Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Division of Human Genetics, Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Genes (Basel). 2021 Feb 22;12(2):310. doi: 10.3390/genes12020310.
Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with poorly understood molecular mechanisms that results in significant impairment in children. In this study, we sought to assess the role of rare recurrent variants in non-European populations and outside of coding regions. We generated whole genome sequence (WGS) data on 875 individuals, including 205 ADHD cases and 670 non-ADHD controls. The cases included 116 African Americans (AA) and 89 European Americans (EA), and the controls included 408 AA and 262 EA. Multiple novel rare recurrent variants were identified in exonic regions, functionally classified as stop-gains and frameshifts for known ADHD genes. Deletion in introns of the protocadherins families and the ncRNA were identified in two independent EA ADHD patients. A meta-analysis of the two ethnicities for differential ADHD recurrent variants compared to controls shows a small number of overlaps. These results suggest that rare recurrent variants in noncoding regions may be involved in the pathogenesis of ADHD in children of both AA and EA ancestry; thus, WGS could be a powerful discovery tool for studying the molecular mechanisms of ADHD.
注意缺陷多动障碍（ADHD）是一种神经发育障碍，其分子机制尚不清楚，会导致儿童出现明显的障碍。在这项研究中，我们试图评估罕见的反复出现的变异在非欧洲人群和编码区以外的作用。我们对 875 个人进行了全基因组测序（WGS）数据分析，其中包括 205 例 ADHD 病例和 670 例非 ADHD 对照。病例组包括 116 名非裔美国人（AA）和 89 名欧裔美国人（EA），对照组包括 408 名 AA 和 262 名 EA。在已知的 ADHD 基因的外显子区域中鉴定出了多个新的罕见的反复出现的变异，这些变异被功能分类为已知 ADHD 基因的终止增益和移码。在两个独立的 EA ADHD 患者中，发现了原钙黏蛋白家族和 ncRNA 的内含子缺失。与对照组相比，两种族之间 ADHD 反复出现的变异的荟萃分析显示重叠的数量很少。这些结果表明，非编码区域的罕见反复出现的变异可能与 AA 和 EA 血统的儿童 ADHD 的发病机制有关；因此，WGS 可能是研究 ADHD 分子机制的有力发现工具。
