The Centre for Applied Genomics and Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
Sci Transl Med. 2011 Aug 10;3(95):95ra75. doi: 10.1126/scitranslmed.3002464.
Attention deficit hyperactivity disorder (ADHD) is a common and persistent condition characterized by developmentally atypical and impairing inattention, hyperactivity, and impulsiveness. We identified de novo and rare copy number variations (CNVs) in 248 unrelated ADHD patients using million-feature genotyping arrays. We found de novo CNVs in 3 of 173 (1.7%) ADHD patients for whom we had DNA from both parents. These CNVs affected brain-expressed genes: DCLK2, SORCS1, SORCS3, and MACROD2. We also detected rare inherited CNVs in 19 of 248 (7.7%) ADHD probands, which were absent in 2357 controls and which either overlapped previously implicated ADHD loci (for example, DRD5 and 15q13 microduplication) or identified new candidate susceptibility genes (ASTN2, CPLX2, ZBBX, and PTPRN2). Among these de novo and rare inherited CNVs, there were also examples of genes (ASTN2, GABRG1, and CNTN5) previously implicated by rare CNVs in other neurodevelopmental conditions including autism spectrum disorder (ASD). To further explore the overlap of risks in ADHD and ASD, we used the same microarrays to test for rare CNVs in an independent, newly collected cohort of 349 unrelated individuals with a primary diagnosis of ASD. Deletions of the neuronal ASTN2 and the ASTN2-intronic TRIM32 genes yielded the strongest association with ADHD and ASD, but numerous other shared candidate genes (such as CHCHD3, MACROD2, and the 16p11.2 region) were also revealed. Our results provide support for a role for rare CNVs in ADHD risk and reinforce evidence for the existence of common underlying susceptibility genes for ADHD, ASD, and other neuropsychiatric disorders.
注意缺陷多动障碍（ADHD）是一种常见且持续存在的病症，其特征为发育异常且有损伤性的注意力不集中、多动和冲动。我们使用百万特征基因分型阵列在 248 名无关的 ADHD 患者中鉴定了新发和罕见的拷贝数变异（CNVs）。我们发现，在 173 名（1.7%）有父母双方 DNA 的 ADHD 患者中，有 3 名患者存在新发 CNVs。这些 CNVs 影响了大脑表达的基因：DCLK2、SORCS1、SORCS3 和 MACROD2。我们还在 248 名 ADHD 患者中的 19 名（7.7%）中检测到罕见的遗传性 CNVs，这些 CNVs 在 2357 名对照中不存在，且要么与先前报道的 ADHD 相关基因座重叠（例如，DRD5 和 15q13 微重复），要么确定了新的候选易感基因（ASTN2、CPLX2、ZBBX 和 PTPRN2）。在这些新发和罕见的遗传性 CNVs 中，还有一些基因（ASTN2、GABRG1 和 CNTN5）先前因其他神经发育病症（包括自闭症谱系障碍（ASD））的罕见 CNVs 而受到牵连。为了进一步探讨 ADHD 和 ASD 风险的重叠，我们使用相同的微阵列在一个新收集的、独立的 349 名主要诊断为 ASD 的个体的队列中，检测罕见的 CNVs。神经元 ASTN2 和 ASTN2 内含子 TRIM32 基因的缺失与 ADHD 和 ASD 相关性最强，但也揭示了许多其他共同的候选基因（如 CHCHD3、MACROD2 和 16p11.2 区域）。我们的研究结果支持罕见 CNVs 在 ADHD 风险中的作用，并加强了 ADHD、ASD 和其他神经精神疾病存在共同潜在易感基因的证据。
