Data_Sheet_1_Association of Epigenetic Differences Screened in a Few Cases of Monozygotic Twins Discordant for Attention-Deficit Hyperactivity Disorder With Brain Structures.CSV

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.

本研究考察了DNA甲基化（DNA methylation）差异与注意缺陷多动障碍（attention-deficit hyperactivity disorder，ADHD）发病相关脑结构变异之间的关联。首先，我们纳入2对存在ADHD表型分歧的单卵双生子（monozygotic，MZ，共4名个体，其中男性2名，平均年龄12.5岁），筛选出与ADHD发病相关的候选DNA甲基化位点；随后，在一项病例对照研究中对上述候选位点进行验证：该研究中ADHD病例组共18名（男性15名，平均年龄10.0岁），对照组共62名（男性40名，平均年龄13.9岁）；最后，我们分析了上述位点的甲基化水平与病例组和对照组间存在显著差异的局部脑结构改变程度之间的关联。最终，我们在2对存在表型分歧的单卵双生子中筛选出61个与ADHD发病相关的候选DNA甲基化位点，其中分选蛋白相关Vps10p结构域包含受体2（sortilin-related Vps10p domain containing receptor 2，SorCS2）基因某一位点的高甲基化现象在病例对照研究中得到了重复验证。此外，我们观察到，与对照组相比，ADHD组患儿的中央前回与后眶回灰质体积（gray matter volume，GMV）显著降低，且该体积缩减程度与SorCS2甲基化水平呈正相关。进一步分析显示，ADHD患儿的灰质体积缩减脑区参与语言加工与情绪调控过程，同时SorCS2甲基化水平与儿童情绪行为问题呈负相关。上述结果表明，SorCS2甲基化可能介导中央前回与后眶回的灰质体积缩减，进而影响ADHD患儿的发病病理机制。