The genetic contribution of additive vs. non-additive (epistatic) effects in the regulation of complex traits is unclear. While genome-wide association studies typically ignore gene-gene interactions, in part because of the lack of statistical power for detecting them, mouse chromosome substitution strains (CSSs) represent an alternate approach for detecting epistasis given their limited allelic variation. Therefore, we utilized CSSs to identify and map both additive and epistatic loci that regulate a range of hematologic- and metabolism-related traits, as well as hepatic gene expression. Quantitative trait loci (QTL) were identified using a CSS-based backcross strategy involving the segregation of variants on the A/J-derived substituted chromosomes 4 and 6 on an otherwise C57BL/6J genetic background. In the liver transcriptomes of offspring from this cross, we identified and mapped additive QTL regulating the hepatic expression of 768 genes, and epistatic QTL pairs for 519 genes. Similarly, we identified additive QTL for fat pad weight, platelets, and the percentage of granulocytes in blood, as well as epistatic QTL pairs controlling the percentage of lymphocytes in blood and red cell distribution width. The variance attributed to the epistatic QTL pairs was approximately equal to that of the additive QTL; however, the SNPs in the epistatic QTL pairs that accounted for the largest variances were undetected in our single locus association analyses. These findings highlight the need to account for epistasis in association studies, and more broadly demonstrate the importance of identifying genetic interactions to understand the complete genetic architecture of complex traits.

添加剂的遗传贡献与。复杂性状调控中的非加性（上位性）效应尚不清楚。虽然全基因组关联研究通常忽略基因-基因相互作用，部分原因是缺乏检测它们的统计能力，但鉴于其有限的等位基因变异，小鼠染色体替代品系 (CSS) 代表了一种检测上位性的替代方法。因此，我们利用 CSS 来识别和绘制调节一系列血液学和代谢相关性状以及肝脏基因表达的加性和上位基因座。使用基于 CSS 的回交策略鉴定数量性状基因座 (QTL)，该策略涉及在其他 C57BL/6J 遗传背景上分离 A/J 衍生的替代染色体 4 和 6 上的变体。在这个杂交后代的肝脏转录组中，我们鉴定并绘制了调节 768 个基因的肝脏表达的加性 QTL，以及 519 个基因的上位性 QTL 对。同样，我们确定了脂肪垫重量、血小板和血液中粒细胞百分比的加性 QTL，以及控制血液中淋巴细胞百分比和红细胞分布宽度的上位性 QTL 对。归因于上位 QTL 对的方差大约等于加性 QTL 的方差；然而，在我们的单基因座关联分析中未检测到占最大方差的上位 QTL 对中的 SNP。这些发现强调了在关联研究中考虑上位性的必要性，并更广泛地证明了识别遗传相互作用以了解复杂性状的完整遗传结构的重要性。