Forstner Andreas J, Basmanav F B, Mattheisen Manuel, Böhmer Anne C, Hollegaard Mads V, Janson Esther, Strengman Eric, Priebe Lutz, Degenhardt Franziska, Hoffmann Per, Herms Stefan, Maier Wolfgang, Mössner Rainald, Rujescu Dan, Ophoff Roel A, Moebus Susanne, Mortensen Preben B, Børglum Anders D, Hougaard David M, Frank Josef, Witt Stephanie H, Rietschel Marcella, Zimmer Andreas, Nöthen Markus M, Miró Xavier, Cichon Sven
The Institute of Human Genetics, University of Bonn, and the Department of Genomics, Life and Brain Center, Bonn, Germany.
The Department of Biomedicine, Human Genetics, and Centre for Integrative Sequencing, iSEQ, Aarhus University, the The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, and Copenhagen, Denmark, and the Department of Genomics Mathematics, University of Bonn, Germany.
J Psychiatry Neurosci. 2014 Nov;39(6):386-96. doi: 10.1503/jpn.130189.
Schizophrenia is a complex neuropsychiatric disorder of unclear etiology. The strongest known genetic risk factor is the 22q11.2 microdeletion. Research has yet to confirm which genes within the deletion region are implicated in schizophrenia. The minimal 1.5 megabase deletion contains MIR185, which encodes microRNA 185.
We determined miR-185 expression in embryonic and adult mouse brains. Common and rare variants at this locus were then investigated using a human genetics approach. First, we performed gene-based analyses for MIR185 common variants and target genes using Psychiatric Genomics Consortium genome-wide association data. Second, MIR185 was resequenced in German patients (n = 1000) and controls (n = 500). We followed up promising variants by genotyping an additional European sample (patients, n = 3598; controls, n = 4082).
In situ hybridization in mice revealed miR-185 expression in brain regions implicated in schizophrenia. Gene-based tests revealed association between common variants in 3 MIR185 target genes (ATAT1, SH3PXD2A, NTRK3) and schizophrenia. Further analyses in mice revealed overlapping expression patterns for these target genes and miR-185. Resequencing identified 2 rare patient-specific novel variants flanking MIR185. However, follow-up genotyping provided no further evidence of their involvement in schizophrenia.
Power to detect rare variant associations was limited.
Human genetic analyses generated no evidence of the involvement of MIR185 in schizophrenia. However, the expression patterns of miR-185 and its target genes in mice, and the genetic association results for the 3 target genes, suggest that further research into the involvement of miR-185 and its downstream pathways in schizophrenia is warranted.
精神分裂症是一种病因不明的复杂神经精神障碍。已知最强的遗传风险因素是22q11.2微缺失。目前尚不清楚该缺失区域内的哪些基因与精神分裂症有关。最小的1.5兆碱基缺失包含MIR185，它编码微小RNA 185。
我们测定了胚胎和成年小鼠大脑中miR - 185的表达。然后使用人类遗传学方法研究该位点的常见和罕见变异。首先，我们使用精神疾病基因组学联盟的全基因组关联数据对MIR185常见变异和靶基因进行基于基因的分析。其次，对1000名德国患者和500名对照进行MIR185重测序。我们通过对另外一个欧洲样本（患者3598名；对照4082名）进行基因分型来跟进有前景的变异。
小鼠原位杂交显示miR - 185在与精神分裂症相关的脑区表达。基于基因的测试显示3个MIR185靶基因（ATAT1、SH3PXD2A、NTRK3）中的常见变异与精神分裂症之间存在关联。对小鼠的进一步分析揭示了这些靶基因和miR - 185重叠的表达模式。重测序鉴定出MIR185两侧有2个罕见的患者特异性新变异。然而，后续基因分型没有提供它们参与精神分裂症的进一步证据。
检测罕见变异关联的能力有限。
人类遗传学分析没有发现MIR185参与精神分裂症的证据。然而，miR - 185及其靶基因在小鼠中的表达模式，以及3个靶基因的遗传关联结果，表明有必要进一步研究miR - 185及其下游通路在精神分裂症中的作用。
