Genome-wide association studies (GWAS) help identify polymorphic sites or genes linked to phenotypic variance, but a few identified genes and/or single nucleotide polymorphisms (SNPs) are unlikely to explain a large part of the phenotypic variability of complex traits. In this study, the focus was moved from single loci to functional units, expressed by the metabolic pathways as defined in the Kyoto Encyclopaedia of Genes and Genomes (KEGG) database. Consequently, the aim of this study was to estimate KEGG effects on stature in three Nordic dairy cattle breeds using SNP effects from GWAS as the dependent variable. The SNPs were annotated to genes, then the genes to KEGG pathways. The effects of KEGG pathways were estimated separately for each breed using a mixed linear model incorporating the similarity between pathways expressed by common genes. The KEGG pathway D-amino acid metabolism (map00473) was estimated to be significant for stature in two of the analysed breeds and revealed a borderline significance in the third breed. Thus, we demonstrate that the approach to statistical modelling of higher order functional effects on complex traits is useful, and provides evidence of the importance of D-amino acids for growth in cattle.

中文翻译：

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基于全基因组关联研究的 SNP 汇总统计，混合线性模型在牛身高功能影响评估中的应用

全基因组关联研究 (GWAS) 有助于识别与表型变异相关的多态性位点或基因，但一些已识别的基因和/或单核苷酸多态性 (SNP) 不太可能解释复杂性状的大部分表型变异性。在这项研究中，重点从单个基因座转移到功能单位，由京都基因和基因组百科全书 (KEGG) 数据库中定义的代谢途径表达。因此，本研究的目的是使用 GWAS 的 SNP 效应作为因变量来估计 KEGG 对三种北欧奶牛品种身高的影响。SNP 被注释到基因，然后基因被注释到 KEGG 通路。使用混合线性模型分别估计每个品种的 KEGG 通路的影响，该模型结合了共同基因表达的通路之间的相似性。据估计，KEGG 通路 D-氨基酸代谢 (map00473) 对两个分析品种的身高具有重要意义，并在第三个品种中显示出临界意义。因此，我们证明了对复杂性状的高阶功能影响进行统计建模的方法是有用的，并提供了 D-氨基酸对牛生长重要性的证据。