Genome-wide association meta-analysis of childhood ADHD symptoms and diagnosis identifies new loci and potential effector genes

Camiel M. van der Laan; Hill F. Ip; Marijn Schipper; Jouke Jan Hottenga; Beate St Pourcain; Tetyana Zayats; René Pool; Eva M.L. Krapohl; Isabell Brikell; María Soler Artigas; Judit Cabana-Domínguez; Natalia Llonga; Ilja M. Nolte; Koen Bolhuis; Teemu Palviainen; Hadi Zafarmand; Scott Gordon; Fazil Aliev; S. Alexandra Burt; Carol A. Wang; Gretchen Saunders; Ville Karhunen; Daniel E. Adkins; Richard Border; Roseann E. Peterson; Joseph A. Prinz; Elisabeth Thiering; Natàlia Vilor-Tejedor; Tarunveer S. Ahluwalia; Andrea Allegrini; Kaili Rimfeld; Qi Chen; Yi Lu; Joanna Martin; Rosa Bosch; Josep Antoni Ramos-Quiroga; Alexander Neumann; Judith Ensink; Katrina L. Grasby; José J. Morosoli; Xiaoran Tong; Shelby Marrington; James G. Scott; Andrey A. Shabalin; Robin Corley; Luke M. Evans; Karen Sugden; Silvia Alemany; Lærke Sass; Rebecca Vinding; Erik A. Ehli; Fiona A. Hagenbeek; Eske M. Derks; Henrik Larsson; Harold Snieder; Charlotte Cecil; Alyce M. Whipp; Tellervo Korhonen; Eero Vuoksimaa; Richard J. Rose; André G. Uitterlinden; 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 A. Reynolds; Andrew Smolen; Michael Stallings; Sally Wadsworth; Tamara L. Wall; Lindon Eaves; Judy L. Silberg; Allison Miller; Alexandra Havdahl; Sabrina Llop; Maria Jose Lopez-Espinosa; Klaus Bønnelykke; Jordi Sunyer; Louise Arseneault; Marie Standl; Joachim Heinrich; Joseph Boden; John Pearson; John Horwood; Martin Kennedy; Richie Poulton; Hermine H. Maes; John Hewitt; William E. Copeland; Christel M. Middeldorp; Gail M. Williams; Naomi Wray; Marjo Riitta Järvelin; Matt McGue; William Iacono; Avshalom Caspi; Terrie E. Moffitt; Andrew J.O. Whitehouse; Craig E. Pennell; Kelly L. Klump; Chang Jiang; 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/s41588-025-02295-y

Genome-wide association meta-analysis of childhood ADHD symptoms and diagnosis identifies new loci and potential effector genes

Camiel M. van der Laan^*
, Hill F. Ip
, Marijn Schipper
, Jouke Jan Hottenga
, Beate St Pourcain
, Tetyana Zayats
, René Pool
, Eva M.L. Krapohl
, Isabell Brikell
, María Soler Artigas
, Judit Cabana-Domínguez
, Natalia Llonga
, Ilja M. Nolte
, Koen Bolhuis
, Teemu Palviainen
, Hadi Zafarmand
, Scott Gordon
, Fazil Aliev
, S. Alexandra Burt
, Carol A. Wang

Gretchen Saunders, Ville Karhunen, Daniel E. Adkins, Richard Border, Roseann E. Peterson, Joseph A. Prinz, Elisabeth Thiering, Natàlia Vilor-Tejedor, Tarunveer S. Ahluwalia, Andrea Allegrini, Kaili Rimfeld, Qi Chen, Yi Lu, Joanna Martin, Rosa Bosch, Josep Antoni Ramos-Quiroga, Alexander Neumann, Judith Ensink, Katrina L. Grasby, José J. Morosoli, Xiaoran Tong, Shelby Marrington, James G. Scott, Andrey A. Shabalin, Robin Corley, Luke M. Evans, Karen Sugden, Silvia Alemany, Lærke Sass, Rebecca Vinding, Erik A. Ehli, Fiona A. Hagenbeek, Eske M. Derks, Henrik Larsson, Harold Snieder, Charlotte Cecil, Alyce M. Whipp, Tellervo Korhonen, Eero Vuoksimaa, Richard J. Rose, André G. Uitterlinden, 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 A. Reynolds, Andrew Smolen, Michael Stallings, Sally Wadsworth, Tamara L. Wall, Lindon Eaves, Judy L. Silberg, Allison Miller, Alexandra Havdahl, Sabrina Llop, Maria Jose Lopez-Espinosa, Klaus Bønnelykke, Jordi Sunyer, Louise Arseneault, Marie Standl, Joachim Heinrich, Joseph Boden, John Pearson, John Horwood, Martin Kennedy, Richie Poulton, Hermine H. Maes, John Hewitt, William E. Copeland, Christel M. Middeldorp, Gail M. Williams, Naomi Wray, Marjo Riitta Järvelin, Matt McGue, William Iacono, Avshalom Caspi, Terrie E. Moffitt, Andrew J.O. Whitehouse, Craig E. Pennell, Kelly L. Klump, Chang Jiang, 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

^*Corresponding author for this work

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

1 Citation (Scopus)

Abstract

We performed a genome-wide association meta-analysis (GWAMA) of 290,134 attention-deficit/hyperactivity disorder (ADHD) symptom measures of 70,953 unique individuals from multiple raters, ages and instruments (ADHD(SYMP)). Next, we meta-analyzed the results with a study of ADHD diagnosis (ADHD(OVERALL)). ADHD(SYMP) returned no genome-wide significant variants. We show that the combined ADHD(OVERALL) GWAMA identified 39 independent loci, of which 17 were new. Using a recently developed gene-mapping method, Fine-mapped Locus Assessment Model of Effector genes, we identified 22 potential ADHD effector genes implicating several new biological processes and pathways. Moderate negative genetic correlations (r(g) < -0.40) were observed with multiple cognitive traits. In three cohorts, polygenic scores (PGSs) based on ADHD(OVERALL) outperformed PGSs based on ADHD symptoms and diagnosis alone. Our findings support the notion that clinical ADHD is at the extreme end of a continuous liability that is indexed by ADHD symptoms. We show that including ADHD symptom counts helps to identify new genes implicated in ADHD.

Original language	English
Pages (from-to)	2427-+
Number of pages	12
Journal	Nature Genetics
Volume	57
Issue number	10
DOIs	https://doi.org/10.1038/s41588-025-02295-y
Publication status	Published - Oct 2025
Externally published	Yes

Keywords

Attention-deficit/hyperactivity disorder
Deficit hyperactivity disorder
Informant
Prediction

Access to Document

10.1038/s41588-025-02295-y

Cite this

van der Laan, C. M., Ip, H. F., Schipper, M., Hottenga, J. J., St Pourcain, B., Zayats, T., Pool, R., Krapohl, E. M. L., Brikell, I., Soler Artigas, M., Cabana-Domínguez, J., Llonga, N., Nolte, I. M., Bolhuis, K., Palviainen, T., Zafarmand, H., Gordon, S., Aliev, F., Burt, S. A., ... Boomsma, D. I. (2025). Genome-wide association meta-analysis of childhood ADHD symptoms and diagnosis identifies new loci and potential effector genes. Nature Genetics, 57(10), 2427-+. https://doi.org/10.1038/s41588-025-02295-y

@article{b3256d280222423083648ebf863d020e,

title = "Genome-wide association meta-analysis of childhood ADHD symptoms and diagnosis identifies new loci and potential effector genes",

abstract = "We performed a genome-wide association meta-analysis (GWAMA) of 290,134 attention-deficit/hyperactivity disorder (ADHD) symptom measures of 70,953 unique individuals from multiple raters, ages and instruments (ADHD(SYMP)). Next, we meta-analyzed the results with a study of ADHD diagnosis (ADHD(OVERALL)). ADHD(SYMP) returned no genome-wide significant variants. We show that the combined ADHD(OVERALL) GWAMA identified 39 independent loci, of which 17 were new. Using a recently developed gene-mapping method, Fine-mapped Locus Assessment Model of Effector genes, we identified 22 potential ADHD effector genes implicating several new biological processes and pathways. Moderate negative genetic correlations (r(g) < -0.40) were observed with multiple cognitive traits. In three cohorts, polygenic scores (PGSs) based on ADHD(OVERALL) outperformed PGSs based on ADHD symptoms and diagnosis alone. Our findings support the notion that clinical ADHD is at the extreme end of a continuous liability that is indexed by ADHD symptoms. We show that including ADHD symptom counts helps to identify new genes implicated in ADHD.",

keywords = "Attention-deficit/hyperactivity disorder, Deficit hyperactivity disorder, Informant, Prediction",

author = "\{van der Laan\}, \{Camiel M.\} and Ip, \{Hill F.\} and Marijn Schipper and Hottenga, \{Jouke Jan\} and \{St Pourcain\}, Beate and Tetyana Zayats and Ren{\'e} Pool and Krapohl, \{Eva M.L.\} and Isabell Brikell and \{Soler Artigas\}, Mar{\'i}a and Judit Cabana-Dom{\'i}nguez and Natalia Llonga and Nolte, \{Ilja M.\} and Koen Bolhuis and Teemu Palviainen and Hadi Zafarmand and Scott Gordon and Fazil Aliev and Burt, \{S. Alexandra\} and Wang, \{Carol A.\} and Gretchen Saunders and Ville Karhunen and Adkins, \{Daniel E.\} and Richard Border and Peterson, \{Roseann E.\} and Prinz, \{Joseph A.\} and Elisabeth Thiering and Nat{\`a}lia Vilor-Tejedor and Ahluwalia, \{Tarunveer S.\} and Andrea Allegrini and Kaili Rimfeld and Qi Chen and Yi Lu and Joanna Martin and Rosa Bosch and Ramos-Quiroga, \{Josep Antoni\} and Alexander Neumann and Judith Ensink and Grasby, \{Katrina L.\} and Morosoli, \{Jos{\'e} J.\} and Xiaoran Tong and Shelby Marrington and Scott, \{James G.\} 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 Ehli, \{Erik A.\} and Hagenbeek, \{Fiona A.\} and Derks, \{Eske M.\} and Henrik Larsson and Harold Snieder and Charlotte Cecil and Whipp, \{Alyce M.\} and Tellervo Korhonen and Eero Vuoksimaa and Rose, \{Richard J.\} and Uitterlinden, \{Andr{\'e} G.\} 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 Reynolds, \{Chandra A.\} and Andrew Smolen and Michael Stallings and Sally Wadsworth and Wall, \{Tamara L.\} and Lindon Eaves and Silberg, \{Judy L.\} and Allison Miller and Alexandra Havdahl and Sabrina Llop and Lopez-Espinosa, \{Maria Jose\} and Klaus B{\o}nnelykke and Jordi Sunyer and Louise Arseneault and Marie Standl and Joachim Heinrich and Joseph Boden and John Pearson and John Horwood and Martin Kennedy and Richie Poulton and Maes, \{Hermine H.\} and John Hewitt and Copeland, \{William E.\} and Middeldorp, \{Christel M.\} 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 Whitehouse, \{Andrew J.O.\} and Pennell, \{Craig E.\} and Klump, \{Kelly L.\} and Chang Jiang 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 = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.",

year = "2025",

month = oct,

doi = "10.1038/s41588-025-02295-y",

language = "English",

volume = "57",

pages = "2427--+",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "10",

}

van der Laan, CM, Ip, HF, Schipper, M, Hottenga, JJ, St Pourcain, B, Zayats, T, Pool, R, Krapohl, EML, Brikell, I, Soler Artigas, M, Cabana-Domínguez, J, Llonga, N, Nolte, IM, Bolhuis, K, Palviainen, T, Zafarmand, H, Gordon, S, Aliev, F, Burt, SA, Wang, CA, Saunders, G, Karhunen, V, Adkins, DE, Border, R, Peterson, RE, Prinz, JA, Thiering, E, Vilor-Tejedor, N, Ahluwalia, TS, Allegrini, A, Rimfeld, K, Chen, Q, Lu, Y, Martin, J, Bosch, R, Ramos-Quiroga, JA, Neumann, A, Ensink, J, Grasby, KL, Morosoli, JJ, Tong, X, Marrington, S, Scott, JG, Shabalin, AA, Corley, R, Evans, LM, Sugden, K, Alemany, S, Sass, L, Vinding, R, Ehli, EA, Hagenbeek, FA, Derks, EM, Larsson, H, Snieder, H, Cecil, C, Whipp, AM, Korhonen, T, Vuoksimaa, E, Rose, RJ, Uitterlinden, AG, 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, CA, Smolen, A, Stallings, M, Wadsworth, S, Wall, TL, Eaves, L, Silberg, JL, Miller, A, Havdahl, A, Llop, S, Lopez-Espinosa, MJ, Bønnelykke, K, Sunyer, J, Arseneault, L, Standl, M, Heinrich, J, Boden, J, Pearson, J, Horwood, J, Kennedy, M, Poulton, R, Maes, HH, Hewitt, J, Copeland, WE, Middeldorp, CM, Williams, GM, Wray, N, Järvelin, MR, McGue, M, Iacono, W, Caspi, A, Moffitt, TE, Whitehouse, AJO, Pennell, CE, Klump, KL, Jiang, C, 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 2025, 'Genome-wide association meta-analysis of childhood ADHD symptoms and diagnosis identifies new loci and potential effector genes', Nature Genetics, vol. 57, no. 10, pp. 2427-+. https://doi.org/10.1038/s41588-025-02295-y

TY - JOUR

T1 - Genome-wide association meta-analysis of childhood ADHD symptoms and diagnosis identifies new loci and potential effector genes

AU - van der Laan, Camiel M.

AU - Ip, Hill F.

AU - Schipper, Marijn

AU - Hottenga, Jouke Jan

AU - St Pourcain, Beate

AU - Zayats, Tetyana

AU - Pool, René

AU - Krapohl, Eva M.L.

AU - Brikell, Isabell

AU - Soler Artigas, María

AU - Cabana-Domínguez, Judit

AU - Llonga, Natalia

AU - Nolte, Ilja M.

AU - Bolhuis, Koen

AU - Palviainen, Teemu

AU - Zafarmand, Hadi

AU - Gordon, Scott

AU - Aliev, Fazil

AU - Burt, S. Alexandra

AU - Wang, Carol A.

AU - Saunders, Gretchen

AU - Karhunen, Ville

AU - Adkins, Daniel E.

AU - Border, Richard

AU - Peterson, Roseann E.

AU - Prinz, Joseph A.

AU - Thiering, Elisabeth

AU - Vilor-Tejedor, Natàlia

AU - Ahluwalia, Tarunveer S.

AU - Allegrini, Andrea

AU - Rimfeld, Kaili

AU - Chen, Qi

AU - Lu, Yi

AU - Martin, Joanna

AU - Bosch, Rosa

AU - Ramos-Quiroga, Josep Antoni

AU - Neumann, Alexander

AU - Ensink, Judith

AU - Grasby, Katrina L.

AU - Morosoli, José J.

AU - Tong, Xiaoran

AU - Marrington, Shelby

AU - Scott, James G.

AU - Shabalin, Andrey A.

AU - Corley, Robin

AU - Evans, Luke M.

AU - Sugden, Karen

AU - Alemany, Silvia

AU - Sass, Lærke

AU - Vinding, Rebecca

AU - Ehli, Erik A.

AU - Hagenbeek, Fiona A.

AU - Derks, Eske M.

AU - Larsson, Henrik

AU - Snieder, Harold

AU - Cecil, Charlotte

AU - Whipp, Alyce M.

AU - Korhonen, Tellervo

AU - Vuoksimaa, Eero

AU - Rose, Richard J.

AU - Uitterlinden, André G.

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 A.

AU - Smolen, Andrew

AU - Stallings, Michael

AU - Wadsworth, Sally

AU - Wall, Tamara L.

AU - Eaves, Lindon

AU - Silberg, Judy L.

AU - Miller, Allison

AU - Havdahl, Alexandra

AU - Llop, Sabrina

AU - Lopez-Espinosa, Maria Jose

AU - Bønnelykke, Klaus

AU - Sunyer, Jordi

AU - Arseneault, Louise

AU - Standl, Marie

AU - Heinrich, Joachim

AU - Boden, Joseph

AU - Pearson, John

AU - Horwood, John

AU - Kennedy, Martin

AU - Poulton, Richie

AU - Maes, Hermine H.

AU - Hewitt, John

AU - Copeland, William E.

AU - Middeldorp, Christel M.

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 J.O.

AU - Pennell, Craig E.

AU - Klump, Kelly L.

AU - Jiang, Chang

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.

PY - 2025/10

Y1 - 2025/10

N2 - We performed a genome-wide association meta-analysis (GWAMA) of 290,134 attention-deficit/hyperactivity disorder (ADHD) symptom measures of 70,953 unique individuals from multiple raters, ages and instruments (ADHD(SYMP)). Next, we meta-analyzed the results with a study of ADHD diagnosis (ADHD(OVERALL)). ADHD(SYMP) returned no genome-wide significant variants. We show that the combined ADHD(OVERALL) GWAMA identified 39 independent loci, of which 17 were new. Using a recently developed gene-mapping method, Fine-mapped Locus Assessment Model of Effector genes, we identified 22 potential ADHD effector genes implicating several new biological processes and pathways. Moderate negative genetic correlations (r(g) < -0.40) were observed with multiple cognitive traits. In three cohorts, polygenic scores (PGSs) based on ADHD(OVERALL) outperformed PGSs based on ADHD symptoms and diagnosis alone. Our findings support the notion that clinical ADHD is at the extreme end of a continuous liability that is indexed by ADHD symptoms. We show that including ADHD symptom counts helps to identify new genes implicated in ADHD.

AB - We performed a genome-wide association meta-analysis (GWAMA) of 290,134 attention-deficit/hyperactivity disorder (ADHD) symptom measures of 70,953 unique individuals from multiple raters, ages and instruments (ADHD(SYMP)). Next, we meta-analyzed the results with a study of ADHD diagnosis (ADHD(OVERALL)). ADHD(SYMP) returned no genome-wide significant variants. We show that the combined ADHD(OVERALL) GWAMA identified 39 independent loci, of which 17 were new. Using a recently developed gene-mapping method, Fine-mapped Locus Assessment Model of Effector genes, we identified 22 potential ADHD effector genes implicating several new biological processes and pathways. Moderate negative genetic correlations (r(g) < -0.40) were observed with multiple cognitive traits. In three cohorts, polygenic scores (PGSs) based on ADHD(OVERALL) outperformed PGSs based on ADHD symptoms and diagnosis alone. Our findings support the notion that clinical ADHD is at the extreme end of a continuous liability that is indexed by ADHD symptoms. We show that including ADHD symptom counts helps to identify new genes implicated in ADHD.

KW - Attention-deficit/hyperactivity disorder

KW - Deficit hyperactivity disorder

KW - Informant

KW - Prediction

UR - https://www.scopus.com/pages/publications/105016606413

U2 - 10.1038/s41588-025-02295-y

DO - 10.1038/s41588-025-02295-y

M3 - Article

C2 - 40962958

AN - SCOPUS:105016606413

SN - 1061-4036

VL - 57

SP - 2427-+

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -

Genome-wide association meta-analysis of childhood ADHD symptoms and diagnosis identifies new loci and potential effector genes

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this