<em>In Silico</em> Whole Genome Association Scan for Murine Prepulse Inhibition

BackgroundThe complex trait of prepulse inhibition (PPI) is a sensory gating measure related to schizophrenia and can be measured in mice. Large-scale public repositories of inbred mouse strain genotypes and phenotypes such as PPI can be used to detect Quantitative Trait Loci (QTLs) in silico. However, the method has been criticized for issues including insufficient number of strains, not controlling for false discoveries, the complex haplotype structure of inbred mice, and failing to account for genotypic and phenotypic subgroups. Methodology/Principal FindingsWe have implemented a method that addresses these issues by incorporating phylogenetic analyses, multilevel regression with mixed effects, and false discovery rate (FDR) control. A genome-wide scan for PPI was conducted using over 17,000 single nucleotide polymorphisms (SNPs) in 37 strains phenotyped. Eighty-nine SNPs were significant at a false discovery rate (FDR) of 5%. After accounting for long-range linkage disequilibrium, we found 3 independent QTLs located on murine chromosomes 1 and 13. One of the PPI positives corresponds to a region of human chromosome 6p which includes DTNBP1, a gene implicated in schizophrenia. Another region includes the gene Tsn which alters PPI when knocked out. These genes also appear to have correlated expression with PPI. Conclusions/SignificanceThese results support the usefulness of using an improved in silico mapping method to identify QTLs for complex traits such as PPI which can be then be used for to help identify loci influencing schizophrenia in humans.背景 前脉冲抑制（prepulse inhibition，PPI）是一种与精神分裂症相关的感觉门控指标，可在小鼠中进行检测。大型近交系小鼠基因型与表型（如PPI）公共数据集资源，可用于开展数量性状位点（Quantitative Trait Loci, QTLs）的计算机模拟（in silico）定位。但现有方法存在诸多局限，包括品系样本量不足、未控制假阳性发现、近交系小鼠复杂的单倍型结构，以及未纳入基因型与表型亚组校正等问题。 方法/主要发现 本研究构建了一种改进方法，通过整合系统发育分析、混合效应多水平回归与错误发现率（false discovery rate, FDR）控制来解决上述局限。研究针对37个完成表型分型的小鼠品系，利用超过17000个单核苷酸多态性（single nucleotide polymorphisms, SNPs）开展PPI的全基因组扫描，最终在5%的FDR阈值下鉴定出89个显著SNPs。在校正长距离连锁不平衡（linkage disequilibrium）后，共筛选到位于小鼠1号和13号染色体上的3个独立QTLs。其中一个PPI阳性区域对应人类6号染色体6p区域，该区段包含DTNBP1基因，该基因已被证实与精神分裂症发病相关；另一个区域则包含Tsn基因，该基因敲除后会显著改变PPI水平。此外，上述基因的表达水平与PPI存在显著相关性。 结论与意义 本研究结果证实，采用改进的计算机模拟定位方法，可有效识别PPI等复杂性状相关QTLs，后续可用于辅助鉴定影响人类精神分裂症的易感遗传位点。