Cell type-specific methylome-wide association studies of childhood ADHD symptoms

Mandy Meijer; Marieke Klein; Doretta Caramaschi; Shaunna L. Clark; Marta Cosin-Tomas; Nastassja Koen; Xueling Lu; Rosa H. Mulder; Stefan W. Röder; Yining Zhang; Lea Zilich; Mariona Bustamente; Michael Deuschle; Janine F. Felix; Juan Ramos González; Regina Gražulevičiene; Fabian Streit; John Wright; Angel Carracedo; Charlotte A.M. Cecil; Eva Corpeleijn; Catharina A. Hartman; Gunda Herberth; Anke Huels; Caroline Relton; Harold Snieder; Dan J. Stein; Jordi Sunyer; Stephanie H. Witt; Heather J. Zar; Ana C. Zenclussen; Barbara Franke; William Copeland; Karolina A. Aberg; Edwin J.C.G. van den Oord

doi:10.1016/j.euroneuro.2025.09.010

Cell type-specific methylome-wide association studies of childhood ADHD symptoms

Mandy Meijer
, Marieke Klein^*
, Doretta Caramaschi
, Shaunna L. Clark
, Marta Cosin-Tomas
, Nastassja Koen
, Xueling Lu
, Rosa H. Mulder
, Stefan W. Röder
, Yining Zhang
, Lea Zilich
, Mariona Bustamente
, Michael Deuschle
, Janine F. Felix
, Juan Ramos González
, Regina Gražulevičiene
, Fabian Streit
, John Wright
, Angel Carracedo
, Charlotte A.M. Cecil

Eva Corpeleijn, Catharina A. Hartman, Gunda Herberth, Anke Huels, Caroline Relton, Harold Snieder, Dan J. Stein, Jordi Sunyer, Stephanie H. Witt, Heather J. Zar, Ana C. Zenclussen, Barbara Franke, William Copeland, Karolina A. Aberg, Edwin J.C.G. van den Oord

^*Corresponding author for this work

Donders Institute for Brain, Cognition and Behaviour
Radboud University Medical Center
University of Exeter
Texas A&M University
Pompeu Fabra University
University of Cape Town
University Medical Centre Groningen
Helmholtz Centre for Environmental Research
Emory University
Heidelberg University
Vytautas Magnus University
Bradford Institute for Health Research
Instituto de Investigación Sanitaria de Santiago de Compostela
University of Bristol
University of Vermont College of Medicine
Virginia Commonwealth University

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

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Abstract

Studying DNA methylation (DNAm) can provide insights into gene-regulatory mechanisms underlying attention-deficit/hyperactivity disorder (ADHD). While most DNAm studies were performed in bulk tissue, this study used statistical deconvolution to identify cell type-specific DNAm profiles, from five major blood cell types, associated with childhood ADHD symptoms. We performed meta-analyses of methylome-wide association studies (MWAS) for ADHD symptoms (age_range=4–16 years) in peripheral blood collected during childhood and in cord blood. The investigated cohorts included seven array-based methylation datasets assaying up to 450 K CpGs from the Pregnancy And Childhood Epigenetics Consortium (N=2 934 peripheral blood; N=2 546 cord blood) and a sequencing-based methylation dataset assaying nearly all 28 million CpGs in blood from the Great Smoky Mountain Study (GSMS; N=583). The meta-analyses resulted in methylome-wide significant (FDR<0.05) ADHD associations in CD8T cells ( RPL31P11 and KCNJ5) for peripheral blood, and, in cord blood, in monocytes ( PDE6B ), CD8T cells ( KCNA3 and HAND2 ), and NK cells ( KIFC1 ). Notably, several significant sites detected in peripheral blood ( RPL31P11 and KCNJ5 ) were also detected in cord blood. Furthermore, extended MWAS of all sites available for GSMS detected 69 and 17 additional CpGs in monocytes and granulocytes, respectively. In this first cell type-specific MWAS for ADHD, we identified DNAm associations for ADHD symptoms; some associations were seen in both peripheral blood and cord blood, suggesting potential susceptibility markers for increased ADHD risk. These findings show that cell type-specific analyses and sequencing-based approaches can increase insights into the epigenetic patterns associated with ADHD symptoms in childhood.

Original language	English
Pages (from-to)	7-17
Number of pages	11
Journal	European Neuropsychopharmacology
Volume	101
DOIs	https://doi.org/10.1016/j.euroneuro.2025.09.010
Publication status	Published - Dec 2025

Bibliographical note

Publisher Copyright:
Copyright © 2025. Published by Elsevier B.V.

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1-s2.0-S0924977X25007618-mainFinal published version, 4.24 MBLicence: CC BY

Cite this

Meijer, M., Klein, M., Caramaschi, D., Clark, S. L., Cosin-Tomas, M., Koen, N., Lu, X., Mulder, R. H., Röder, S. W., Zhang, Y., Zilich, L., Bustamente, M., Deuschle, M., Felix, J. F., González, J. R., Gražulevičiene, R., Streit, F., Wright, J., Carracedo, A., ... van den Oord, E. J. C. G. (2025). Cell type-specific methylome-wide association studies of childhood ADHD symptoms. European Neuropsychopharmacology, 101, 7-17. https://doi.org/10.1016/j.euroneuro.2025.09.010

@article{3d617f517fe348b090f21b286e7d4c3a,

title = "Cell type-specific methylome-wide association studies of childhood ADHD symptoms",

abstract = "Studying DNA methylation (DNAm) can provide insights into gene-regulatory mechanisms underlying attention-deficit/hyperactivity disorder (ADHD). While most DNAm studies were performed in bulk tissue, this study used statistical deconvolution to identify cell type-specific DNAm profiles, from five major blood cell types, associated with childhood ADHD symptoms. We performed meta-analyses of methylome-wide association studies (MWAS) for ADHD symptoms (agerange=4{\textendash}16 years) in peripheral blood collected during childhood and in cord blood. The investigated cohorts included seven array-based methylation datasets assaying up to 450 K CpGs from the Pregnancy And Childhood Epigenetics Consortium (N=2 934 peripheral blood; N=2 546 cord blood) and a sequencing-based methylation dataset assaying nearly all 28 million CpGs in blood from the Great Smoky Mountain Study (GSMS; N=583). The meta-analyses resulted in methylome-wide significant (FDR<0.05) ADHD associations in CD8T cells ( RPL31P11 and KCNJ5) for peripheral blood, and, in cord blood, in monocytes ( PDE6B ), CD8T cells ( KCNA3 and HAND2 ), and NK cells ( KIFC1 ). Notably, several significant sites detected in peripheral blood ( RPL31P11 and KCNJ5 ) were also detected in cord blood. Furthermore, extended MWAS of all sites available for GSMS detected 69 and 17 additional CpGs in monocytes and granulocytes, respectively. In this first cell type-specific MWAS for ADHD, we identified DNAm associations for ADHD symptoms; some associations were seen in both peripheral blood and cord blood, suggesting potential susceptibility markers for increased ADHD risk. These findings show that cell type-specific analyses and sequencing-based approaches can increase insights into the epigenetic patterns associated with ADHD symptoms in childhood.",

author = "Mandy Meijer and Marieke Klein and Doretta Caramaschi and Clark, \{Shaunna L.\} and Marta Cosin-Tomas and Nastassja Koen and Xueling Lu and Mulder, \{Rosa H.\} and R{\"o}der, \{Stefan W.\} and Yining Zhang and Lea Zilich and Mariona Bustamente and Michael Deuschle and Felix, \{Janine F.\} and Gonz{\'a}lez, \{Juan Ramos\} and Regina Gra{\v z}ulevi{\v c}iene and Fabian Streit and John Wright and Angel Carracedo and Cecil, \{Charlotte A.M.\} and Eva Corpeleijn and Hartman, \{Catharina A.\} and Gunda Herberth and Anke Huels and Caroline Relton and Harold Snieder and Stein, \{Dan J.\} and Jordi Sunyer and Witt, \{Stephanie H.\} and Zar, \{Heather J.\} and Zenclussen, \{Ana C.\} and Barbara Franke and William Copeland and Aberg, \{Karolina A.\} and \{van den Oord\}, \{Edwin J.C.G.\}",

note = "Publisher Copyright: Copyright {\textcopyright} 2025. Published by Elsevier B.V.",

year = "2025",

month = dec,

doi = "10.1016/j.euroneuro.2025.09.010",

language = "English",

volume = "101",

pages = "7--17",

journal = "European Neuropsychopharmacology",

issn = "0924-977X",

publisher = "Elsevier",

}

Meijer, M, Klein, M, Caramaschi, D, Clark, SL, Cosin-Tomas, M, Koen, N, Lu, X, Mulder, RH, Röder, SW, Zhang, Y, Zilich, L, Bustamente, M, Deuschle, M, Felix, JF, González, JR, Gražulevičiene, R, Streit, F, Wright, J, Carracedo, A, Cecil, CAM, Corpeleijn, E, Hartman, CA, Herberth, G, Huels, A, Relton, C, Snieder, H, Stein, DJ, Sunyer, J, Witt, SH, Zar, HJ, Zenclussen, AC, Franke, B, Copeland, W, Aberg, KA & van den Oord, EJCG 2025, 'Cell type-specific methylome-wide association studies of childhood ADHD symptoms', European Neuropsychopharmacology, vol. 101, pp. 7-17. https://doi.org/10.1016/j.euroneuro.2025.09.010

TY - JOUR

T1 - Cell type-specific methylome-wide association studies of childhood ADHD symptoms

AU - Meijer, Mandy

AU - Klein, Marieke

AU - Caramaschi, Doretta

AU - Clark, Shaunna L.

AU - Cosin-Tomas, Marta

AU - Koen, Nastassja

AU - Lu, Xueling

AU - Mulder, Rosa H.

AU - Röder, Stefan W.

AU - Zhang, Yining

AU - Zilich, Lea

AU - Bustamente, Mariona

AU - Deuschle, Michael

AU - Felix, Janine F.

AU - González, Juan Ramos

AU - Gražulevičiene, Regina

AU - Streit, Fabian

AU - Wright, John

AU - Carracedo, Angel

AU - Cecil, Charlotte A.M.

AU - Corpeleijn, Eva

AU - Hartman, Catharina A.

AU - Herberth, Gunda

AU - Huels, Anke

AU - Relton, Caroline

AU - Snieder, Harold

AU - Stein, Dan J.

AU - Sunyer, Jordi

AU - Witt, Stephanie H.

AU - Zar, Heather J.

AU - Zenclussen, Ana C.

AU - Franke, Barbara

AU - Copeland, William

AU - Aberg, Karolina A.

AU - van den Oord, Edwin J.C.G.

PY - 2025/12

Y1 - 2025/12

N2 - Studying DNA methylation (DNAm) can provide insights into gene-regulatory mechanisms underlying attention-deficit/hyperactivity disorder (ADHD). While most DNAm studies were performed in bulk tissue, this study used statistical deconvolution to identify cell type-specific DNAm profiles, from five major blood cell types, associated with childhood ADHD symptoms. We performed meta-analyses of methylome-wide association studies (MWAS) for ADHD symptoms (agerange=4–16 years) in peripheral blood collected during childhood and in cord blood. The investigated cohorts included seven array-based methylation datasets assaying up to 450 K CpGs from the Pregnancy And Childhood Epigenetics Consortium (N=2 934 peripheral blood; N=2 546 cord blood) and a sequencing-based methylation dataset assaying nearly all 28 million CpGs in blood from the Great Smoky Mountain Study (GSMS; N=583). The meta-analyses resulted in methylome-wide significant (FDR<0.05) ADHD associations in CD8T cells ( RPL31P11 and KCNJ5) for peripheral blood, and, in cord blood, in monocytes ( PDE6B ), CD8T cells ( KCNA3 and HAND2 ), and NK cells ( KIFC1 ). Notably, several significant sites detected in peripheral blood ( RPL31P11 and KCNJ5 ) were also detected in cord blood. Furthermore, extended MWAS of all sites available for GSMS detected 69 and 17 additional CpGs in monocytes and granulocytes, respectively. In this first cell type-specific MWAS for ADHD, we identified DNAm associations for ADHD symptoms; some associations were seen in both peripheral blood and cord blood, suggesting potential susceptibility markers for increased ADHD risk. These findings show that cell type-specific analyses and sequencing-based approaches can increase insights into the epigenetic patterns associated with ADHD symptoms in childhood.

AB - Studying DNA methylation (DNAm) can provide insights into gene-regulatory mechanisms underlying attention-deficit/hyperactivity disorder (ADHD). While most DNAm studies were performed in bulk tissue, this study used statistical deconvolution to identify cell type-specific DNAm profiles, from five major blood cell types, associated with childhood ADHD symptoms. We performed meta-analyses of methylome-wide association studies (MWAS) for ADHD symptoms (agerange=4–16 years) in peripheral blood collected during childhood and in cord blood. The investigated cohorts included seven array-based methylation datasets assaying up to 450 K CpGs from the Pregnancy And Childhood Epigenetics Consortium (N=2 934 peripheral blood; N=2 546 cord blood) and a sequencing-based methylation dataset assaying nearly all 28 million CpGs in blood from the Great Smoky Mountain Study (GSMS; N=583). The meta-analyses resulted in methylome-wide significant (FDR<0.05) ADHD associations in CD8T cells ( RPL31P11 and KCNJ5) for peripheral blood, and, in cord blood, in monocytes ( PDE6B ), CD8T cells ( KCNA3 and HAND2 ), and NK cells ( KIFC1 ). Notably, several significant sites detected in peripheral blood ( RPL31P11 and KCNJ5 ) were also detected in cord blood. Furthermore, extended MWAS of all sites available for GSMS detected 69 and 17 additional CpGs in monocytes and granulocytes, respectively. In this first cell type-specific MWAS for ADHD, we identified DNAm associations for ADHD symptoms; some associations were seen in both peripheral blood and cord blood, suggesting potential susceptibility markers for increased ADHD risk. These findings show that cell type-specific analyses and sequencing-based approaches can increase insights into the epigenetic patterns associated with ADHD symptoms in childhood.

UR - https://www.scopus.com/pages/publications/105022149897

U2 - 10.1016/j.euroneuro.2025.09.010

DO - 10.1016/j.euroneuro.2025.09.010

M3 - Article

C2 - 41145087

AN - SCOPUS:105022149897

SN - 0924-977X

VL - 101

SP - 7

EP - 17

JO - European Neuropsychopharmacology

JF - European Neuropsychopharmacology

ER -

Cell type-specific methylome-wide association studies of childhood ADHD symptoms

Abstract

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