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GWAS 支持的 DRD2 基因座中的精神分裂症变异对疾病风险、快感缺失和前额叶皮质厚度的影响。

Effects of a GWAS-Supported Schizophrenia Variant in the DRD2 Locus on Disease Risk, Anhedonia, and Prefrontal Cortical Thickness.

机构信息

Mental Health Research Center, 34 Kashirskoe shosse, 115522, Moscow, Russia.

出版信息

J Mol Neurosci. 2019 Aug;68(4):658-666. doi: 10.1007/s12031-019-01324-w. Epub 2019 May 3.

Abstract

The study aimed to confirm the association of the schizophrenia genome-wide association study (GWAS) hit rs2514218 located near the DRD2 gene with the risk of the disease and to investigate the relationships between rs2514218 and schizophrenia-related clinical and neuroimaging phenotypes. Genotypes at the rs2514218 site were determined for 2148 schizophrenia spectrum patients and 1273 control subjects from the Russian population. In subsets of subjects, we assessed symptomatic dimensions using the Positive and Negative Syndrome Scale (n = 1651) and Temporal Experience of Pleasure Scale (n = 471). At the brain level, gray matter volumes in striatal structures and cortical thickness in the lateral prefrontal cortical regions were investigated (n = 97). Genotype frequencies did not differ between patients and controls. The allelic association analysis yielded a near-threshold p value (p = 0.054), the magnitude (OR = 0.90), and direction of the minor allele (T) effect being in accord with those in the schizophrenia GWAS. Also, patients homozygous for the risk allele C had more severe consummatory anhedonia and a thinner cortex than controls and patients carrying the T allele. The largest effect size of the genotype with diagnosis interaction was seen in the right pars opercularis area. The findings support the role of rs2514218 in schizophrenia risk and presentation and suggest rs2514218 has an influence on brain morphology and negative symptoms.

摘要

本研究旨在确认位于 DRD2 基因附近的精神分裂症全基因组关联研究(GWAS)靶点 rs2514218 与疾病风险的关联,并探讨 rs2514218 与精神分裂症相关临床和神经影像学表型之间的关系。在俄罗斯人群中,对 2148 名精神分裂症谱系患者和 1273 名对照者的 rs2514218 位点基因型进行了确定。在部分患者中,我们使用阳性和阴性症状量表(n=1651)和时间体验愉悦量表(n=471)评估了症状维度。在大脑水平上,研究了纹状体结构的灰质体积和外侧前额皮质区域的皮质厚度(n=97)。患者和对照组之间的基因型频率没有差异。等位基因关联分析产生了一个接近阈值的 p 值(p=0.054),等位基因(T)的效应大小(OR=0.90)和方向与精神分裂症 GWAS 中的一致。此外,携带风险等位基因 C 的纯合子患者比对照组和携带 T 等位基因的患者有更严重的消费性快感缺失和更薄的皮质。基因型与诊断相互作用的最大效应量出现在右侧脑岛盖区。这些发现支持 rs2514218 在精神分裂症风险和表现中的作用,并表明 rs2514218 对大脑形态和阴性症状有影响。

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