A genome-wide association study of shared risk across psychiatric disorders implicates gene regulation during fetal neurodevelopment
A genome-wide association study of shared risk across psychiatric disorders implicates gene regulation during fetal neurodevelopment
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DOI：
10.1038/s41593-018-0320-0
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发表时间：
2019-03-01
影响因子：
25
通讯作者：
Werge, Thomas
中科院分区：
文献类型：
--
作者：
Schork, Andrew J.;Won, Hyejung;Werge, Thomas
越来越多的证据表明，看似不同的精神疾病共享遗传病因，但介导这种重叠的生物基质没有得到很好的表征。在这里，我们利用独特的综合精神病学研究联盟（iPSYCH）研究，这是一个通过丹麦国家健康登记册中指示的临床精神病诊断确定的全国代表性队列。我们证实了以前的报告，个人和跨疾病单核苷酸多态性遗传性的主要精神疾病，并进行跨疾病全基因组关联研究。我们确定了四个新的全基因组显着的基因座，包括预测调控基因表达的放射状神经胶质细胞和中间神经元在发育中的新皮层在妊娠中期的变异。这一时期的支持分区交叉障碍单核苷酸多态性遗传性，这是丰富的调节染色质活跃在胎儿神经发育。这些发现表明，由常见的遗传变异导致的指导神经发育的基因失调可能导致许多后来的精神病结果的一般责任。
There is mounting evidence that seemingly diverse psychiatric disorders share genetic etiology, but the biological substrates mediating this overlap are not well characterized. Here we leverage the unique Integrative Psychiatric Research Consortium (iPSYCH) study, a nationally representative cohort ascertained through clinical psychiatric diagnoses indicated in Danish national health registers. We confirm previous reports of individual and cross-disorder single-nucleotide polymorphism heritability for major psychiatric disorders and perform a cross-disorder genome-wide association study. We identify four novel genome-wide significant loci encompassing variants predicted to regulate genes expressed in radial glia and interneurons in the developing neocortex during mid-gestation. This epoch is supported by partitioning cross-disorder single-nucleotide polymorphism heritability, which is enriched at regulatory chromatin active during fetal neurodevelopment. These findings suggest that dysregulation of genes that direct neurodevelopment by common genetic variants may result in general liability for many later psychiatric outcomes.