Associations of DNA Methylation With Behavioral Problems, Gray Matter Volumes, and Negative Life Events Across Adolescence: Evidence From the Longitudinal IMAGEN Study

Yan Sun; Tianye Jia; Edward D. Barker; Di Chen; Zuo Zhang; Jiayuan Xu; Suhua Chang; Guangdong Zhou; Yun Liu; Nicole Tay; Qiang Luo; Xiao Chang; Tobias Banaschewski; Arun L.w. Bokde; Herta Flor; Antoine Grigis; Hugh Garavan; Andreas Heinz; Jean-luc Martinot; Marie-laure Paillère martinot; Eric Artiges; Frauke Nees; Dimitri Papadopoulos Orfanos; Tomáš Paus; Luise Poustka; Sarah Hohmann; Sabina Millenet; Juliane H. Fröhner; Michael N. Smolka; Henrik Walter; Robert Whelan; Lin Lu; Jie Shi; Gunter Schumann; Sylvane Desrivières

doi:10.1016/j.biopsych.2022.06.012

Associations of DNA Methylation With Behavioral Problems, Gray Matter Volumes, and Negative Life Events Across Adolescence: Evidence From the Longitudinal IMAGEN Study

Yan Sun, Tianye Jia, Edward D. Barker, Di Chen, Zuo Zhang, Jiayuan Xu, Suhua Chang, Guangdong Zhou, Yun Liu, Nicole Tay, Qiang Luo, Xiao Chang, Tobias Banaschewski, Arun L.w. Bokde, Herta Flor, Antoine Grigis, Hugh Garavan, Andreas Heinz, Jean-luc Martinot, Marie-laure Paillère martinotEric Artiges, Frauke Nees, Dimitri Papadopoulos Orfanos, Tomáš Paus, Luise Poustka, Sarah Hohmann, Sabina Millenet, Juliane H. Fröhner, Michael N. Smolka, Henrik Walter, Robert Whelan, Lin Lu, Jie Shi, Gunter Schumann, Sylvane Desrivières

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

7 Citations (Scopus)

Abstract

Background
Negative life events (NLEs) increase the risk for externalizing behaviors (EBs) and internalizing behaviors (IBs) in adolescence and adult psychopathology. DNA methylation associated with behavioral problems may reflect this risk and long-lasting effects of NLEs.

Methods
To identify consistent associations between blood DNA methylation and EBs or IBs across adolescence, we conducted longitudinal epigenome-wide association studies (EWASs) using data from the IMAGEN cohort, collected at ages 14 and 19 years (n = 506). Significant findings were validated in a separate subsample (n = 823). Methylation risk scores were generated by 10-fold cross-validation and further tested for their associations with gray matter volumes and NLEs.

Results
No significant findings were obtained for the IB-EWAS. The EB-EWAS identified a genome-wide significant locus in a gene linked to attention-deficit/hyperactivity disorder (ADHD) (IQSEC1, cg01460382; p = 1.26 × 10−8). Other most significant CpG sites were near ADHD-related genes and enriched for genes regulating tumor necrosis factor and interferon-γ signaling, highlighting the relevance of EB-EWAS findings for ADHD. Analyses with the EB methylation risk scores suggested that it partly reflected comorbidity with IBs in late adolescence. Specific to EBs, EB methylation risk scores correlated with smaller gray matter volumes in medial orbitofrontal and anterior/middle cingulate cortices, brain regions known to associate with ADHD and conduct problems. Longitudinal mediation analyses indicated that EB-related DNA methylation were more likely the outcomes of problematic behaviors accentuated by NLEs, and less likely the epigenetic bases of such behaviors.

Conclusions
Our findings suggest that novel epigenetic mechanisms through which NLEs exert short and longer-term effects on behavior may contribute to ADHD.

Original language	English
Pages (from-to)	342-351
Number of pages	10
Journal	Biological psychiatry
Volume	93
Issue number	4
Early online date	16 Jan 2023
DOIs	https://doi.org/10.1016/j.biopsych.2022.06.012
Publication status	Published - 15 Feb 2023

Keywords

ADHD
Adolescents
Brain
Epigenome-wide Association Study
externalizing behaviors
Life events

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10.1016/j.biopsych.2022.06.012

Cite this

Sun, Y., Jia, T., Barker, E. D., Chen, D., Zhang, Z., Xu, J., Chang, S., Zhou, G., Liu, Y., Tay, N., Luo, Q., Chang, X., Banaschewski, T., Bokde, A. L. W., Flor, H., Grigis, A., Garavan, H., Heinz, A., Martinot, J., ... Desrivières, S. (2023). Associations of DNA Methylation With Behavioral Problems, Gray Matter Volumes, and Negative Life Events Across Adolescence: Evidence From the Longitudinal IMAGEN Study. Biological psychiatry, 93(4), 342-351. https://doi.org/10.1016/j.biopsych.2022.06.012

@article{67145e9b734745d6a9afb7309c8470c4,

title = "Associations of DNA Methylation With Behavioral Problems, Gray Matter Volumes, and Negative Life Events Across Adolescence: Evidence From the Longitudinal IMAGEN Study",

abstract = "BackgroundNegative life events (NLEs) increase the risk for externalizing behaviors (EBs) and internalizing behaviors (IBs) in adolescence and adult psychopathology. DNA methylation associated with behavioral problems may reflect this risk and long-lasting effects of NLEs.MethodsTo identify consistent associations between blood DNA methylation and EBs or IBs across adolescence, we conducted longitudinal epigenome-wide association studies (EWASs) using data from the IMAGEN cohort, collected at ages 14 and 19 years (n = 506). Significant findings were validated in a separate subsample (n = 823). Methylation risk scores were generated by 10-fold cross-validation and further tested for their associations with gray matter volumes and NLEs.ResultsNo significant findings were obtained for the IB-EWAS. The EB-EWAS identified a genome-wide significant locus in a gene linked to attention-deficit/hyperactivity disorder (ADHD) (IQSEC1, cg01460382; p = 1.26 × 10−8). Other most significant CpG sites were near ADHD-related genes and enriched for genes regulating tumor necrosis factor and interferon-γ signaling, highlighting the relevance of EB-EWAS findings for ADHD. Analyses with the EB methylation risk scores suggested that it partly reflected comorbidity with IBs in late adolescence. Specific to EBs, EB methylation risk scores correlated with smaller gray matter volumes in medial orbitofrontal and anterior/middle cingulate cortices, brain regions known to associate with ADHD and conduct problems. Longitudinal mediation analyses indicated that EB-related DNA methylation were more likely the outcomes of problematic behaviors accentuated by NLEs, and less likely the epigenetic bases of such behaviors.ConclusionsOur findings suggest that novel epigenetic mechanisms through which NLEs exert short and longer-term effects on behavior may contribute to ADHD.",

keywords = "ADHD, Adolescents, Brain, Epigenome-wide Association Study, externalizing behaviors, Life events",

author = "Yan Sun and Tianye Jia and Barker, {Edward D.} and Di Chen and Zuo Zhang and Jiayuan Xu and Suhua Chang and Guangdong Zhou and Yun Liu and Nicole Tay and Qiang Luo and Xiao Chang and Tobias Banaschewski and Bokde, {Arun L.w.} and Herta Flor and Antoine Grigis and Hugh Garavan and Andreas Heinz and Jean-luc Martinot and {Paill{\`e}re martinot}, Marie-laure and Eric Artiges and Frauke Nees and Orfanos, {Dimitri Papadopoulos} and Tom{\'a}{\v s} Paus and Luise Poustka and Sarah Hohmann and Sabina Millenet and Fr{\"o}hner, {Juliane H.} and Smolka, {Michael N.} and Henrik Walter and Robert Whelan and Lin Lu and Jie Shi and Gunter Schumann and Sylvane Desrivi{\`e}res",

note = "Funding Information: This work received support from the following sources: the European Union-funded FP6 Integrated Project IMAGEN (Reinforcement-related behavior in normal brain function and psychopathology; Grant No. LSHM-CT- 2007-037286 [to GS]), the Horizon 2020 funded ERC Advanced Grant {\textquoteleft}STRATIFY{\textquoteright} (Brain network-based stratification of reinforcement-related disorders; Grant No. 695313 [to GS]), the Medical Research Council and Medical Research Foundation (ESTRA: Neurobiological underpinning of eating disorders: integrative biopsychosocial longitudinal analyses in adolescents; Grant Nos. MR/R00465X/1 [to SD]; MRF-058-0004-RG-DESRI and Establishing causal relationships between biopsychosocial predictors and correlates of eating disorders and their mediation by neural pathways; Grant Nos. MR/S020306/1 and MRF-058-0009-RG-DESR-C0759 [to SD]), the Human Brain Project (Grant Nos. HBP SGA 2, 785907, and HBP SGA 3, 945539 [to GS]), the Medical Research Council Grant {\textquoteleft}c-VEDA{\textquoteright} (Consortium on Vulnerability to Externalizing Disorders and Addictions; Grant No. MR/N000390/1 [to GS]), the National Institute of Health (A decentralized macro and micro gene-by-environment interaction analysis of substance use behavior and its brain biomarkers; Grant No. R01DA049238 [to GS]), the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, the Bundesministeriumf{\"u}r Bildung und Forschung (BMBF Grant Nos. 01GS08152; 01EV0711 [to GS]; Forschungsnetz AERIAL 01EE1406A, 01EE1406B [to GS]; Forschungsnetz IMAC-Mind 01GL1745B [to GS]), the Medical Research Foundation (Grant No. MRF-058-0014-F-ZHAN-C0866 [to ZZ]), the Deutsche Forschungsgemeinschaft (DFG Grant Nos. SM 80/7-2, SFB 940, TRR 265, NE 1383/14-1 [to GS]), the cross-NIH alliance that funds Big Data to Knowledge Centres of Excellence (ENIGMA, Grant Nos. 5U54EB020403-05 and 1R56AG058854-01 [to SD]), the European Union and UKRI funded project {\textquoteleft}environMENTAL{\textquoteright} (grants 101057429 [to GS] and 10038599 [to SD]). Further support was provided by grants from the Agence Nationale de la Recherche (Grant Nos. ANR-12-SAMA-0004 [to MLPM], AAPG2019—GeBra [to JLM]), the Eranet- Neuron (Grant Nos. AF12-NEUR0008-01—WM2NA [to JLM] and ANR-18-NEUR00002-01—ADORe [to JLM]), the Fondation de France (Grant No. 00081242 [to JLM]), the Fondation Pour la Recherche M{\'e}dicale (Grant No. DPA20140629802 [to JLM]), the Mission Interminist{\'e}rielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA [to JLM]), the Assistance Publique-H{\^o}pitaux de Paris and INSERM (interface grant) [to MLPM], Paris Sud University IDEX 2012 [to JLM], the Fondation de l'Avenir (Grant No. AP-RM-17-013) [to MLPM], the F{\'e}d{\'e}ration Pour la Recherche sur le Cerveau [to JLM], the National Institutes of Health (Axon, Testosterone and Mental Health during Adolescence; Grant No. RO1 MH085772-01A1 [to TP]), Science Foundation Ireland (Grant No. 16/ERCD/3797 [to RW]), the National Key Research and Development Program of China (Grant Nos. 2022ZD0211200 and 2021YFF0306500 [to YS], 2021YFC2501402, 2019YFA0709501, 2019YFA0709502, and 2018YFC1312900 [to TJ]), the National Natural Science Foundation of China (Grant Nos. 82171488 [to YS], T2122005, 81801773 [to TJ], and 82150710554 [to GS]), the 111 Project (Grant No. B18015 [to TJ]), the Key Project of Shanghai Science &Technology Innovation Plan (Grant No. 16JC1420402 [to TJ]), Shanghai Municipal Science and Technology Major Project (Grant No. 2018SHZDZX01 [to TJ]), the Zhangjiang Laboratory and Shanghai Pujiang Project (Grant No. 18PJ1400900 [to TJ]). TB served in an advisory or consultancy role for Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, and Shire. He received conference support or speaker's fee by Lilly, Medice, Novartis, and Shire. He has been involved in clinical trials conducted by Shire and Vifor Pharma. He received royalties from Hogrefe Publishing, Kohlhammer, CIP Medien, and Oxford University Press. The present work is unrelated to the above grants and relationships. EDB has received honoraria from General Electric Healthcare for teaching on scanner programing courses. LP served in an advisory or consultancy role for Roche and Vifor Pharm and received speaker's fee by Shire. She received royalties from Hogrefe Publishing, Kohlhammer, and Schattauer. The present work is unrelated to the above grants and relationships. All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: This work received support from the following sources: the European Union-funded FP6 Integrated Project IMAGEN (Reinforcement-related behavior in normal brain function and psychopathology; Grant No. LSHM-CT- 2007-037286 [to GS]), the Horizon 2020 funded ERC Advanced Grant {\textquoteleft}STRATIFY{\textquoteright} (Brain network-based stratification of reinforcement-related disorders; Grant No. 695313 [to GS]), the Medical Research Council and Medical Research Foundation (ESTRA: Neurobiological underpinning of eating disorders: integrative biopsychosocial longitudinal analyses in adolescents; Grant Nos. MR/R00465X/1 [to SD]; MRF-058-0004-RG-DESRI and Establishing causal relationships between biopsychosocial predictors and correlates of eating disorders and their mediation by neural pathways; Grant Nos. MR/S020306/1 and MRF-058-0009-RG-DESR-C0759 [to SD]), the Human Brain Project (Grant Nos. HBP SGA 2, 785907, and HBP SGA 3, 945539 [to GS]), the Medical Research Council Grant {\textquoteleft}c-VEDA{\textquoteright} (Consortium on Vulnerability to Externalizing Disorders and Addictions; Grant No. MR/N000390/1 [to GS]), the National Institute of Health (A decentralized macro and micro gene-by-environment interaction analysis of substance use behavior and its brain biomarkers; Grant No. R01DA049238 [to GS]), the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King{\textquoteright}s College London, the Bundesministeriumf{\"u}r Bildung und Forschung (BMBF Grant Nos. 01GS08152; 01EV0711 [to GS]; Forschungsnetz AERIAL 01EE1406A, 01EE1406B [to GS]; Forschungsnetz IMAC-Mind 01GL1745B [to GS]), the Medical Research Foundation (Grant No. MRF-058-0014-F-ZHAN-C0866 [to ZZ]), the Deutsche Forschungsgemeinschaft (DFG Grant Nos. SM 80/7-2, SFB 940, TRR 265, NE 1383/14-1 [to GS]), the cross-NIH alliance that funds Big Data to Knowledge Centres of Excellence (ENIGMA, Grant Nos. 5U54EB020403-05 and 1R56AG058854-01 [to SD]), the European Union and UKRI funded project {\textquoteleft}environMENTAL{\textquoteright} (grants 101057429 [to GS] and 10038599 [to SD]). Further support was provided by grants from the Agence Nationale de la Recherche (Grant Nos. ANR-12-SAMA-0004 [to MLPM], AAPG2019—GeBra [to JLM]), the Eranet- Neuron (Grant Nos. AF12-NEUR0008-01—WM2NA [to JLM] and ANR-18-NEUR00002-01—ADORe [to JLM]), the Fondation de France (Grant No. 00081242 [to JLM]), the Fondation Pour la Recherche M{\'e}dicale (Grant No. DPA20140629802 [to JLM]), the Mission Interminist{\'e}rielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA [to JLM]), the Assistance Publique-H{\^o}pitaux de Paris and INSERM (interface grant) [to MLPM], Paris Sud University IDEX 2012 [to JLM], the Fondation de l{\textquoteright}Avenir (Grant No. AP-RM-17-013) [to MLPM], the F{\'e}d{\'e}ration Pour la Recherche sur le Cerveau [to JLM], the National Institutes of Health (Axon, Testosterone and Mental Health during Adolescence; Grant No. RO1 MH085772-01A1 [to TP]), Science Foundation Ireland (Grant No. 16/ERCD/3797 [to RW]), the National Key Research and Development Program of China (Grant Nos. 2022ZD0211200 and 2021YFF0306500 [to YS], 2021YFC2501402, 2019YFA0709501, 2019YFA0709502, and 2018YFC1312900 [to TJ]), the National Natural Science Foundation of China (Grant Nos. 82171488 [to YS], T2122005, 81801773 [to TJ], and 82150710554 [to GS]), the 111 Project (Grant No. B18015 [to TJ]), the Key Project of Shanghai Science &Technology Innovation Plan (Grant No. 16JC1420402 [to TJ]), Shanghai Municipal Science and Technology Major Project (Grant No. 2018SHZDZX01 [to TJ]), the Zhangjiang Laboratory and Shanghai Pujiang Project (Grant No. 18PJ1400900 [to TJ]). Publisher Copyright: {\textcopyright} 2022",

year = "2023",

month = feb,

day = "15",

doi = "10.1016/j.biopsych.2022.06.012",

language = "English",

volume = "93",

pages = "342--351",

journal = "Biological psychiatry",

issn = "0006-3223",

publisher = "Elsevier",

number = "4",

}

Sun, Y, Jia, T , Barker, ED, Chen, D, Zhang, Z, Xu, J, Chang, S, Zhou, G, Liu, Y, Tay, N, Luo, Q, Chang, X, Banaschewski, T, Bokde, ALW, Flor, H, Grigis, A, Garavan, H, Heinz, A, Martinot, J, Paillère martinot, M, Artiges, E, Nees, F, Orfanos, DP, Paus, T, Poustka, L, Hohmann, S, Millenet, S, Fröhner, JH, Smolka, MN, Walter, H, Whelan, R, Lu, L, Shi, J, Schumann, G & Desrivières, S 2023, 'Associations of DNA Methylation With Behavioral Problems, Gray Matter Volumes, and Negative Life Events Across Adolescence: Evidence From the Longitudinal IMAGEN Study', Biological psychiatry, vol. 93, no. 4, pp. 342-351. https://doi.org/10.1016/j.biopsych.2022.06.012

TY - JOUR

T1 - Associations of DNA Methylation With Behavioral Problems, Gray Matter Volumes, and Negative Life Events Across Adolescence: Evidence From the Longitudinal IMAGEN Study

AU - Sun, Yan

AU - Jia, Tianye

AU - Barker, Edward D.

AU - Chen, Di

AU - Zhang, Zuo

AU - Xu, Jiayuan

AU - Chang, Suhua

AU - Zhou, Guangdong

AU - Liu, Yun

AU - Tay, Nicole

AU - Luo, Qiang

AU - Chang, Xiao

AU - Banaschewski, Tobias

AU - Bokde, Arun L.w.

AU - Flor, Herta

AU - Grigis, Antoine

AU - Garavan, Hugh

AU - Heinz, Andreas

AU - Martinot, Jean-luc

AU - Paillère martinot, Marie-laure

AU - Artiges, Eric

AU - Nees, Frauke

AU - Orfanos, Dimitri Papadopoulos

AU - Paus, Tomáš

AU - Poustka, Luise

AU - Hohmann, Sarah

AU - Millenet, Sabina

AU - Fröhner, Juliane H.

AU - Smolka, Michael N.

AU - Walter, Henrik

AU - Whelan, Robert

AU - Lu, Lin

AU - Shi, Jie

AU - Schumann, Gunter

AU - Desrivières, Sylvane

N1 - Funding Information: This work received support from the following sources: the European Union-funded FP6 Integrated Project IMAGEN (Reinforcement-related behavior in normal brain function and psychopathology; Grant No. LSHM-CT- 2007-037286 [to GS]), the Horizon 2020 funded ERC Advanced Grant ‘STRATIFY’ (Brain network-based stratification of reinforcement-related disorders; Grant No. 695313 [to GS]), the Medical Research Council and Medical Research Foundation (ESTRA: Neurobiological underpinning of eating disorders: integrative biopsychosocial longitudinal analyses in adolescents; Grant Nos. MR/R00465X/1 [to SD]; MRF-058-0004-RG-DESRI and Establishing causal relationships between biopsychosocial predictors and correlates of eating disorders and their mediation by neural pathways; Grant Nos. MR/S020306/1 and MRF-058-0009-RG-DESR-C0759 [to SD]), the Human Brain Project (Grant Nos. HBP SGA 2, 785907, and HBP SGA 3, 945539 [to GS]), the Medical Research Council Grant ‘c-VEDA’ (Consortium on Vulnerability to Externalizing Disorders and Addictions; Grant No. MR/N000390/1 [to GS]), the National Institute of Health (A decentralized macro and micro gene-by-environment interaction analysis of substance use behavior and its brain biomarkers; Grant No. R01DA049238 [to GS]), the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, the Bundesministeriumfür Bildung und Forschung (BMBF Grant Nos. 01GS08152; 01EV0711 [to GS]; Forschungsnetz AERIAL 01EE1406A, 01EE1406B [to GS]; Forschungsnetz IMAC-Mind 01GL1745B [to GS]), the Medical Research Foundation (Grant No. MRF-058-0014-F-ZHAN-C0866 [to ZZ]), the Deutsche Forschungsgemeinschaft (DFG Grant Nos. SM 80/7-2, SFB 940, TRR 265, NE 1383/14-1 [to GS]), the cross-NIH alliance that funds Big Data to Knowledge Centres of Excellence (ENIGMA, Grant Nos. 5U54EB020403-05 and 1R56AG058854-01 [to SD]), the European Union and UKRI funded project ‘environMENTAL’ (grants 101057429 [to GS] and 10038599 [to SD]). Further support was provided by grants from the Agence Nationale de la Recherche (Grant Nos. ANR-12-SAMA-0004 [to MLPM], AAPG2019—GeBra [to JLM]), the Eranet- Neuron (Grant Nos. AF12-NEUR0008-01—WM2NA [to JLM] and ANR-18-NEUR00002-01—ADORe [to JLM]), the Fondation de France (Grant No. 00081242 [to JLM]), the Fondation Pour la Recherche Médicale (Grant No. DPA20140629802 [to JLM]), the Mission Interministérielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA [to JLM]), the Assistance Publique-Hôpitaux de Paris and INSERM (interface grant) [to MLPM], Paris Sud University IDEX 2012 [to JLM], the Fondation de l'Avenir (Grant No. AP-RM-17-013) [to MLPM], the Fédération Pour la Recherche sur le Cerveau [to JLM], the National Institutes of Health (Axon, Testosterone and Mental Health during Adolescence; Grant No. RO1 MH085772-01A1 [to TP]), Science Foundation Ireland (Grant No. 16/ERCD/3797 [to RW]), the National Key Research and Development Program of China (Grant Nos. 2022ZD0211200 and 2021YFF0306500 [to YS], 2021YFC2501402, 2019YFA0709501, 2019YFA0709502, and 2018YFC1312900 [to TJ]), the National Natural Science Foundation of China (Grant Nos. 82171488 [to YS], T2122005, 81801773 [to TJ], and 82150710554 [to GS]), the 111 Project (Grant No. B18015 [to TJ]), the Key Project of Shanghai Science &Technology Innovation Plan (Grant No. 16JC1420402 [to TJ]), Shanghai Municipal Science and Technology Major Project (Grant No. 2018SHZDZX01 [to TJ]), the Zhangjiang Laboratory and Shanghai Pujiang Project (Grant No. 18PJ1400900 [to TJ]). TB served in an advisory or consultancy role for Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, and Shire. He received conference support or speaker's fee by Lilly, Medice, Novartis, and Shire. He has been involved in clinical trials conducted by Shire and Vifor Pharma. He received royalties from Hogrefe Publishing, Kohlhammer, CIP Medien, and Oxford University Press. The present work is unrelated to the above grants and relationships. EDB has received honoraria from General Electric Healthcare for teaching on scanner programing courses. LP served in an advisory or consultancy role for Roche and Vifor Pharm and received speaker's fee by Shire. She received royalties from Hogrefe Publishing, Kohlhammer, and Schattauer. The present work is unrelated to the above grants and relationships. All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: This work received support from the following sources: the European Union-funded FP6 Integrated Project IMAGEN (Reinforcement-related behavior in normal brain function and psychopathology; Grant No. LSHM-CT- 2007-037286 [to GS]), the Horizon 2020 funded ERC Advanced Grant ‘STRATIFY’ (Brain network-based stratification of reinforcement-related disorders; Grant No. 695313 [to GS]), the Medical Research Council and Medical Research Foundation (ESTRA: Neurobiological underpinning of eating disorders: integrative biopsychosocial longitudinal analyses in adolescents; Grant Nos. MR/R00465X/1 [to SD]; MRF-058-0004-RG-DESRI and Establishing causal relationships between biopsychosocial predictors and correlates of eating disorders and their mediation by neural pathways; Grant Nos. MR/S020306/1 and MRF-058-0009-RG-DESR-C0759 [to SD]), the Human Brain Project (Grant Nos. HBP SGA 2, 785907, and HBP SGA 3, 945539 [to GS]), the Medical Research Council Grant ‘c-VEDA’ (Consortium on Vulnerability to Externalizing Disorders and Addictions; Grant No. MR/N000390/1 [to GS]), the National Institute of Health (A decentralized macro and micro gene-by-environment interaction analysis of substance use behavior and its brain biomarkers; Grant No. R01DA049238 [to GS]), the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, the Bundesministeriumfür Bildung und Forschung (BMBF Grant Nos. 01GS08152; 01EV0711 [to GS]; Forschungsnetz AERIAL 01EE1406A, 01EE1406B [to GS]; Forschungsnetz IMAC-Mind 01GL1745B [to GS]), the Medical Research Foundation (Grant No. MRF-058-0014-F-ZHAN-C0866 [to ZZ]), the Deutsche Forschungsgemeinschaft (DFG Grant Nos. SM 80/7-2, SFB 940, TRR 265, NE 1383/14-1 [to GS]), the cross-NIH alliance that funds Big Data to Knowledge Centres of Excellence (ENIGMA, Grant Nos. 5U54EB020403-05 and 1R56AG058854-01 [to SD]), the European Union and UKRI funded project ‘environMENTAL’ (grants 101057429 [to GS] and 10038599 [to SD]). Further support was provided by grants from the Agence Nationale de la Recherche (Grant Nos. ANR-12-SAMA-0004 [to MLPM], AAPG2019—GeBra [to JLM]), the Eranet- Neuron (Grant Nos. AF12-NEUR0008-01—WM2NA [to JLM] and ANR-18-NEUR00002-01—ADORe [to JLM]), the Fondation de France (Grant No. 00081242 [to JLM]), the Fondation Pour la Recherche Médicale (Grant No. DPA20140629802 [to JLM]), the Mission Interministérielle de Lutte-contre-les-Drogues-et-les-Conduites-Addictives (MILDECA [to JLM]), the Assistance Publique-Hôpitaux de Paris and INSERM (interface grant) [to MLPM], Paris Sud University IDEX 2012 [to JLM], the Fondation de l’Avenir (Grant No. AP-RM-17-013) [to MLPM], the Fédération Pour la Recherche sur le Cerveau [to JLM], the National Institutes of Health (Axon, Testosterone and Mental Health during Adolescence; Grant No. RO1 MH085772-01A1 [to TP]), Science Foundation Ireland (Grant No. 16/ERCD/3797 [to RW]), the National Key Research and Development Program of China (Grant Nos. 2022ZD0211200 and 2021YFF0306500 [to YS], 2021YFC2501402, 2019YFA0709501, 2019YFA0709502, and 2018YFC1312900 [to TJ]), the National Natural Science Foundation of China (Grant Nos. 82171488 [to YS], T2122005, 81801773 [to TJ], and 82150710554 [to GS]), the 111 Project (Grant No. B18015 [to TJ]), the Key Project of Shanghai Science &Technology Innovation Plan (Grant No. 16JC1420402 [to TJ]), Shanghai Municipal Science and Technology Major Project (Grant No. 2018SHZDZX01 [to TJ]), the Zhangjiang Laboratory and Shanghai Pujiang Project (Grant No. 18PJ1400900 [to TJ]). Publisher Copyright: © 2022

PY - 2023/2/15

Y1 - 2023/2/15

N2 - BackgroundNegative life events (NLEs) increase the risk for externalizing behaviors (EBs) and internalizing behaviors (IBs) in adolescence and adult psychopathology. DNA methylation associated with behavioral problems may reflect this risk and long-lasting effects of NLEs.MethodsTo identify consistent associations between blood DNA methylation and EBs or IBs across adolescence, we conducted longitudinal epigenome-wide association studies (EWASs) using data from the IMAGEN cohort, collected at ages 14 and 19 years (n = 506). Significant findings were validated in a separate subsample (n = 823). Methylation risk scores were generated by 10-fold cross-validation and further tested for their associations with gray matter volumes and NLEs.ResultsNo significant findings were obtained for the IB-EWAS. The EB-EWAS identified a genome-wide significant locus in a gene linked to attention-deficit/hyperactivity disorder (ADHD) (IQSEC1, cg01460382; p = 1.26 × 10−8). Other most significant CpG sites were near ADHD-related genes and enriched for genes regulating tumor necrosis factor and interferon-γ signaling, highlighting the relevance of EB-EWAS findings for ADHD. Analyses with the EB methylation risk scores suggested that it partly reflected comorbidity with IBs in late adolescence. Specific to EBs, EB methylation risk scores correlated with smaller gray matter volumes in medial orbitofrontal and anterior/middle cingulate cortices, brain regions known to associate with ADHD and conduct problems. Longitudinal mediation analyses indicated that EB-related DNA methylation were more likely the outcomes of problematic behaviors accentuated by NLEs, and less likely the epigenetic bases of such behaviors.ConclusionsOur findings suggest that novel epigenetic mechanisms through which NLEs exert short and longer-term effects on behavior may contribute to ADHD.

AB - BackgroundNegative life events (NLEs) increase the risk for externalizing behaviors (EBs) and internalizing behaviors (IBs) in adolescence and adult psychopathology. DNA methylation associated with behavioral problems may reflect this risk and long-lasting effects of NLEs.MethodsTo identify consistent associations between blood DNA methylation and EBs or IBs across adolescence, we conducted longitudinal epigenome-wide association studies (EWASs) using data from the IMAGEN cohort, collected at ages 14 and 19 years (n = 506). Significant findings were validated in a separate subsample (n = 823). Methylation risk scores were generated by 10-fold cross-validation and further tested for their associations with gray matter volumes and NLEs.ResultsNo significant findings were obtained for the IB-EWAS. The EB-EWAS identified a genome-wide significant locus in a gene linked to attention-deficit/hyperactivity disorder (ADHD) (IQSEC1, cg01460382; p = 1.26 × 10−8). Other most significant CpG sites were near ADHD-related genes and enriched for genes regulating tumor necrosis factor and interferon-γ signaling, highlighting the relevance of EB-EWAS findings for ADHD. Analyses with the EB methylation risk scores suggested that it partly reflected comorbidity with IBs in late adolescence. Specific to EBs, EB methylation risk scores correlated with smaller gray matter volumes in medial orbitofrontal and anterior/middle cingulate cortices, brain regions known to associate with ADHD and conduct problems. Longitudinal mediation analyses indicated that EB-related DNA methylation were more likely the outcomes of problematic behaviors accentuated by NLEs, and less likely the epigenetic bases of such behaviors.ConclusionsOur findings suggest that novel epigenetic mechanisms through which NLEs exert short and longer-term effects on behavior may contribute to ADHD.

KW - ADHD

KW - Adolescents

KW - Brain

KW - Epigenome-wide Association Study

KW - externalizing behaviors

KW - Life events

UR - http://www.scopus.com/inward/record.url?scp=85145958462&partnerID=8YFLogxK

U2 - 10.1016/j.biopsych.2022.06.012

DO - 10.1016/j.biopsych.2022.06.012

M3 - Article

SN - 0006-3223

VL - 93

SP - 342

EP - 351

JO - Biological psychiatry

JF - Biological psychiatry

IS - 4

ER -

Associations of DNA Methylation With Behavioral Problems, Gray Matter Volumes, and Negative Life Events Across Adolescence: Evidence From the Longitudinal IMAGEN Study

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