Human CRY1 variants associate with attention deficit/hyperactivity disorder
Human CRY1 variants associate with attention deficit/hyperactivity disorder
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DOI：
10.1172/jci135500
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发表时间：
2020-07-01
影响因子：
15.9
通讯作者：
Ozcelik, Tayfun
中科院分区：
文献类型：
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作者：
Onat, O. Emre;Kars, M. Ece;Ozcelik, Tayfun
注意力缺陷多动障碍（ADHD）是一种常见的遗传性表型，常伴有失眠、焦虑和抑郁。在这里，使用反向表型分析方法，我们报告杂合编码变异的核心生物钟基因隐花色素1在15个不相关的多代家庭合并多动症和失眠。这些变异导致了昼夜分子节律的功能改变，为行为症状提供了一种机制性联系。其中一种变异体，即β 1 Delta 11 c.1657+3A>C，存在于大约1%的欧洲人中，因此作为诊断和治疗标志物而突出。我们通过外显子组测序显示，在一个独立的ADHD和失眠合并患者队列中，62名患者中有8名和369名对照中有0名携带Δ 11。此外，我们还鉴定了一种变体，C1116 c.825+1G>A，它对BMAL 1/CLOCK的亲和力降低，并导致一种白血病表型。基因型-表型相关分析表明，该变异与ADHD和睡眠时相延迟障碍（DSPD）的影响家庭分离。最后，我们在一项涉及9438名无关成年欧洲人的全表型关联研究中发现，δ 11与重度抑郁症、失眠和焦虑有关。这些结果定义了一组独特的昼夜精神病表型，我们建议指定为“circiatric”疾病。
Attention deficit/hyperactivity disorder (ADHD) is a common and heritable phenotype frequently accompanied by insomnia, anxiety, and depression. Here, using a reverse phenotyping approach, we report heterozygous coding variations in the core circadian clock gene cryptochrome 1 in 15 unrelated multigenerational families with combined ADHD and insomnia. The variants led to functional alterations in the circadian molecular rhythms, providing a mechanistic link to the behavioral symptoms. One variant, CRY1 Delta 11 c.1657+3A>C, is present in approximately 1% of Europeans, therefore standing out as a diagnostic and therapeutic marker. We showed by exome sequencing in an independent cohort of patients with combined ADHD and insomnia that 8 of 62 patients and 0 of 369 controls carried CRY1 Delta 11. Also, we identified a variant, CRY116 c.825+1G>A, that shows reduced affinity for BMAL1/CLOCK and causes an arrhythmic phenotype. Genotype-phenotype correlation analysis revealed that this variant segregated with ADHD and delayed sleep phase disorder (DSPD) in the affected family. Finally, we found in a phenome-wide association study involving 9438 unrelated adult Europeans that CRY1 Delta 11 was associated with major depressive disorder, insomnia, and anxiety. These results defined a distinctive group of circadian psychiatric phenotypes that we propose to designate as "circiatric" disorders.