神经精神障碍中新生突变的跨疾病分析。

Cross-Disorder Analysis of De Novo Mutations in Neuropsychiatric Disorders.

机构信息

National Clinical Research Center for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Xiangya Road, Kaifu District, Changsha, 410013, Hunan, China.

Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Xiangya Road, Kaifu District, Changsha, 410013, Hunan, China.

出版信息

J Autism Dev Disord. 2022 Mar;52(3):1299-1313. doi: 10.1007/s10803-021-05031-7. Epub 2021 May 10.

DOI:10.1007/s10803-021-05031-7

PMID:33970367

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8854168/

Abstract

The clinical similarity among different neuropsychiatric disorders (NPDs) suggested a shared genetic basis. We catalogued 23,109 coding de novo mutations (DNMs) from 6511 patients with autism spectrum disorder (ASD), 4,293 undiagnosed developmental disorder (UDD), 933 epileptic encephalopathy (EE), 1022 intellectual disability (ID), 1094 schizophrenia (SCZ), and 3391 controls. We evaluated that putative functional DNMs contribute to 38.11%, 34.40%, 33.31%, 10.98% and 6.91% of patients with ID, EE, UDD, ASD and SCZ, respectively. Consistent with phenotype similarity and heterogeneity in different NPDs, they show different degree of genetic association. Cross-disorder analysis of DNMs prioritized 321 candidate genes (FDR < 0.05) and showed that genes shared in more disorders were more likely to exhibited specific expression pattern, functional pathway, genetic convergence, and genetic intolerance.

摘要

不同神经精神障碍（NPD）之间的临床相似性表明存在共同的遗传基础。我们从自闭症谱系障碍（ASD）患者的 6511 例、未确诊的发育障碍（UDD）患者的 4293 例、癫痫性脑病（EE）患者的 933 例、智力障碍（ID）患者的 1022 例、精神分裂症（SCZ）患者的 1094 例和对照组的 3391 例中，对 23109 个编码新生突变（DNMs）进行了编目。我们评估了假定的功能 DNMs 分别导致 ID、EE、UDD、ASD 和 SCZ 患者的 38.11%、34.40%、33.31%、10.98%和 6.91%。与不同 NPD 之间的表型相似性和异质性一致，它们显示出不同程度的遗传相关性。DNMs 的跨疾病分析优先考虑了 321 个候选基因（FDR<0.05），并表明在更多疾病中共享的基因更有可能表现出特定的表达模式、功能途径、遗传趋同和遗传不耐受性。