Association of Epigenetic Differences Screened in a Few Cases of Monozygotic Twins Discordant for Attention-Deficit Hyperactivity Disorder With Brain Structures.

Takashi X Fujisawa,Kai Makita,Shota Nishitani,Koji Shimada,Akiko Yao,Shinichiro Takiguchi,Hideo Matsuzaki,Akemi Tomoda,Hidehiko Okazawa,Shoko Hamamura

doi:10.3389/fnins.2021.799761

Abstract

The present study examined the relationship between DNA methylation differences and variations in brain structures involved in the development of attention-deficit hyperactivity disorder (ADHD). First, we used monozygotic (MZ) twins discordant (2 pairs of 4 individuals, 2 boys, mean age 12.5 years) for ADHD to identify candidate DNA methylation sites involved in the development of ADHD. Next, we tried to replicate these candidates in a case-control study (ADHD: N = 18, 15 boys, mean age 10.0 years; Controls: N = 62, 40 boys, mean age 13.9 years). Finally, we examined how methylation rates at those sites relate to the degree of local structural alterations where significant differences were observed between cases and controls. As a result, we identified 61 candidate DNA methylation sites involved in ADHD development in two pairs of discordant MZ twins, among which elevated methylation at a site in the sortilin-related Vps10p domain containing receptor 2 (SorCS2) gene was replicated in the case-control study. We also observed that the ADHD group had significantly reduced gray matter volume (GMV) in the precentral and posterior orbital gyri compared to the control group and that this volume reduction was positively associated with SorCS2 methylation. Furthermore, the reduced GMV regions in children with ADHD are involved in language processing and emotional control, while SorCS2 methylation is also negatively associated with emotional behavioral problems in children. These results indicate that SorCS2 methylation might mediate a reduced GMV in the precentral and posterior orbital gyri and therefore influence the pathology of children with ADHD.

Highlights

Attention-deficit hyperactivity disorder (ADHD) is one of the most common mental disorders in childhood, characterized by inattention, hyperactivity, and impulsivity, according to the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (American Psychiatric Association, 2013) and often reaching into adulthood
This study investigated the relationship between DNA methylation differences based on array data and brain structure involved variations in the development of ADHD
We investigated two pairs of MZ twins discordant for ADHD and identified 61 candidates for DNA methylation sites involved in the development of ADHD

Summary

Introduction

Attention-deficit hyperactivity disorder (ADHD) is one of the most common mental disorders in childhood, characterized by inattention, hyperactivity, and impulsivity, according to the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (American Psychiatric Association, 2013) and often reaching into adulthood. According to a prospective follow-up study, approximately 50% of children with ADHD continue to have symptoms until adulthood, and if left untreated, they can be at higher risk of psychiatric problems such as depression, substance abuse, and social problems such as unemployment and criminal offenses (Biederman et al, 2006; Molina et al, 2009). Candidate gene studies on ADHD’s DNA methylation profile based on peripheral samples such as blood or saliva have shown different methylation patterns of genes involved in dopaminergic, serotonergic, and neurotrophic systems including SLC6A4, DRD4, COMT, BDNF, and NGFR, and neurotransmitter release or neurite outgrowth including ERC2 and CREB5 and associated with the symptoms and severity of ADHD (van Mil et al, 2014; Park et al, 2015; Xu et al, 2015; Dadds et al, 2016; Heinrich et al, 2017; Sengupta et al, 2017; Neumann et al, 2020)

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