近日，丹麦灵北基金会综合精神病学研究计划教授Anders D. Børglum及其课题组探明了罕见的遗传变异赋予多动症的高风险，并涉及神经生物学。相关论文于2025年11月12日发表在《自然》杂志上。

通过分析8895名ADHD患者和53780名对照个体的外显子组测序数据中的罕见编码变异，小组确定了3个与ADHD相关的基因（MAP1A、ANO8和ANK2；P = 3.07 × 10^-6；比值比5.55-15.13）。这三个基因的蛋白-蛋白相互作用网络富集了其他神经发育障碍的罕见变异风险基因，以及参与细胞骨架组织、突触功能和RNA加工的基因。顶部相关的罕见变异风险基因在产前和产后大脑发育阶段以及几种神经细胞类型中表达增加，包括GABAergic （γ-氨基丁酸产生）和多巴胺能神经元。有害变异与ADHD个体较低的社会经济地位和较低的教育水平相关，并且在ADHD成人样本中，每个罕见的有害变体使智商（IQ）降低2.25点（n=962）。患有多动症和智力残疾的个体总体上显示出罕见变异的负荷增加，而其他精神共病只有与这些共病相关的特定基因集的负荷增加。这表明ADHD的精神共病主要是由特定基因的罕见变异驱动的，而不是由受限制基因的普遍负荷增加驱动的。

据介绍，注意缺陷多动障碍（ADHD）是一种儿童期发病的神经发育障碍，具有很大的遗传成分。它影响约5%的儿童和2.5%的成人，并与几种严重后果有关。与这种疾病相关的常见遗传变异已经被确定，但罕见变异在多动症中的作用大多是未知的。

附：英文原文

Title: Rare genetic variants confer a high risk of ADHD and implicate neuronal biology

Author: Demontis, Ditte, Duan, Jinjie, Hsu, Yu-Han H., Pintacuda, Greta, Grove, Jakob, Nielsen, Trine Tollerup, Thirstrup, Janne, Martorana, Makayla, Botts, Travis, Satterstrom, F. Kyle, Bybjerg-Grauholm, Jonas, Tsai, Jason H. Y., Glerup, Simon, Hoogman, Martine, Buitelaar, Jan, Klein, Marieke, Ziegler, Georg C., Jacob, Christian, Grimm, Oliver, Bayas, Maximilian, Kobayashi, Nene F., Kittel-Schneider, Sarah, Lesch, Klaus-Peter, Franke, Barbara, Reif, Andreas, Agerbo, Esben, Werge, Thomas, Nordentoft, Merete, Mors, Ole, Mortensen, Preben Bo, Lage, Kasper, Daly, Mark J., Neale, Benjamin M., Brglum, Anders D.

Issue&Volume: 2025-11-12

Abstract: Attention deficit hyperactivity disorder (ADHD) is a childhood-onset neurodevelopmental disorder with a large genetic component1. It affects around 5% of children and 2.5% of adults2, and is associated with several severe outcomes3,4,5,6,7,8,9,10,11. Common genetic variants associated with the disorder have been identified12,13, but the role of rare variants in ADHD is mostly unknown. Here, by analysing rare coding variants in exome-sequencing data from 8,895 individuals with ADHD and 53,780 control individuals, we identify three genes (MAP1A, ANO8 and ANK2; P<3.07×106; odds ratios 5.55–15.13) that are implicated in ADHD. The protein–protein interaction networks of these three genes were enriched for rare-variant risk genes of other neurodevelopmental disorders, and for genes involved in cytoskeleton organization, synapse function and RNA processing. Top associated rare-variant risk genes showed increased expression across pre- and postnatal brain developmental stages and in several neuronal cell types, including GABAergic (γ-aminobutyric-acid-producing) and dopaminergic neurons. Deleterious variants were associated with lower socioeconomic status and lower levels of education in individuals with ADHD, and a decrease of 2.25 intelligence quotient (IQ) points per rare deleterious variant in a sample of adults with ADHD (n=962). Individuals with ADHD and intellectual disability showed an increased load of rare variants overall, whereas other psychiatric comorbidities had an increased load only for specific gene sets associated with those comorbidities. This suggests that psychiatric comorbidity in ADHD is driven mainly by rare variants in specific genes, rather than by a general increased load across constrained genes.

DOI: 10.1038/s41586-025-09702-8

Source: https://www.nature.com/articles/s41586-025-09702-8