Del Corvo Marcello, Luini Mario, Stella Alessandra, Pagnacco Giulio, Ajmone-Marsan Paolo, Williams John L, Minozzi Giulietta
Parco Tecnologico Padano, via Einstein, 2600, Lodi, Italy.
Istituto di Zootecnica, Università Cattolica del Sacro Cuore, Piacenza, Italy.
Mamm Genome. 2017 Dec;28(11-12):520-527. doi: 10.1007/s00335-017-9714-7. Epub 2017 Sep 1.
Mycobacterium avium subsp. paratuberculosis: (MAP) causes a contagious chronic infection results in Johne's disease in a wide range of animal species, including cattle. Several genome-wide association studies (GWAS) have been carried out to identify loci putatively associated with MAP susceptibility by testing each marker separately and identifying SNPs that show a significant association with the phenotype, while SNP with modest effects are usually ignored. The objective of this study was to identify modest-effect genes associated with MAP susceptibility using a pathway-based approach. The Illumina BovineSNP50 BeadChip was used to genotype 966 Holstein cows, 483 positive and 483 negative for antibody response to MAP, data were then analyzed using novel SNP-based Gene Set Enrichment Analysis (GSEA-SNP) and validated with Adaptive Rank Truncated Product methodology. An allele-based test was carried out to estimate the statistical association for each marker with the phenotype, subsequently SNPs were mapped to the closest genes, considering for each gene the single variant with the highest value within a window of 50 kb, then pathway-statistics were tested using the GSEA-SNP method. The GO biological process "embryogenesis and morphogenesis" was most highly associated with antibody response to MAP. Within this pathway, five genes code for proteins which play a role in the immune defense relevant to response to bacterial infection. The immune response genes identified would not have been considered using a standard GWAS, thus demonstrating that the pathway approach can extend the interpretation of genome-wide association analyses and identify additional candidate genes for target traits.
副结核分枝杆菌（Mycobacterium avium subsp. paratuberculosis，MAP）会引发一种传染性慢性感染，导致包括牛在内的多种动物患上副结核病。已经开展了多项全基因组关联研究（GWAS），通过单独测试每个标记并识别与表型显示出显著关联的单核苷酸多态性（SNP）来确定可能与MAP易感性相关联的基因座，而效应较小的SNP通常被忽略不计。本研究的目的是使用基于通路的方法来识别与MAP易感性相关的效应较小基因。使用Illumina BovineSNP50基因芯片对966头荷斯坦奶牛进行基因分型，其中483头对MAP抗体反应呈阳性，483头呈阴性，然后使用基于SNP的新型基因集富集分析（GSEA-SNP）对数据进行分析，并采用自适应秩截断乘积方法进行验证。进行基于等位基因的测试以估计每个标记与表型之间的统计关联，随后将SNP定位到最接近的基因，对于每个基因，考虑50 kb窗口内具有最高值的单个变体，然后使用GSEA-SNP方法测试通路统计数据。GO生物学过程“胚胎发生和形态发生”与对MAP的抗体反应关联度最高。在该通路中，有五个基因编码在与细菌感染反应相关的免疫防御中起作用的蛋白质。使用标准的GWAS不会考虑到所鉴定的免疫反应基因，因此表明通路方法可以扩展对全基因组关联分析的解释，并识别目标性状的额外候选基因。
