, Williams, N, Owen, MJ, Holmans, P, O'Donovan, MC & Thapar, A 2013, 'High Loading of Polygenic Risk for ADHD in Children With Comorbid Aggression', The American Journal of Psychiatry. https://doi.org/10.1176/appi.ajp.2013.12081129

TY - JOUR

T1 - High Loading of Polygenic Risk for ADHD in Children With Comorbid Aggression

AU - Hamshere, Marian L

AU - Langley, Kate

AU - Martin, Joanna

AU - Agha, Sharifah Shameem

AU - Stergiakouli, Evangelia

AU - Anney, Richard J L

AU - Buitelaar, Jan

AU - Faraone, Stephen V

AU - Lesch, Klaus-Peter

AU - Neale, Benjamin M

AU - Franke, Barbara

AU - Sonuga-Barke, Edmund

AU - Asherson, Philip

AU - Merwood, Andrew

AU - Kuntsi, Jonna

AU - Medland, Sarah E

AU - Ripke, Stephan

AU - Steinhausen, Hans-Christoph

AU - Freitag, Christine

AU - Reif, Andreas

AU - Renner, Tobias J

AU - Romanos, Marcel

AU - Romanos, Jasmin

AU - Warnke, Andreas

AU - Meyer, Jobst

AU - Palmason, Haukur

AU - Vasquez, Alejandro Arias

AU - Lambregts-Rommelse, Nanda

AU - Roeyers, Herbert

AU - Biederman, Joseph

AU - Doyle, Alysa E

AU - Hakonarson, Hakon

AU - Rothenberger, Aribert

AU - Banaschewski, Tobias

AU - Oades, Robert D

AU - McGough, James J

AU - Kent, Lindsey

AU - Williams, Nigel

AU - Owen, Michael J

AU - Holmans, Peter

AU - O'Donovan, Michael C

AU - Thapar, Anita

PY - 2013

Y1 - 2013

N2 - Objective: Although attention deficit hyperactivity disorder (ADHD) is highly heritable, genome-wide association studies (GWAS) have not yet identified any common genetic variants that contribute to risk. There is evidence that aggression or conduct disorder in children with ADHD indexes higher genetic loading and clinical severity. The authors examine whether common genetic variants considered en masse as polygenic scores for ADHD are especially enriched in children with comorbid conduct disorder.Method: Polygenic scores derived from an ADHD GWAS meta-analysis were calculated in an independent ADHD sample (452 case subjects, 5,081 comparison subjects). Multivariate logistic regression analyses were employed to compare polygenic scores in the ADHD and comparison groups and test for higher scores in ADHD case subjects with comorbid conduct disorder relative to comparison subjects and relative to those without comorbid conduct disorder. Association with symptom scores was tested using linear regression.Results: Polygenic risk for ADHD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group. Polygenic score was significantly higher in ADHD case subjects with conduct disorder relative to ADHD case subjects without conduct disorder. ADHD polygenic score showed significant association with comorbid conduct disorder symptoms. This relationship was explained by the aggression items.Conclusions: Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression. The findings suggest that the previously published ADHD GWAS meta-analysis contains weak but true associations with common variants, support for which falls below genome-wide significance levels. The findings also highlight the fact that aggression in ADHD indexes genetic as well as clinical severity.

AB - Objective: Although attention deficit hyperactivity disorder (ADHD) is highly heritable, genome-wide association studies (GWAS) have not yet identified any common genetic variants that contribute to risk. There is evidence that aggression or conduct disorder in children with ADHD indexes higher genetic loading and clinical severity. The authors examine whether common genetic variants considered en masse as polygenic scores for ADHD are especially enriched in children with comorbid conduct disorder.Method: Polygenic scores derived from an ADHD GWAS meta-analysis were calculated in an independent ADHD sample (452 case subjects, 5,081 comparison subjects). Multivariate logistic regression analyses were employed to compare polygenic scores in the ADHD and comparison groups and test for higher scores in ADHD case subjects with comorbid conduct disorder relative to comparison subjects and relative to those without comorbid conduct disorder. Association with symptom scores was tested using linear regression.Results: Polygenic risk for ADHD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group. Polygenic score was significantly higher in ADHD case subjects with conduct disorder relative to ADHD case subjects without conduct disorder. ADHD polygenic score showed significant association with comorbid conduct disorder symptoms. This relationship was explained by the aggression items.Conclusions: Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression. The findings suggest that the previously published ADHD GWAS meta-analysis contains weak but true associations with common variants, support for which falls below genome-wide significance levels. The findings also highlight the fact that aggression in ADHD indexes genetic as well as clinical severity.

U2 - 10.1176/appi.ajp.2013.12081129

DO - 10.1176/appi.ajp.2013.12081129

M3 - Article

C2 - 23599091

SN - 0002-953X

JO - The American Journal of Psychiatry

JF - The American Journal of Psychiatry

ER -

High Loading of Polygenic Risk for ADHD in Children With Comorbid Aggression

Abstract

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