全转录组关联研究提示精神分裂症存在特定的突触前和突触后异常。

A transcriptome-wide association study implicates specific pre- and post-synaptic abnormalities in schizophrenia.

机构信息

MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK.

Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK.

出版信息

Hum Mol Genet. 2020 Jan 1;29(1):159-167. doi: 10.1093/hmg/ddz253.

Abstract

Schizophrenia is a complex highly heritable disorder. Genome-wide association studies (GWAS) have identified multiple loci that influence the risk of developing schizophrenia, although the causal variants driving these associations and their impacts on specific genes are largely unknown. We identify a significant correlation between schizophrenia risk and expression at 89 genes in the dorsolateral prefrontal cortex (P ≤ 9.43 × 10-6), including 20 novel genes. Genes whose expression correlate with schizophrenia were enriched for those involved in abnormal CNS synaptic transmission (PFDR = 0.02) and antigen processing and presentation of peptide antigen via MHC class I (PFDR = 0.02). Within the CNS synaptic transmission set, we identify individual significant candidate genes to which we assign direction of expression changes in schizophrenia. The findings provide strong candidates for experimentally probing the molecular basis of synaptic pathology in schizophrenia.

摘要

精神分裂症是一种复杂的高度遗传性疾病。全基因组关联研究(GWAS)已经确定了多个影响精神分裂症发病风险的基因座,尽管导致这些关联的因果变异及其对特定基因的影响在很大程度上仍是未知的。我们在背外侧前额叶皮层(DLPFC)中鉴定出 89 个基因的表达与精神分裂症风险之间存在显著相关性(P≤9.43×10-6),其中包括 20 个新基因。与精神分裂症相关的基因表达富集于那些与中枢神经系统(CNS)突触传递异常(PFDR=0.02)和通过 MHC 类 I 抗原加工和呈递肽抗原(PFDR=0.02)相关的基因。在 CNS 突触传递组中,我们鉴定出了与精神分裂症相关的单个显著候选基因,并确定了其表达变化的方向。这些发现为实验性探索精神分裂症中突触病理学的分子基础提供了强有力的候选基因。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/380a/7416679/fb7d4eed5a5b/ddz253f1.jpg

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