Genome-wide association study of behavioral, physiological and gene expression traits in outbred CFW mice

Although mice are the most widely used mammalian model organism, genetic studies have suffered from limited mapping resolution due to extensive linkage disequilibrium (LD) that is characteristic of crosses among inbred strains. Carworth Farms White (CFW) mice are a commercially available outbred mouse population that exhibit rapid LD decay in comparison to other available mouse populations. We performed a genome-wide association study (GWAS) of behavioral, physiological and gene expression phenotypes using 1,200 male CFW mice. We used genotyping by sequencing (GBS) to obtain genotypes at 92,734 SNPs. We also measured gene expression using RNA sequencing in three brain regions. Our study identified numerous behavioral, physiological and expression quantitative trait loci (QTLs). We integrated the behavioral QTL and eQTL results to implicate specific genes, including Azi2 in sensitivity to methamphetamine and Zmynd11 in anxiety-like behavior. The combination of CFW mice, GBS and RNA seque...

尽管小鼠是目前应用最为广泛的哺乳动物模式生物，但由于近交品系杂交所特有的广泛连锁不平衡（linkage disequilibrium, LD），遗传学研究的作图分辨率始终受限。卡沃思农场白色（CFW）小鼠是商业化繁育的远交小鼠种群，与其他现有小鼠种群相比，其连锁不平衡衰减速度更快。本研究针对1200只雄性CFW小鼠的行为、生理及基因表达表型开展了全基因组关联分析（genome-wide association study, GWAS）。研究采用测序分型（genotyping by sequencing, GBS）技术获取了92,734个单核苷酸多态性（SNPs）位点的基因型数据，并通过RNA测序对三个脑区的基因表达水平进行了检测。本研究鉴定出大量行为、生理及表达数量性状位点（quantitative trait loci, QTLs）。我们整合了行为QTL与表达QTL（eQTL）的分析结果，明确了多个候选基因，包括与甲基苯丙胺敏感性相关的Azi2以及参与类焦虑行为调控的Zmynd11。CFW小鼠、GBS技术与RNA测序的结合……