Amygdala 5-HTT Gene Network Moderates the Effects of Postnatal Adversity on Attention Problems: Anatomo-Functional Correlation and Epigenetic Changes

Randriely Merscher Sobreira de Lima; Barbara Barth; Danusa Mar Arcego; Euclides José de Mendonça Filho; Andrew Clappison; Sachin Patel; Zihan Wang; Irina Pokhvisneva; Roberto Britto Sassi; Geoffrey B C Hall; Michael S Kobor; Kieran J O'Donnell; Ana Paula Santana de Vasconcellos Bittencourt; Michael J Meaney; Carla Dalmaz; Patrícia Pelufo Silveira

doi:10.3389/fnins.2020.00198

Amygdala 5-HTT Gene Network Moderates the Effects of Postnatal Adversity on Attention Problems: Anatomo-Functional Correlation and Epigenetic Changes

Front Neurosci. 2020 Mar 17:14:198. doi: 10.3389/fnins.2020.00198. eCollection 2020.

Authors

Randriely Merscher Sobreira de Lima¹, Barbara Barth², Danusa Mar Arcego³, Euclides José de Mendonça Filho^{3

4}, Andrew Clappison⁵, Sachin Patel⁵, Zihan Wang⁵, Irina Pokhvisneva⁵, Roberto Britto Sassi⁶, Geoffrey B C Hall⁷, Michael S Kobor⁸, Kieran J O'Donnell^{2

3

5}, Ana Paula Santana de Vasconcellos Bittencourt⁹, Michael J Meaney^{2

3

5

10}, Carla Dalmaz¹, Patrícia Pelufo Silveira^{2

3

5}

Affiliations

¹ Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde (ICBS), Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
² Integrated Program in Neuroscience (IPN), McGill University, Montreal, QC, Canada.
³ Department of Psychiatry, Faculty of Medicine, McGill University, Montreal, QC, Canada.
⁴ Programa de Pós-Graduação em Psicologia, Instituto de Psicologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
⁵ Ludmer Centre for Neuroinformatics and Mental Health, Douglas Hospital Research Centre, McGill University, Montreal, QC, Canada.
⁶ Mood Disorders Program, Department of Psychiatry & Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada.
⁷ Department of Psychology, Neuroscience & Behaviour, McMaster University, Hamilton, ON, Canada.
⁸ Centre for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute, Department of Medical Genetics, The University of British Columbia, Vancouver, BC, Canada.
⁹ Departamento de Ciências Fisiológicas, Universidade Federal do Espírito Santo, Vitoria, Brazil.
¹⁰ Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (ASTAR), Singapore, Singapore.

Abstract

Variations in serotoninergic signaling have been related to behavioral outcomes. Alterations in the genome, such as DNA methylation and histone modifications, are affected by serotonin neurotransmission. The amygdala is an important brain region involved in emotional responses and impulsivity, which receives serotoninergic input. In addition, studies suggest that the serotonin transporter gene network may interact with the environment and influence the risk for psychiatric disorders. We propose to investigate whether/how interactions between the exposure to early life adversity and serotonin transporter gene network in the amygdala associate with behavioral disorders. We constructed a co-expression-based polygenic risk score (ePRS) reflecting variations in the function of the serotonin transporter gene network in the amygdala and investigated its interaction with postnatal adversity on attention problems in two independent cohorts from Canada and Singapore. We also described how interactions between ePRS-5-HTT and postnatal adversity exposure predict brain gray matter density and variation in DNA methylation across the genome. We observed that the expression-based polygenic risk score, reflecting the function of the amygdala 5-HTT gene network, interacts with postnatal adversity, to predict attention and hyperactivity problems across both cohorts. Also, both postnatal adversity score and amygdala ePRS-5-HTT score, as well as their interaction, were observed to be associated with variation in DNA methylation across the genome. Variations in gray matter density in brain regions linked to attentional processes were also correlated to our ePRS score. These results confirm that the amygdala 5-HTT gene network is strongly associated with ADHD-related behaviors, brain cortical density, and epigenetic changes in the context of adversity in young children.

Keywords: ADHD; DNA methylation; attention; ePRS; early environment; impulsivity; parallel independent component analysis; serotonin transporter.