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Global DNA methylation changes in adults with attention deficit-hyperactivity disorder and its comorbidity with bipolar disorder: links with polygenic scores

Molecular Psychiatry volume 27, pages 2485–2491 (2022)Cite this article

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Abstract

Genetic and environmental factors contribute to the etiology of Attention Deficit-Hyperactivity Disorder (ADHD). In this sense, the study of epigenetic mechanisms could contribute to the understanding of the disorder’s neurobiology. Global DNA methylation (GMe) evaluated through 5-methylcytosine levels could be a promising epigenetic biomarker to capture long-lasting biological effects in response to environmental and hormonal changes. We conducted the first assessment of GMe levels in subjects with ADHD (n = 394) and its main comorbidities in comparison to populational controls (n = 390). Furthermore, given the high genetic contribution to ADHD (heritability of 80%), polygenic risk scores (PRS) were calculated to verify the genetic contribution to GMe levels in ADHD and the comorbidities associated with GMe levels. The GMe levels observed in patients were lower than controls (P = 1.1e-8), with women being significantly less globally methylated than men (P = 0.002). Regarding comorbidities, the presence of bipolar disorder (BD) among patients with ADHD was associated with higher methylation levels compared to patients with ADHD without BD (P = 0.031). The results did not change when pharmacological treatment was accounted for in the analyses. The ADHD and BD most predictive PRSs were negatively (P = 0.0064) and positively (P = 0.0042) correlated with GMe, respectively. This study is the first to report an association between GMe, ADHD, and its comorbidity with BD and associations between PRSs for specific psychiatric disorders and GMe. Our findings add to previous evidence that GMe may be a relevant piece in the psychiatric disorders’ etiological landscape.

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Fig. 1: Case-control comparisons stratified by bipolar disorder (BD).

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Acknowledgements

This work received financial supports from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq 431472/2018-1; 424041/2016-2, 466722/2014-1, 476529/2012-3, and 484403/2007-9), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES AUX-PE-PROEX-1234/2011 and 376/2009 and financial code 001), Brain & Behavior Research Foundation (grant number 29056/2020), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS - Pesquisador Gaúcho (PqG) 19/2551-0001731-6 and 19/2551-0001668-9), and Hospital de Clínicas de Porto Alegre (FIPE-HCPA 100358, 08543 and 05451). Also, DM received a doctoral scholarship from CNPq.

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  1. These authors jointly supervised this work: Diego L. Rovaris, Claiton H. D. Bau.

Authors and Affiliations

  1. Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

    Diana Müller, Cibele E. Bandeira, Bruna S. da Silva & Claiton H. D. Bau

  2. Adulthood ADHD Outpatient Program (ProDAH), Clinical Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil

    Diana Müller, Eugenio H. Grevet, Natasha A. Figueira da Silva, Cibele E. Bandeira, Eduardo S. Vitola, Luis A. Rohde, Bruna S. da Silva, Diego L. Rovaris & Claiton H. D. Bau

  3. Developmental Psychiatry Program, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil

    Diana Müller, Eugenio H. Grevet, Natasha A. Figueira da Silva, Cibele E. Bandeira, Luis A. Rohde, Bruna S. da Silva, Diego L. Rovaris & Claiton H. D. Bau

  4. Department of Psychiatry, Faculty of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

    Eugenio H. Grevet, Eduardo S. Vitola & Luis A. Rohde

  5. Graduate Program on Toxicology and Analytical Toxicology, Universidade Feevale, Novo Hamburgo, RS, Brazil

    Eduardo Barbosa, Mariele F. Charão & Rafael Linden

  6. Universidade de Sao Paulo Instituto de Ciencias Biomedicas Departamento de Fisiologia e Biofisica, São Paulo, Brazil

    João K. N. Ramos & Diego L. Rovaris

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Contributions

DM: Conceptualization, methodology, formal analysis, writing—original draft, writing—review and editing. EHG: Conceptualization, resources, writing—review and editing, funding acquisition. NAFS: Methodology, formal analysis, writing—review and editing. CEB: Methodology, formal analysis, writing—original draft, writing—review and editing. EB: Methodology, writing—review and editing. ESV: Methodology, formal analysis, writing—original draft, writing—review and editing. MFC: Methodology, formal analysis, writing—original draft, writing—review and editing. RL: Methodology, formal analysis, writing—original draft, writing—review and editing. LAR: Methodology, writing—review and editing. JKNR: Methodology, formal analysis, writing—review and editing. BSS: Software, formal analysis, writing—review and editing, funding acquisition. DLR: Conceptualization, software, methodology, resources, writing—original draft, writing—review and editing, supervision, funding acquisition. CHDB: Conceptualization, resources, writing—original draft, writing—review and editing, supervision, funding acquisition.

Corresponding authors

Correspondence to Diego L. Rovaris or Claiton H. D. Bau.

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Competing interests

Dr. Grevet was on the speaker’s bureau for Novartis and Shire for 3 years. Dr. Rohde has received Honoraria, has been on the speakers’ bureau/advisory board and/or has acted as a consultant for Eli-Lilly, Janssen-Cilag, Medice, Novartis and Shire for 3 years. He receives authorship royalties from Oxford Press and ArtMed. The ADHD and Juvenile Bipolar Disorder Outpatient Programs chaired by him received unrestricted educational and research support from the following pharmaceutical companies for 3 years: Eli-Lilly, Janssen-Cilag, Novartis, and Shire. All other authors report no potential conflicts of interest.

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Müller, D., Grevet, E.H., Figueira da Silva, N.A. et al. Global DNA methylation changes in adults with attention deficit-hyperactivity disorder and its comorbidity with bipolar disorder: links with polygenic scores. Mol Psychiatry 27, 2485–2491 (2022). https://doi.org/10.1038/s41380-022-01493-y

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