注意力缺陷多动障碍的全基因组关联研究。

Genome-wide association studies in ADHD.

作者信息

Franke Barbara, Neale Benjamin M, Faraone Stephen V

机构信息

Department of Psychiatry, Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

出版信息

Hum Genet. 2009 Jul;126(1):13-50. doi: 10.1007/s00439-009-0663-4. Epub 2009 Apr 22.

Abstract

Attention-deficit/hyperactivity disorder, ADHD, is a common and highly heritable neuropsychiatric disorder that is seen in children and adults. Although heritability is estimated at around 76%, it has been hard to find genes underlying the disorder. ADHD is a multifactorial disorder, in which many genes, all with a small effect, are thought to cause the disorder in the presence of unfavorable environmental conditions. Whole genome linkage analyses have not yet lead to the identification of genes for ADHD, and results of candidate gene-based association studies have been able to explain only a tiny part of the genetic contribution to disease, either. A novel way of performing hypothesis-free analysis of the genome suitable for the identification of disease risk genes of considerably smaller effect is the genome-wide association study (GWAS). So far, five GWAS have been performed on the diagnosis of ADHD and related phenotypes. Four of these are based on a sample set of 958 parent-child trio's collected as part of the International Multicentre ADHD Genetics (IMAGE) study and genotyped with funds from the Genetic Association Information Network (GAIN). The other is a pooled GWAS including adult patients with ADHD and controls. None of the papers reports any associations that are formally genome-wide significant after correction for multiple testing. There is also very limited overlap between studies, apart from an association with CDH13, which is reported in three of the studies. Little evidence supports an important role for the 'classic' ADHD genes, with possible exceptions for SLC9A9, NOS1 and CNR1. There is extensive overlap with findings from other psychiatric disorders. Though not genome-wide significant, findings from the individual studies converge to paint an interesting picture: whereas little evidence-as yet-points to a direct involvement of neurotransmitters (at least the classic dopaminergic, noradrenergic and serotonergic pathways) or regulators of neurotransmission, some suggestions are found for involvement of 'new' neurotransmission and cell-cell communication systems. A potential involvement of potassium channel subunits and regulators warrants further investigation. More basic processes also seem involved in ADHD, like cell division, adhesion (especially via cadherin and integrin systems), neuronal migration, and neuronal plasticity, as well as related transcription, cell polarity and extracellular matrix regulation, and cytoskeletal remodeling processes. In conclusion, the GWAS performed so far in ADHD, though far from conclusive, provide a first glimpse at genes for the disorder. Many more (much larger studies) will be needed. For this, collaboration between researchers as well as standardized protocols for phenotyping and DNA-collection will become increasingly important.

摘要

注意力缺陷多动障碍(ADHD)是一种常见且具有高度遗传性的神经精神疾病,在儿童和成人中均有出现。尽管遗传度估计约为76%,但一直难以找到导致该疾病的基因。ADHD是一种多因素疾病,许多基因都有微小作用,在不利的环境条件下被认为会导致该疾病。全基因组连锁分析尚未鉴定出ADHD的相关基因,基于候选基因的关联研究结果也仅能解释疾病遗传因素中的一小部分。一种适用于鉴定效应小得多的疾病风险基因的无假设基因组分析新方法是全基因组关联研究(GWAS)。到目前为止,已针对ADHD的诊断及相关表型进行了五项GWAS研究。其中四项基于作为国际多中心ADHD遗传学(IMAGE)研究一部分收集的958个亲子三联体样本集,并由遗传关联信息网络(GAIN)资助进行基因分型。另一项是汇集了成年ADHD患者和对照的GWAS研究。在多重检验校正后,没有一篇论文报告任何具有全基因组显著性的关联。除了三项研究中均报告的与CDH13的关联外,各研究之间的重叠也非常有限。几乎没有证据支持“经典”ADHD基因发挥重要作用,SLC9A9、NOS1和CNR1可能是例外。与其他精神疾病的研究结果存在广泛重叠。尽管尚未达到全基因组显著性,但各独立研究的结果汇聚在一起描绘出了一幅有趣的图景:虽然几乎没有证据表明神经递质(至少是经典的多巴胺能、去甲肾上腺素能和5-羟色胺能途径)或神经传递调节因子直接参与其中,但发现了一些“新”神经传递和细胞间通讯系统参与的迹象。钾通道亚基和调节因子的潜在参与值得进一步研究。更多的基础过程似乎也与ADHD有关,如细胞分裂、黏附(特别是通过钙黏蛋白和整合素系统)、神经元迁移和神经元可塑性,以及相关的转录、细胞极性和细胞外基质调节,还有细胞骨架重塑过程。总之,目前针对ADHD进行的GWAS研究虽然远未得出定论,但为该疾病的相关基因提供了初步线索。还需要更多(规模大得多的研究)。为此,研究人员之间的合作以及表型分型和DNA收集的标准化方案将变得越来越重要。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/903b/3774416/a58c047d7248/439_2009_663_Fig1_HTML.jpg

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