A cross-species genetic analysis identifies candidate genes for mouse anxiety and human bipolar disorder.
A cross-species genetic analysis identifies candidate genes for mouse anxiety and human bipolar disorder.
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DOI：
10.3389/fnbeh.2015.00171
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发表时间：
2015
影响因子：
3
通讯作者：
Hager R
中科院分区：
文献类型：
--
作者：
Ashbrook DG;Williams RW;Lu L;Hager R
双相情感障碍（BD）是一种重要的神经精神疾病，终生患病率约为1%。为了鉴定BD潜在的遗传变异，已经进行了全基因组关联研究（GWAS）。虽然已经确定了许多与BD相关的小效应变体，但很少有被证实的，部分原因是由于进行了多重比较，GWAS的功效较低。使用小鼠模型的互补作图研究已经鉴定了与BD相关的行为特征的遗传变异，通常具有高功效，但是这些鉴定的区域通常包含太多的基因，无法清楚地鉴定候选基因。在目前的研究中，我们已经将人类BD GWAS结果和小鼠连锁研究进行了比对，以帮助定义和评估与BD相关的候选基因，寻求利用小鼠作图的能力和GWAS的精确度。我们使用数量性状映射在最大的哺乳动物模型系统，BXD重组近交系小鼠种群，以确定与这些BD样表型相关的基因组区域的旷场测试和高架零迷宫数据。然后，我们研究这些区域的全基因组数据从精神基因组学联盟的双相情感障碍GWAS，以确定与BD相关的候选基因。最后，我们建立了这些基因的生物相关性和途径，在一个全面的系统遗传学分析。我们确定了与小鼠焦虑和人类BD相关的四个基因。虽然TNR是BD的新候选者，但我们可以证实先前提出的与CMYA5，MCTP 1和RXRG的关联。一项跨物种的系统遗传学分析表明，MCTP 1、RXRG和TNR与精神疾病相关基因共表达，并将纹状体确定为潜在的作用部位。CMYA5、MCTP 1、RXRG和TNR与小鼠焦虑和人类BD相关。我们假设MCTP 1、RXRG和TNR影响纹状体中的细胞间信号传导。
Bipolar disorder (BD) is a significant neuropsychiatric disorder with a lifetime prevalence of ~1%. To identify genetic variants underlying BD genome-wide association studies (GWAS) have been carried out. While many variants of small effect associated with BD have been identified few have yet been confirmed, partly because of the low power of GWAS due to multiple comparisons being made. Complementary mapping studies using murine models have identified genetic variants for behavioral traits linked to BD, often with high power, but these identified regions often contain too many genes for clear identification of candidate genes. In the current study we have aligned human BD GWAS results and mouse linkage studies to help define and evaluate candidate genes linked to BD, seeking to use the power of the mouse mapping with the precision of GWAS. We use quantitative trait mapping for open field test and elevated zero maze data in the largest mammalian model system, the BXD recombinant inbred mouse population, to identify genomic regions associated with these BD-like phenotypes. We then investigate these regions in whole genome data from the Psychiatric Genomics Consortium's bipolar disorder GWAS to identify candidate genes associated with BD. Finally we establish the biological relevance and pathways of these genes in a comprehensive systems genetics analysis. We identify four genes associated with both mouse anxiety and human BD. While TNR is a novel candidate for BD, we can confirm previously suggested associations with CMYA5, MCTP1, and RXRG. A cross-species, systems genetics analysis shows that MCTP1, RXRG, and TNR coexpress with genes linked to psychiatric disorders and identify the striatum as a potential site of action. CMYA5, MCTP1, RXRG, and TNR are associated with mouse anxiety and human BD. We hypothesize that MCTP1, RXRG, and TNR influence intercellular signaling in the striatum.
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影响因子：
5.7
作者：
Bartra, Oscar;McGuire, Joseph T.;Kable, Joseph W.
通讯作者：
Kable, Joseph W.
影响因子：
4.8
作者：
Benson, MA;Tinsley, CL;Blake, DJ
通讯作者：
Blake, DJ
影响因子：
17.7
作者：
Breen, Gerome;Prata, Diana;Collier, David
通讯作者：
Collier, David
影响因子：
8.2
作者：
Bitanihirwe, Byron K. Y.;Woo, Tsung-Ung W.
通讯作者：
Woo, Tsung-Ung W.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y