Next-gen sequencing identifies non-coding variation disrupting miRNA-binding sites in neurological disorders.
Next-gen sequencing identifies non-coding variation disrupting miRNA-binding sites in neurological disorders.
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DOI：
10.1038/mp.2017.30
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发表时间：
2018-05
影响因子：
11
通讯作者：
Vernes SC
中科院分区：
文献类型：
--
作者：
Devanna P;Chen XS;Ho J;Gajewski D;Smith SD;Gialluisi A;Francks C;Fisher SE;Newbury DF;Vernes SC
了解神经发育和神经精神疾病的遗传因素是一项重大挑战，因为它们的患病率和潜在的严重程度影响生活质量。虽然大规模基因组筛选在这一领域取得了重大进展，但对于许多疾病来说，遗传基础是复杂的，而且知之甚少。迄今为止，该领域主要关注蛋白质编码变异，但考虑到严格控制基因表达对正常大脑发育和疾病的重要性，影响基因组非编码调控区域的变异可能在这些表型中发挥重要作用。在这里，我们展示了3‘非翻译区（3’ utr）非编码调节变异在神经发育和神经精神疾病中的重要性。我们设计了一个从下一代测序（NGS）数据中识别和功能验证推定致病变异的管道。我们将该管道应用于患有严重特异性语言障碍（SLI）的儿童队列，并确定了影响细胞和死后人类大脑中基因调控的功能性、与SLI相关的变异。这种变异和受影响的基因（ARHGEF39）代表了新的假定的SLI危险因素。此外，我们在自闭症、精神分裂症和双相情感障碍NGS队列中发现了3'UTR调节变异，证明了它们对神经发育和神经精神疾病的影响。我们的研究结果表明，在确定导致神经发育和神经精神疾病的危险因素时，研究非编码调节变异的重要性。在未来，这种调节变异与蛋白质编码变化的整合对于揭示复杂神经系统疾病的遗传原因和健康和疾病的基本机制至关重要。
Understanding the genetic factors underlying neurodevelopmental and neuropsychiatric disorders is a major challenge given their prevalence and potential severity for quality of life. While large-scale genomic screens have made major advances in this area, for many disorders the genetic underpinnings are complex and poorly understood. To date the field has focused predominantly on protein coding variation, but given the importance of tightly controlled gene expression for normal brain development and disorder, variation that affects non-coding regulatory regions of the genome is likely to play an important role in these phenotypes. Herein we show the importance of 3 prime untranslated region (3'UTR) non-coding regulatory variants across neurodevelopmental and neuropsychiatric disorders. We devised a pipeline for identifying and functionally validating putatively pathogenic variants from next generation sequencing (NGS) data. We applied this pipeline to a cohort of children with severe specific language impairment (SLI) and identified a functional, SLI-associated variant affecting gene regulation in cells and post-mortem human brain. This variant and the affected gene (ARHGEF39) represent new putative risk factors for SLI. Furthermore, we identified 3′UTR regulatory variants across autism, schizophrenia and bipolar disorder NGS cohorts demonstrating their impact on neurodevelopmental and neuropsychiatric disorders. Our findings show the importance of investigating non-coding regulatory variants when determining risk factors contributing to neurodevelopmental and neuropsychiatric disorders. In the future, integration of such regulatory variation with protein coding changes will be essential for uncovering the genetic causes of complex neurological disorders and the fundamental mechanisms underlying health and disease.