Integration of genome-wide association and extant brain expression QTL identifies candidate genes influencing prepulse inhibition in inbred F1 mice.
Integration of genome-wide association and extant brain expression QTL identifies candidate genes influencing prepulse inhibition in inbred F1 mice.
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DOI：
10.1111/gbb.12262
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发表时间：
2016-02
期刊：
影响因子：
--
通讯作者：
Palmer AA
中科院分区：
文献类型：
--
作者：
Sittig LJ;Carbonetto P;Engel KA;Krauss KS;Palmer AA
模式生物结构化群体的遗传关联作图可以通过产生关于复杂性状的新的生物学假设，为人类遗传学研究提供富有成效的补充。在这里，我们调查了前脉冲抑制（PPI），感觉运动门控的措施，是在一些精神疾病中断。为了鉴定影响PPI的基因，我们构建了一组半同胞，通过将来自普通近交系小鼠品系的30只雌性与近交系C57 BL/6 J雄性杂交来产生雄性和雌性F1后代。我们使用这些近交系的公开单核苷酸多态性（SNP）基因型数据，在代表30种不同F1基因型的604只小鼠的组合样本中使用超过150 000个SNP的密集面板进行全基因组关联扫描。我们在2号和7号染色体上发现了两个独立的PPI相关位点，每个位点解释了PPI变异的12 - 14%。对现有数据库的检索没有发现这些基因座内任何可能的致病编码多态性。然而，以前收集的表达数量性状基因座（eQTL）的数据从海马和纹状体表明，在染色体2和7上的SNP显示出最强的关联与PPI也强烈相关的几个转录本的表达，其中一些已被牵连在人类精神疾病。这种综合方法成功地确定了一组重点基因，可以优先进行后续研究。更广泛地说，我们的研究结果表明，常见近交系之间的F1杂交可以与其他信息学和表达数据集结合使用，以识别复杂行为性状的候选基因。
Genetic association mapping in structured populations of model organisms can offer a fruitful complement to human genetic studies by generating new biological hypotheses about complex traits. Here we investigated prepulse inhibition (PPI), a measure of sensorimotor gating that is disrupted in a number of psychiatric disorders. To identify genes that influence PPI, we constructed a panel of half-sibs by crossing 30 females from common inbred mouse strains with inbred C57BL/6J males to create male and female F1 offspring. We used publicly available single nucleotide polymorphism (SNP) genotype data from these inbred strains to perform a genome-wide association scan using a dense panel of over 150 000 SNPs in a combined sample of 604 mice representing 30 distinct F1 genotypes. We identified two independent PPI-associated loci on Chromosomes 2 and 7, each of which explained 12 – 14% of the variance in PPI. Searches of available databases did not identify any plausible causative coding polymorphisms within these loci. However, previously collected expression quantitative trait locus (eQTL) data from hippocampus and striatum indicated that the SNPs on Chromosomes 2 and 7 that showed the strongest association with PPI were also strongly associated with expression of several transcripts, some of which have been implicated in human psychiatric disorders. This integrative approach successfully identified a focused set of genes which can be prioritized for follow-up studies. More broadly, our results show that F1 crosses among common inbred strains can be used in combination with other informatics and expression datasets to identify candidate genes for complex behavioral traits.
影响因子：
3.7
作者：
Webb BT;McClay JL;Vargas-Irwin C;York TP;van den Oord EJ
通讯作者：
van den Oord EJ