Genome-wide association studies in ADHD.
Genome-wide association studies in ADHD.
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DOI：
10.1007/s00439-009-0663-4
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发表时间：
2009-07
期刊：
影响因子：
5.3
通讯作者：
Faraone SV
中科院分区：
文献类型：
--
作者：
Franke B;Neale BM;Faraone SV
注意力缺陷多动障碍（ADHD）是一种常见的高度遗传性神经精神障碍，见于儿童和成人。虽然遗传率估计在76%左右，但很难找到这种疾病的潜在基因。ADHD是一种多因素的疾病，其中许多基因，都具有很小的影响，被认为是在不利的环境条件下引起这种疾病的原因。全基因组连锁分析尚未导致ADHD基因的鉴定，基于候选基因的关联研究结果也只能解释遗传对疾病的贡献的一小部分。全基因组关联研究（genome-wide association study，GWAS）是一种新的无假设基因组分析方法，适用于识别影响小得多的疾病风险基因。到目前为止，已经对ADHD和相关表型的诊断进行了五次GWAS。其中四个是基于作为国际多中心ADHD遗传学（IMAGE）研究的一部分收集的958个亲子三人组的样本集，并由遗传协会信息网络（GAIN）提供资金进行基因分型。另一个是一个汇总的GWAS，包括成人ADHD患者和对照组。没有一篇论文报告了在多次测试校正后正式全基因组显著的任何关联。研究之间的重叠也非常有限，除了与CDH 13的相关性外，其中三项研究报告了这一点。几乎没有证据支持“经典”ADHD基因的重要作用，SLC 9A 9，NOS 1和CNR 1可能是例外。与其他精神疾病的发现有广泛的重叠。虽然不是全基因组的意义，从个别研究的结果汇聚到描绘一个有趣的画面：虽然很少有证据-至今-点直接参与的神经递质（至少是经典的多巴胺，去甲肾上腺素和多巴胺能途径）或调节神经传递，一些建议被发现参与“新的”神经传递和细胞间通讯系统。钾通道亚基和调节剂的潜在参与值得进一步研究。更多的基本过程似乎也参与了ADHD，如细胞分裂，粘附（特别是通过钙粘蛋白和整合素系统），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，和细胞骨架重塑过程。总之，到目前为止，在ADHD中进行的GWAS，虽然远未得出结论，但提供了对该疾病基因的第一次一瞥。还需要更多（更大规模的研究）。为此，研究人员之间的合作以及表型和DNA收集的标准化方案将变得越来越重要。
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.
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DOI：
10.1002/ajmg.b.30672
发表时间：
2008-12-05
影响因子：
2.8
作者：
Chen, Wai;Zhou, Kaixin;Asherson, Philip
通讯作者：
Asherson, Philip
影响因子：
9.8
作者：
Arcos-Burgos, M;Castellanos, FX;Muenke, M
通讯作者：
Muenke, M
影响因子：
11
作者：
Asherson, P.;Zhou, K.;Faraone, S. V.
通讯作者：
Faraone, S. V.
影响因子：
11
作者：
Brookes, K.;Xu, X.;Johansson, L.
通讯作者：
Johansson, L.
DOI：
10.1073/pnas.0609184103
发表时间：
2006-12-19
影响因子：
11.1
作者：
Alcaraz, Wendy A.;Gold, David A.;Hamilton, Bruce A.
通讯作者：
Hamilton, Bruce A.