Risk variants and polygenic architecture of disruptive behavior disorders in the context of attention-deficit/hyperactivity disorder

Ditte Demontis; Raymond K. Walters; Veera M. Rajagopal; Irwin D. Waldman; Jakob Grove; Thomas D. Als; Søren Dalsgaard; Marta Ribasas; Jonas Bybjerg-Grauholm; Maria Bækvad-Hansen; Thomas Werge; Merete Nordentoft; Ole Mors; Preben Bo Mortensen; ADHD Working Group of the Psychiatric Genomics Consortium (PGC); Ole A. Andreassen; Maria Jesús Arranz; Tobias Banaschewski; Claiton Bau; Mark Bellgrove; Joseph Biederman; Isabell Brikell; Jan K. Buitelaar; Christie L. Burton; Miguel Casas; Jennifer Crosbie; Alysa E. Doyle; Richard P. Ebstein; Josephine Elia; Corfield C. Elizabeth; Eugenio Grevet; Natalie Grizenko; Alexandra Havdahl; Ziarih Hawi; Johannes Hebebrand; Amaia Hervas; Sarah Hohmann; Jan Haavik; Ridha Joober; Lindsey Kent; Jonna Kuntsi; Kate Langley; Henrik Larsson; Klaus-Peter Lesch; Patrick W. L. Leung; Calwing Liao; Sandra K. Loo; Joanna Martin; Nicholas G. Martin; Sarah E. Medland; Ana Miranda; Nina Roth Mota; Robert D. Oades; Josep Antoni Ramos-Quiroga; Andreas Reif; Marcella Rietschel; Herbert Roeyers; Luis Augusto Rohde; Aribert Rothenberger; Paula Rovira; Cristina Sánchez-Mora; Russell James Schachar; Sarojini Sengupta; Maria Soler Artigas; Hans-Christoph Steinhausen; Anita Thapar; Stephanie H. Witt; Li Yang; Tetyana Zayats; Yanli Zhang-James; Bru Cormand; David M. Hougaard; Benjamin M. Neale; Barbara Franke; Stephen V. Faraone; Anders D. Børglum

doi:10.1038/s41467-020-20443-2

Risk variants and polygenic architecture of disruptive behavior disorders in the context of attention-deficit/hyperactivity disorder

Ditte Demontis, Raymond K. Walters, Veera M. Rajagopal, Irwin D. Waldman, Jakob Grove, Thomas D. Als, Søren Dalsgaard, Marta Ribasas, Jonas Bybjerg-Grauholm, Maria Bækvad-Hansen, Thomas Werge, Merete Nordentoft, Ole Mors, Preben Bo Mortensen, ADHD Working Group of the Psychiatric Genomics Consortium (PGC), Ole A. Andreassen, Maria Jesús Arranz, Tobias Banaschewski, Claiton Bau, Mark BellgroveJoseph Biederman, Isabell Brikell, Jan K. Buitelaar, Christie L. Burton, Miguel Casas, Jennifer Crosbie, Alysa E. Doyle, Richard P. Ebstein, Josephine Elia, Corfield C. Elizabeth, Eugenio Grevet, Natalie Grizenko, Alexandra Havdahl, Ziarih Hawi, Johannes Hebebrand, Amaia Hervas, Sarah Hohmann, Jan Haavik, Ridha Joober, Lindsey Kent, Jonna Kuntsi, Kate Langley, Henrik Larsson, Klaus-Peter Lesch, Patrick W. L. Leung, Calwing Liao, Sandra K. Loo, Joanna Martin, Nicholas G. Martin, Sarah E. Medland, Ana Miranda, Nina Roth Mota, Robert D. Oades, Josep Antoni Ramos-Quiroga, Andreas Reif, Marcella Rietschel, Herbert Roeyers, Luis Augusto Rohde, Aribert Rothenberger, Paula Rovira, Cristina Sánchez-Mora, Russell James Schachar, Sarojini Sengupta, Maria Soler Artigas, Hans-Christoph Steinhausen, Anita Thapar, Stephanie H. Witt, Li Yang, Tetyana Zayats, Yanli Zhang-James, Bru Cormand, David M. Hougaard, Benjamin M. Neale, Barbara Franke, Stephen V. Faraone, Anders D. Børglum

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Abstract

Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). Here, we report a GWAS meta-analysis of ADHD comorbid with DBDs (ADHD + DBDs) including 3802 cases and 31,305 controls. We identify three genome-wide significant loci on chromosomes 1, 7, and 11. A meta-analysis including a Chinese cohort supports that the locus on chromosome 11 is a strong risk locus for ADHD + DBDs across European and Chinese ancestries (rs7118422, P = 3.15×10⁻¹⁰, OR = 1.17). We find a higher SNP heritability for ADHD + DBDs (h²_SNP = 0.34) when compared to ADHD without DBDs (h²_SNP= 0.20), high genetic correlations between ADHD + DBDs and aggressive (r_g = 0.81) and anti-social behaviors (r_g = 0.82), and an increased burden (polygenic score) of variants associated with ADHD and aggression in ADHD + DBDs compared to ADHD without DBDs. Our results suggest an increased load of common risk variants in ADHD + DBDs compared to ADHD without DBDs, which in part can be explained by variants associated with aggressive behavior.

Original language	English
Article number	576
Number of pages	12
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-20443-2
Publication status	Published - 25 Jan 2021

Keywords

ADHD
Genome-wide association studies

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Demontis, D., Walters, R. K., Rajagopal, V. M., Waldman, I. D., Grove, J., Als, T. D., Dalsgaard, S., Ribasas, M., Bybjerg-Grauholm, J., Bækvad-Hansen, M., Werge, T., Nordentoft, M., Mors, O., Mortensen, P. B., (PGC), ADHD. W. G. O. T. P. G. C., Andreassen, O. A., Arranz, M. J., Banaschewski, T., Bau, C., ... Børglum, A. D. (2021). Risk variants and polygenic architecture of disruptive behavior disorders in the context of attention-deficit/hyperactivity disorder. Nature Communications, 12(1), Article 576 . https://doi.org/10.1038/s41467-020-20443-2

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abstract = "Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). Here, we report a GWAS meta-analysis of ADHD comorbid with DBDs (ADHD + DBDs) including 3802 cases and 31,305 controls. We identify three genome-wide significant loci on chromosomes 1, 7, and 11. A meta-analysis including a Chinese cohort supports that the locus on chromosome 11 is a strong risk locus for ADHD + DBDs across European and Chinese ancestries (rs7118422, P = 3.15×10−10, OR = 1.17). We find a higher SNP heritability for ADHD + DBDs (h2SNP = 0.34) when compared to ADHD without DBDs (h2SNP = 0.20), high genetic correlations between ADHD + DBDs and aggressive (rg = 0.81) and anti-social behaviors (rg = 0.82), and an increased burden (polygenic score) of variants associated with ADHD and aggression in ADHD + DBDs compared to ADHD without DBDs. Our results suggest an increased load of common risk variants in ADHD + DBDs compared to ADHD without DBDs, which in part can be explained by variants associated with aggressive behavior.",

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Demontis, D, Walters, RK, Rajagopal, VM, Waldman, ID, Grove, J, Als, TD, Dalsgaard, S, Ribasas, M, Bybjerg-Grauholm, J, Bækvad-Hansen, M, Werge, T, Nordentoft, M, Mors, O, Mortensen, PB, (PGC), ADHDWGOTPGC, Andreassen, OA, Arranz, MJ, Banaschewski, T, Bau, C, Bellgrove, M, Biederman, J, Brikell, I, Buitelaar, JK, Burton, CL, Casas, M, Crosbie, J, Doyle, AE, Ebstein, RP, Elia, J, Elizabeth, CC, Grevet, E, Grizenko, N, Havdahl, A, Hawi, Z, Hebebrand, J, Hervas, A, Hohmann, S, Haavik, J, Joober, R, Kent, L, Kuntsi, J, Langley, K, Larsson, H, Lesch, K-P, Leung, PWL, Liao, C, Loo, SK, Martin, J, Martin, NG, Medland, SE, Miranda, A, Mota, NR, Oades, RD, Ramos-Quiroga, JA, Reif, A, Rietschel, M, Roeyers, H, Rohde, LA, Rothenberger, A, Rovira, P, Sánchez-Mora, C, Schachar, RJ, Sengupta, S, Artigas, MS, Steinhausen, H-C, Thapar, A, Witt, SH, Yang, L, Zayats, T, Zhang-James, Y, Cormand, B, Hougaard, DM, Neale, BM, Franke, B, Faraone, SV & Børglum, AD 2021, 'Risk variants and polygenic architecture of disruptive behavior disorders in the context of attention-deficit/hyperactivity disorder', Nature Communications, vol. 12, no. 1, 576 . https://doi.org/10.1038/s41467-020-20443-2

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T1 - Risk variants and polygenic architecture of disruptive behavior disorders in the context of attention-deficit/hyperactivity disorder

AU - Demontis, Ditte

AU - Walters, Raymond K.

AU - Rajagopal, Veera M.

AU - Waldman, Irwin D.

AU - Grove, Jakob

AU - Als, Thomas D.

AU - Dalsgaard, Søren

AU - Ribasas, Marta

AU - Bybjerg-Grauholm, Jonas

AU - Bækvad-Hansen, Maria

AU - Werge, Thomas

AU - Nordentoft, Merete

AU - Mors, Ole

AU - Mortensen, Preben Bo

AU - (PGC), ADHD Working Group of the Psychiatric Genomics Consortium

AU - Andreassen, Ole A.

AU - Arranz, Maria Jesús

AU - Banaschewski, Tobias

AU - Bau, Claiton

AU - Bellgrove, Mark

AU - Biederman, Joseph

AU - Brikell, Isabell

AU - Buitelaar, Jan K.

AU - Burton, Christie L.

AU - Casas, Miguel

AU - Crosbie, Jennifer

AU - Doyle, Alysa E.

AU - Ebstein, Richard P.

AU - Elia, Josephine

AU - Elizabeth, Corfield C.

AU - Grevet, Eugenio

AU - Grizenko, Natalie

AU - Havdahl, Alexandra

AU - Hawi, Ziarih

AU - Hebebrand, Johannes

AU - Hervas, Amaia

AU - Hohmann, Sarah

AU - Haavik, Jan

AU - Joober, Ridha

AU - Kent, Lindsey

AU - Kuntsi, Jonna

AU - Langley, Kate

AU - Larsson, Henrik

AU - Lesch, Klaus-Peter

AU - Leung, Patrick W. L.

AU - Liao, Calwing

AU - Loo, Sandra K.

AU - Martin, Joanna

AU - Martin, Nicholas G.

AU - Medland, Sarah E.

AU - Miranda, Ana

AU - Mota, Nina Roth

AU - Oades, Robert D.

AU - Ramos-Quiroga, Josep Antoni

AU - Reif, Andreas

AU - Rietschel, Marcella

AU - Roeyers, Herbert

AU - Rohde, Luis Augusto

AU - Rothenberger, Aribert

AU - Rovira, Paula

AU - Sánchez-Mora, Cristina

AU - Schachar, Russell James

AU - Sengupta, Sarojini

AU - Artigas, Maria Soler

AU - Steinhausen, Hans-Christoph

AU - Thapar, Anita

AU - Witt, Stephanie H.

AU - Yang, Li

AU - Zayats, Tetyana

AU - Zhang-James, Yanli

AU - Cormand, Bru

AU - Hougaard, David M.

AU - Neale, Benjamin M.

AU - Franke, Barbara

AU - Faraone, Stephen V.

AU - Børglum, Anders D.

PY - 2021/1/25

Y1 - 2021/1/25

N2 - Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). Here, we report a GWAS meta-analysis of ADHD comorbid with DBDs (ADHD + DBDs) including 3802 cases and 31,305 controls. We identify three genome-wide significant loci on chromosomes 1, 7, and 11. A meta-analysis including a Chinese cohort supports that the locus on chromosome 11 is a strong risk locus for ADHD + DBDs across European and Chinese ancestries (rs7118422, P = 3.15×10−10, OR = 1.17). We find a higher SNP heritability for ADHD + DBDs (h2SNP = 0.34) when compared to ADHD without DBDs (h2SNP = 0.20), high genetic correlations between ADHD + DBDs and aggressive (rg = 0.81) and anti-social behaviors (rg = 0.82), and an increased burden (polygenic score) of variants associated with ADHD and aggression in ADHD + DBDs compared to ADHD without DBDs. Our results suggest an increased load of common risk variants in ADHD + DBDs compared to ADHD without DBDs, which in part can be explained by variants associated with aggressive behavior.

AB - Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). Here, we report a GWAS meta-analysis of ADHD comorbid with DBDs (ADHD + DBDs) including 3802 cases and 31,305 controls. We identify three genome-wide significant loci on chromosomes 1, 7, and 11. A meta-analysis including a Chinese cohort supports that the locus on chromosome 11 is a strong risk locus for ADHD + DBDs across European and Chinese ancestries (rs7118422, P = 3.15×10−10, OR = 1.17). We find a higher SNP heritability for ADHD + DBDs (h2SNP = 0.34) when compared to ADHD without DBDs (h2SNP = 0.20), high genetic correlations between ADHD + DBDs and aggressive (rg = 0.81) and anti-social behaviors (rg = 0.82), and an increased burden (polygenic score) of variants associated with ADHD and aggression in ADHD + DBDs compared to ADHD without DBDs. Our results suggest an increased load of common risk variants in ADHD + DBDs compared to ADHD without DBDs, which in part can be explained by variants associated with aggressive behavior.

KW - ADHD

KW - Genome-wide association studies

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DO - 10.1038/s41467-020-20443-2

M3 - Article

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 576

ER -

Risk variants and polygenic architecture of disruptive behavior disorders in the context of attention-deficit/hyperactivity disorder

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