Haavik Jan
Department of Biomedicine, University of Bergen, Bergen, Norway.
Bergen Center of Brain Plasticity, Division of Psychiatry, Haukeland University Hospital, Bergen, Norway.
Front Psychiatry. 2022 Jun 27;13:925442. doi: 10.3389/fpsyt.2022.925442. eCollection 2022.
ADHD is a common behavioral syndrome with a heritability of 70-80%. Genome wide sequencing and association studies indicate that ADHD risk variants are distributed across a wide range of allele frequencies and relative risks. Several common single nucleotide variants (SNPs) have been identified that increase the risk of ADHD with a few percent. Many of the reported risk genes and copy number variants are shared with other neuropsychiatric disorders. Moreover, ADHD often coexists with common or rare somatic diseases, including rare Mendelian neurometabolic diseases that can affect normal brain development and function. Some genetic/metabolic syndromes masquerading as common ADHD may lead to irreversible brain damage if not properly identified and treated during early childhood. As ADHD is such a heterogeneous condition in terms of severity, clinical features and most probably also underlying biology, it is crucial to offer individualized treatments. Recent progress in ADHD genetics is reviewed, prospects of using this information for targeted pharmacotherapy are discussed and critical knowledge gaps are identified. It is suggested that genome guided therapies could be introduced gradually, starting with rare ADHD syndromes with highly penetrant risk genes. Routine diagnostic application of whole exome or whole genome sequencing combined with metabolomic screening, and brain imaging may be needed in cases with suspected neurometabolic disorders. Identification and treatment of ADHD patients with defined neurometabolic aberrations could be a first step toward genome guided personalized treatment of ADHD. Possibly, screening for relevant biomarkers may gradually be implemented to guide treatment choices in larger patient groups.
注意缺陷多动障碍（ADHD）是一种常见的行为综合征，遗传度为70%-80%。全基因组测序和关联研究表明，ADHD风险变异分布在广泛的等位基因频率和相对风险范围内。已经确定了几种常见的单核苷酸变异（SNP），它们会使ADHD风险增加几个百分点。许多已报道的风险基因和拷贝数变异与其他神经精神疾病共有。此外，ADHD常与常见或罕见的躯体疾病共存，包括罕见的孟德尔神经代谢疾病，这些疾病会影响正常的大脑发育和功能。一些伪装成常见ADHD的遗传/代谢综合征，如果在幼儿期未得到正确识别和治疗，可能会导致不可逆转的脑损伤。由于ADHD在严重程度、临床特征以及很可能在潜在生物学方面都是一种异质性疾病，提供个性化治疗至关重要。本文综述了ADHD遗传学的最新进展，讨论了利用这些信息进行靶向药物治疗的前景，并确定了关键的知识空白。建议可以从具有高外显率风险基因的罕见ADHD综合征开始，逐步引入基因组指导的治疗方法。对于疑似神经代谢疾病的病例，可能需要常规应用全外显子组或全基因组测序结合代谢组学筛查以及脑成像。识别和治疗具有明确神经代谢异常的ADHD患者可能是迈向ADHD基因组指导个性化治疗的第一步。可能的话，可逐步开展相关生物标志物的筛查，以指导更大患者群体的治疗选择。
